gebhart/patrepeval huggingface dataset:
Modularly Constructed Synthetic Granzyme B Molecule Enables Interrogation of Intracellular Proteases for Targeted Cytotoxicity (2017)

Targeted therapies promise to increase the safety and efficacy of treatments against diseases ranging from cancer to viral infections. However, the vast majority of targeted therapeutics relies on the recognition of extracellular biomarkers, which are rarely restricted to diseased cells and are thus prone to severe and sometimes-fatal off-target toxicities. In contrast, intracellular antigens present a diverse yet underutilized repertoire of disease markers. Here, we report a protein-based therapeutic platform-termed Cytoplasmic Oncoprotein VErifier and Response Trigger (COVERT)-which enables the interrogation of intracellular proteases to trigger targeted cytotoxicity. COVERT molecules consist of the cytotoxic protein granzyme B (GrB) fused to an inhibitory N-terminal peptide, which can be removed by researcher-specified proteases to activate GrB function. We demonstrate that fusion of a small ubiquitin-like modifier 1 (SUMO1) protein to GrB yields a SUMO-GrB molecule that is specifically activated by the cancer-associated sentrin-specific protease 1 (SENP1). SUMO-GrB selectively triggers apoptotic phenotypes in HEK293T cells that overexpress SENP1, and it is highly sensitive to different SENP1 levels across cell lines. We further demonstrate the rational design of additional COVERT molecules responsive to enterokinase (EK) and tobacco etch virus protease (TEVp), highlighting the COVERT platform's modularity and adaptability to diverse protease targets. As an initial step toward engineering COVERT-T cells for adoptive T-cell therapy, we verified that primary human T cells can express, package, traffic, and deliver engineered GrB molecules in response to antigen stimulation. Our findings set the foundation for future intracellular-antigen-responsive therapeutics that can complement surface-targeted therapies.
Synthetically attractive indolization processes and newer methods for the preparation of selectively substituted indoles (1988)

Abstract The synthetically interesting processes available for indolization reactions are discussed and illustrated in tabular form and particular emphasis is placed on the more recent methods.
Urban Fear: Building the Fortress City (1997)

Currently one third of all new homes built in the United States are in gated residential developments, and eight million people already live in such communities. Secured neighborhoods are a logical extension of social and political processes producing the built environment of the late‐capitalist city. Although walled and fortified communities are not new, these recent developments are private rather than public, and are exclusively residential. Fortress–like, that is, walled, gated and guarded communities encode fear—materially, not just metaphorically—producing a literal landscape of fear. The study is based upon interviews with residents from gated developments in Los Angeles, New York and San Antonio. [Urban fear, urban studies, suburbs, gated communities, landscapes of fear]
Quantitative RT-PCR analysis and immunohistochemical localization of the kallikrein-related peptidases 13 and 14 in lung (2008)

Expression of the KLK13 and KLK14 genes was examined at the mRNA and protein levels in a cohort of 57 patients with non-small-cell lung cancer (NSCLC). The mRNA levels, assessed by real-time RT-PCR, were significantly different in malignant tissues compared to adjacent non-malignant tissues (KLK13, p=0.006; KLK14, p=0.022). KLK13 and KLK14 mRNA overexpression in tumors (1/3 of the patients) was associated with a positive nodal status in multivariate analysis (p=0.018 and p=0.069, respectively). KLK13 and KLK14 were localized in the cytoplasm of epithelial cells of normal bronchus and NSCLC, as determined by immunohistochemistry. Moreover, positive staining was significantly associated with adenocarcinoma histotype (KLK13, p=0.014) and tumor size (KLK14, p=0.048). Although the results are marginally significant, patients with high KLK13 expression at the mRNA or protein level had lower overall survival.
Folate-targeted non-viral DNA vectors for cancer gene therapy. (2000)

The vitamin folic acid exhibits high affinity for the endocytosed, membrane-bound folate receptor. Conjugation of folic acid via its gamma-carboxyl group to various macromolecules results in binding to, and endocytosis into, cells expressing the folate receptor. The folate receptor is overexpressed on a wide range of cancers, therefore folic acid has been investigated as a targeting ligand for the specific delivery of therapeutic compounds to cancer cells. This review will introduce folate-targeting of macromolecules to cancer cells in vitro and in vivo, and discuss the accumulation of such compounds in non-target tissues in vivo. Folate-targeting of non-viral DNA vectors in vitro and in vivo will be discussed in detail, with particular emphasis on the recent advances in this field.
Fully human monoclonal antibodies to PSMA selectively target cytotoxins, radiotoxins and host immunity to prostate cancer (2004)

2546 Background: Prostate-specific membrane antigen (PSMA) is a type-2 membrane protein that is expressed abundantly on the surface of prostate cancer cells but not on normal human tissues. Furthermore, levels of PSMA expression increase with disease progression and are highest in hormone refractory and metastatic disease. This expression profile makes PSMA an attractive target for targeted antibody therapies for prostate cancer. We have evaluated fully human monoclonal antibodies (mAbs) against PSMA in preclinical settings in anticipation of human clinical trials. Methods: Using novel recombinant forms of PSMA and XenoMouse™ technology (Abgenix, Fremont, CA), we generated a panel of fully human IgG1 mAbs against PSMA. Characterization of these antibodies was conducted using a battery of Biacore, ELISA, flow cytometry, anti- PSMA Western blot and other functional assays. We have evaluated the mAbs' intrinsic cytotoxic effects as well as their ability to specifically deliver cytotoxic agents to PSMA-expressing tumor cells in vitro and in vivo. Results: We demonstrated that these mAbs specifically recognize conformational epitopes on PSMA with sub-nanomolar affinity. Naked mAbs reproducibly induced antibody-dependent cell-mediated cytotoxicity (ADCC) of human prostate cancer cells at nanomolar concentrations in vitro. Toxin-conjugated mAbs rapidly internalized and killed PSMA-expressing tumor cells with picomolar potency and >1000-fold selectivity, and long-term eradication of tumor was obtained without toxicity in mice xenografted with C4.2 cells. Similarly, mAbs labeled with a therapeutic beta-emitting isotope, 177Lu, selectively targeted PSMA-expressing xenografts, with a tumor uptake of 30% injected dose per gram of tumor. A single 400 μCi dose of 177Lu-labeled antibody was well tolerated and increased median survival times in the animals by 3.5 fold compared to untreated control animals (p<0.005). Conclusions: Based on these studies, a lead fully human antibody has been selected for human clinical testing in naked, radiolabeled and toxin-conjugated forms. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PSMA Development Co. LLC
OKT3 F(ABʼ)2 FRAGMENTS—RETENTION OF THE IMMUNOSUPPRESSIVE PROPERTIES OF WHOLE ANTIBODY WITH MARKED REDUCTION IN T CELL ACTIVATION AND LYMPHOKINE RELEASE (1991)

Recent studies in mouse and man indicate that the first dose response to anti-CD3 mAbs likely results from in vivo T cell activation and concomitant lymphokine release. One approach toward amelioration of these effects involves the use of nonactivating digest fragment preparations of anti-CD3 mAbs. In the present study whole and F(ab')2 fragments of OKT3 were prepared and assayed for their immune-activating and -suppressing effects on human peripheral blood mononuclear cells. Immunosuppressive effects were evaluated by quantitation of TCR modulation and coating, and by inhibition of CTL activity. Whole mAb and F(ab')2 fragments both effectively coated the TCR complex. However, whole mAb was more efficient at modulating the TCR complex, suggesting that modulation is enhanced by FcR interactions. Whole and F(ab')2 fragments of OKT3 were equally efficacious in suppressing CTL activity. Immune activation was evaluated by quantitation of proliferation, activation marker expression (IL-2R and Leu-23), and lymphokine release (TNF-alpha, gamma-IFN, and GM-CSF). Rigorously purified F(ab')2 preparations demonstrated minimal T cell activation, suggesting TCR and macrophage FcR crosslinking as necessary. Whole OKT3 mAb induced expression of IL-2R and Leu-23 activation markers on the majority of CD4+ and CD8+ cells at mAb concentrations as low as 1 ng/ml, whereas F(ab')2 fragments induced detectable, but markedly reduced expression of these markers only at mAb concentrations greater than or equal to 100 ng/ml. Similarly, whole mAb induced release of TNF-alpha, gamma-IFN, and GM-CSF at low mAb concentrations, whereas F(ab')2 fragments induced detectable (though markedly reduced) levels of TNF-alpha only. However, increasing degrees of contamination with whole antibody resulted in increasing mitogenic potency of the F(ab')2 preparation, which in some cases, was actually enhanced compared with that observed with whole mAb alone. In conclusion, these studies indicate that OKT3 F(ab')2 digest fragments are markedly less potent than whole mAb in inducing T cell activation, yet they retain significant immunosuppressive effects. However, meticulous purification of F(ab')2 digest fragment preparations will likely be required to avoid T cell and macrophage activation following in vivo administration.
Multiple-Organ Failure and Sepsis Without Bacteria (1986)

Multiple-organ failure is generally attributed to bacterial infection, although a correlation with positive blood cultures is not consistently found. Consequently, we studied the effects of a local nonbacterial inflammatory stimulus on distant organ functions and metabolism. Wistar rats were inoculated intraperitoneally with zymosan. Heart and ventilatory rates, oxygen consumption, and body temperature were measured. Survivors were killed at day 12 for blood analysis, weighing of organs, and microscopy. Intraperitoneal zymosan resulted in an early hyperdynamic "septic" response with a 35% mortality. After a few days, oxygen consumption decreased, serum lactate levels increased, and the function of multiple organs deteriorated, while blood cultures remained sterile. The experiment was repeated in germ-free rats with similar results but a lower mortality. We concluded that a severe inflammatory response in itself is capable of inducing multiple-organ failure with "sepsis."
Continuous deployment of mobile software at facebook (showcase) (2016)

Continuous deployment is the practice of releasing software updates to production as soon as it is ready, which is receiving increased adoption in industry. The frequency of updates of mobile software has traditionally lagged the state of practice for cloud-based services for a number of reasons. Mobile versions can only be released periodically. Users can choose when and if to upgrade, which means that several different releases coexist in production. There are hundreds of Android hardware variants, which increases the risk of having errors in the software being deployed.
Effects of ventilation on the collection of exhaled breath in humans (2004)

A computerized system has been developed to monitor tidal volume, respiration rate, mouth pressure, and carbon dioxide during breath collection. This system was used to investigate variability in the production of breath biomarkers over an 8-h period. Hyperventilation occurred when breath was collected from spontaneously breathing study subjects (n = 8). Therefore, breath samples were collected from study subjects whose breathing were paced at a respiration rate of 10 breaths/min and whose tidal volumes were gauged according to body mass. In this "paced breathing" group (n = 16), end-tidal concentrations of isoprene and ethane correlated with end-tidal carbon dioxide levels [Spearman's rank correlation test (r(s)) = 0.64, P = 0.008 and r(s) = 0.50, P = 0.05, respectively]. Ethane also correlated with heart rate (r(s) = 0.52, P < 0.05). There was an inverse correlation between transcutaneous pulse oximetry and exhaled carbon monoxide (r(s) = -0.64, P = 0.008). Significant differences were identified between men (n = 8) and women (n = 8) in the concentrations of carbon monoxide (4 parts per million in men vs. 3 parts per million in women; P = 0.01) and volatile sulfur-containing compounds (134 parts per billion in men vs. 95 parts per billion in women; P = 0.016). There was a peak in ethanol concentration directly after food consumption and a significant decrease in ethanol concentration 2 h later (P = 0.01; n = 16). Sulfur-containing molecules increased linearly throughout the study period (beta = 7.4, P < 0.003). Ventilation patterns strongly influence quantification of volatile analytes in exhaled breath and thus, accordingly, the breathing pattern should be controlled to ensure representative analyses.
Inhalation chemotherapy for macroscopic primary or metastatic lung tumors: proof of principle using dogs with spontaneously occurring tumors as a model. (1999)

This study represents part of an effort to determine the safety and efficacy of inhaled antineoplastic drugs, using pet dogs with spontaneously arising primary and metastatic lung cancers (including sarcoma, carcinoma, and malignant melanoma) as a model. Dogs received new formulations of either paclitaxel (PTX) or doxorubicin (DOX) by the inhalation route every 2 weeks using a specially designed aerosol device. Response was assessed radiographically using the indices of tumor nodule number and volume measurement of discrete pulmonary nodules. Dogs experiencing progressive disease after two consecutive treatments were crossed over to receive the alternate compound. In 24 dogs, 6 (25%) responses were noted including 5 partial responses (PR) and 1 complete response. These include 4 (22.2%) of 18 responses to DOX and 2 (13.3%) of 15 responses to PTX. Responses were noted with osteosarcoma (including three dogs with metastatic osteosarcoma that had failed prior systemic chemotherapy), liposarcoma, hemangiosarcoma, and undifferentiated sarcoma. One dog with mammary carcinoma experienced a 47% reduction in volume after PTX inhalation, just shy of PR criteria. One dog with liposarcoma is experiencing a long-term (>12 months) stabilization of disease on PTX. To date, no systemic toxicities have been observed with either PTX or DOX inhalations. Local (pulmonary) toxicity was not observed with PTX; however, changes consistent with pneumonitis/fibrosis were observed in some dogs receiving DOX. Only one of these dogs showed clinical signs, which were responsive to steroid and antitussive therapy. These data represent "proof of principle" for the avoidance of systemic toxicity while delivering efficacious local drug levels by the inhalation route.
Task Instance Classification via Graph Kernels (2007)

Knowledge-intensive work plays an increasingly important role in organisations of all types. Knowledge workers contribute their effort to achieve a common purpose; they are part of (business) processes. Workflow Management Systems support them during their daily work, featuring guidance and providing intelligent resource delivery. However, the emergence of richly structured, heterogeneous datasets requires a reassessment of existing mining techniques which do not take possible relations between individual instances into account. Neglecting these relations might lead to inappropriate conclusions about the data. In order to uphold the support quality of knowledge workers, the application of mining methods, that consider structure information rather than content information, is necessary. In the scope of the research project DYONIPOS, user interaction patterns, e.g., relations between users, resources and tasks, are mapped in the form of graphs. We utilize graph kernels to exploit structural information and apply Support Vector Machines to classify task instances to task models. 1
Wrapper Maintenance: A Machine Learning Approach (2003)

The proliferation of online information sources has led to an increased use of wrappers for extracting data from Web sources. While most of the previous research has focused on quick and efficient generation of wrappers, the development of tools for wrapper maintenance has received less attention. This is an important research problem because Web sources often change in ways that prevent the wrappers from extracting data correctly. We present an efficient algorithm that learns structural information about data from positive examples alone. We describe how this information can be used for two wrapper maintenance applications: wrapper verification and reinduction. The wrapper verification system detects when a wrapper is not extracting correct data, usually because the Web source has changed its format. The reinduction algorithm automatically recovers from changes in the Web source by identifying data on Web pages so that a new wrapper may be generated for this source. To validate our approach, we monitored 27 wrappers over a period of a year. The verification algorithm correctly discovered 35 of the 37 wrapper changes, and made 16 mistakes, resulting in precision of 0.73 and recall of 0.95. We validated the reinduction algorithm on ten Web sources. We were able to successfully reinduce the wrappers, obtaining precision and recall values of 0.90 and 0.80 on the data extraction task.
Improved Quenched Fluorescent Probe for Imaging of Cysteine Cathepsin Activity (2013)

The cysteine cathepsins are a family of proteases that play important roles in both normal cellular physiology and many human diseases. In cancer, the activity of many of the cysteine cathepsins is upregulated and can be exploited for tumor imaging. Here we present the design and synthesis of a new class of quenched fluorescent activity-based probes (qABPs) containing a phenoxymethyl ketone (PMK) electrophile. These reagents show enhanced in vivo properties and broad reactivity resulting in dramatically improved labeling and tumor imaging properties compared to those of previously reported ABPs.
MoS2Field-Effect Transistor with Sub-10 nm Channel Length (2016)

Atomically thin molybdenum disulfide (MoS<sub>2</sub>) is an ideal semiconductor material for field-effect transistors (FETs) with sub-10 nm channel lengths. The high effective mass and large bandgap of MoS<sub>2</sub> minimize direct source-drain tunneling, while its atomically thin body maximizes the gate modulation efficiency in ultrashort-channel transistors. However, no experimental study to date has approached the sub-10 nm scale due to the multiple challenges related to nanofabrication at this length scale and the high contact resistance traditionally observed in MoS<sub>2</sub> transistors. Here, using the semiconducting-to-metallic phase transition of MoS<sub>2</sub>, we demonstrate sub-10 nm channel-length transistor fabrication by directed self-assembly patterning of mono- and trilayer MoS<sub>2</sub>. This is done in a 7.5 nm half-pitch periodic chain of transistors where semiconducting (2H) MoS<sub>2</sub> channel regions are seamlessly connected to metallic-phase (1T') MoS<sub>2</sub> access and contact regions. The resulting 7.5 nm channel-length MoS<sub>2</sub> FET has a low off-current of 10 pA/μm, an on/off current ratio of >10<sup>7</sup>, and a subthreshold swing of 120 mV/dec. The experimental results presented in this work, combined with device transport modeling, reveal the remarkable potential of 2D MoS<sub>2</sub> for future sub-10 nm technology nodes.
Therapeutic strategies in onychomycosis (1995)

Abstract Objective: This paper reviews current advantages and limits of modern topical antifungal agents (amorolfine, ciclopirox nail lacquer, bifonazole/urea ointment) and oral antimycotic drugs (itraconazole, terbinafine) in the treatment of onychomycosis, taking into account the results of clinical trials. Results: Clinical studies show that both topical and oral antimycotic therapy are effective in treating onychomycosis. However, topical antimycotic treatment produces high efficacy only in superficial and minor distal subungual onychomycosis. The newer oral antifungal drugs have been relatively well tolerated so far. Nevertheless, if oral antimycotic treatment schedules of several months are used, liver function should be monitored. Conclusion: Knowledge of the advantages and limits of both topical and systemic antimycotic treatment of onychomycosis is a prerequisite for a reasonable and effective therapy. Consequently, a therapeutic strategy in onychomycosis is useful to aid physicians choose a suitable treatment.
Electronic imaging using a logarithmic asphere (2001)

Transmission functions are derived that are valid in the nonparaxial case for a class of lenses that will image a continuum of points along an optical axis to a single image point. This lens, which we call a logarithmic asphere, is then used in a digital camera. The resolution of the camera is limited by the pixel size of the CCD; i.e., it is not diffraction limited. Digital processing is used to recover the image, and image-plane processing is used for speed. We find a tenfold increase in the depth of field over that for the diffraction-limited case.
Tetramethyl 1,1,4,4-cyclohexanetetracarboxylate: preparation and conversion to key precursors of fluorinated, stereochemically defined cyclohexanes (1993)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTetramethyl 1,1,4,4-cyclohexanetetracarboxylate: preparation and conversion to key precursors of fluorinated, stereochemically defined cyclohexanesCharles R. Davis, Dale C. Swenson, and Donald J. BurtonCite this: J. Org. Chem. 1993, 58, 24, 6843–6850Publication Date (Print):November 1, 1993Publication History Published online1 May 2002Published inissue 1 November 1993https://pubs.acs.org/doi/10.1021/jo00076a055https://doi.org/10.1021/jo00076a055research-articleACS PublicationsRequest reuse permissionsArticle Views1084Altmetric-Citations22LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts