gebhart/patrepeval huggingface dataset:
MicroRNA-21 Is Up-Regulated in Allergic Airway Inflammation and Regulates IL-12p35 Expression (2009)

Allergic airway inflammation is characterized by marked in situ changes in gene and protein expression, yet the role of microRNAs (miRNAs), a new family of key mRNA regulatory molecules, in this process has not yet been reported. Using a highly sensitive microarray-based approach, we identified 21 miRNAs with differential expression between doxycycline-induced lung-specific IL-13 transgenic mice (with allergic airway inflammation) and control mice. In particular, we observed overexpression of miR-21 and underexpression of miR-1 in the induced IL-13 transgenic mice compared with control mice. These findings were validated in two independent models of allergen-induced allergic airway inflammation and in IL-4 lung transgenic mice. Although IL-13-induced miR-21 expression was IL-13Ralpha1 dependent, allergen-induced miR-21 expression was mediated mainly independent of IL-13Ralpha1 and STAT6. Notably, predictive algorithms identified potential direct miR-21 targets among IL-13-regulated lung transcripts, such as IL-12p35 mRNA, which was decreased in IL-13 transgenic mice. Introduction of pre-miR-21 dose dependently inhibited cellular expression of a reporter vector harboring the 3'-untranslated region of IL-12p35. Moreover, mutating miR-21 binding sites in IL-12p35 3'-untranslated region abrogated miR-21-mediated repression. In summary, we have identified a miRNA signature in allergic airway inflammation, which includes miR-21 that modulates IL-12, a molecule germane to Th cell polarization.
CD44 in Cancer (2002)

CD44 is a multistructural and multifunctional cell surface molecule involved in cell proliferation, cell differentiation, cell migration, angiogenesis, presentation of cytokines, chemokines, and growth factors to the corresponding receptors, and docking of proteases at the cell membrane, as well as in signaling for cell survival. All these biological properties are essential to the physiological activities of normal cells, but they are also associated with the pathologic activities of cancer cells. Experiments in animals have shown that targeting of CD44 by antibodies, antisense,and CD44-soluble proteins markedly reduces the malignant activities of various neoplasms, stressing the therapeutic potential of anti-CD44 agents. Furthermore, because alternative splicing and posttranslational modifications generate many different CD44 sequences, including, perhaps, tumor-specific sequences, the production of anti-CD44 tumor-specific agents may be a realistic therapeutic approach. However, in many cancers (renal cancer and non-Hodgkin's lymphomas are exceptions), a high level of CD44 expression is not always associated with an unfavorable outcome. On the contrary, in some neoplams CD44 upregulation is associated with a favorable outcome. Even worse, in many cases different research grows analyzing the same neoplastic disease reached contradictory conclusions regarding the correlation between CD44 expression and disease prognosis, possibly due to differences in methodology. These problems must be resolved before applying anti-CD44 therapy to human cancers.
Lumen formation during mammary epithelial morphogenesis: insights from in vitro and in vivo models (2008)

The mammary gland undergoes a morphogenetic program during embryogenesis and puberty that leads to the development of hollow ductal system terminating in acinar units. It later expands to generate an elaborate network to deliver milk to newborn progeny. Previous studies in our laboratory using three-dimensional basement membrane cultures of mammary epithelial cells, in which acini-like structures form from single cells, have indicated that lumen formation requires clearance of the cells in the center of the acini by apoptosis. This apoptotic program in vitro requires the pro-death mediator BIM. Recently we found that BIM is also required in the mouse mammary gland for apoptosis during lumen formation, which correlates the 3D acinar model to mammary morphogenesis in vivo. Herein we put into perspective the relevance of our in vitro and in vivo findings to discuss luminal space formation and maintenance during mammary morphogenesis.
Evolution and Modern Approaches for Thermal Analysis of Electrical Machines (2009)

In this paper, the authors present an extended survey on the evolution and the modern approaches in the thermal analysis of electrical machines. The improvements and the new techniques proposed in the last decade are analyzed in depth and compared in order to highlight the qualities and defects of each. In particular, thermal analysis based on lumped-parameter thermal network, finite-element analysis, and computational fluid dynamics are considered in this paper. In addition, an overview of the problems linked to the thermal parameter determination and computation is proposed and discussed. Taking into account the aims of this paper, a detailed list of books and papers is reported in the references to help researchers interested in these topics.
Dose Proportionality in a Triple Therapy Cosuspension pMDI with Multiple Strengths of an Inhaled Corticosteroid (2013)

Clinical comparison of combination pMDI products for the treatment of asthma and COPD is complicated because in vitro aerosol performance of each active in the combination product may not be equivalent to that of the individual component products. In a multi-drug combination product, dose-ranging one or more active with others at fixed doses could complicate development further due to such non-equivalence. Spray dried porous particles generate uniform and stable cosuspensions (1) with micronized APIs, across wide dose ranges for all principal classes of respiratory therapeutics in mono, dual and triple combinations (2), with aerosol performance of each API being independent of the number or type of cosuspended APIs. Clinical experience with a LAMA and LABA combination demonstrates that Pearl’s cosuspension technology enables fixed dose combination development without co-formulation driven performance in-equivalence (3). Addition of an ICS to the LABA/LAMA combination requires aerosol performance equivalency at much higher strengths because of the larger corticosteroid doses. In this paper, we demonstrate in vitro dose linearity and aerosol performance equivalence of a triple formulation containing mometasone furoate in the range of 100-300 µg/actuation combined with a fixed LABA/LAMA combination.
A 250-mW, 8-b, 52-Msamples/s parallel-pipelined A/D converter with reduced number of amplifiers (1997)

A parallel-pipelined A/D converter with an area and power efficient architecture is described. By sharing amplifiers along the pipeline and also completely eliminating the amplifier from the last stage, an 8-b pipeline is realized using just three amplifiers (instead of seven amplifiers with a conventional pipeline architecture). By using two such pipelines in parallel, a 52 Msamples/s prototype A/D converter that is Intended for a switched digital video application has been implemented in a 0.9-/spl mu/m CMOS technology. The device occupies 15 mm/sup 2/ and dissipates 250 mW from a 5 V supply.
Suppressive Subtractive Hybridization Detects Extensive Genomic Diversity in Thermotoga maritima (2002)

Comparisons between genomes of closely related bacteria often show large variations in gene content, even between strains of the same species. Such studies have focused mainly on pathogens; here, we examined Thermotoga maritima, a free-living hyperthermophilic bacterium, by using suppressive subtractive hybridization. The genome sequence of T. maritima MSB8 is available, and DNA from this strain served as a reference to obtain strain-specific sequences from Thermotoga sp. strain RQ2, a very close relative (approximately 96% identity for orthologous protein-coding genes, 99.7% identity in the small-subunit rRNA sequence). Four hundred twenty-six RQ2 subtractive clones were sequenced. One hundred sixty-six had no DNA match in the MSB8 genome. These differential clones comprise, in sum, 48 kb of RQ2-specific DNA and match 72 genes in the GenBank database. From the number of identical clones, we estimated that RQ2 contains 350 to 400 genes not found in MSB8. Assuming a similar genome size, this corresponds to 20% of the RQ2 genome. A large proportion of the RQ2-specific genes were predicted to be involved in sugar transport and polysaccharide degradation, suggesting that polysaccharides are more important as nutrients for this strain than for MSB8. Several clones encode proteins involved in the production of surface polysaccharides. RQ2 encodes multiple subunits of a V-type ATPase, while MSB8 possesses only an F-type ATPase. Moreover, an RQ2-specific MutS homolog was found among the subtractive clones and appears to belong to a third novel archaeal type MutS lineage. Southern blot analyses showed that some of the RQ2 differential sequences are found in some other members of the order Thermotogales, but the distribution of these variable genes is patchy, suggesting frequent lateral gene transfer within the group.
A phase I study to evaluate safety and antitumor activity of biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in patients with RCC and other advanced refractory malignancies. (2011)

331 Background: Programmed death-1 (PD-1), a T-cell inhibitory receptor, may suppress antitumor immunity. BMS-936558, a fully human PD-1 blocking antibody, has shown antitumor activity and manageable toxicity after biweekly dosing (Sznol, ASCO 2010, #2506). This report provides an update on safety and antitumor activity with special emphasis on RCC. Methods: An open-label phase I dose escalation study of BMS-936558 was conducted in patients (pts) with treatment refractory metastatic clear-cell renal cell carcinoma (RCC), castrate-resistant prostate cancer (CRPC), melanoma (MEL), non-small cell lung cancer, or colorectal cancer (CRC). Dose escalation continued to 10 mg/kg when an expansion cohort for pts (16) with each tumor type was opened for additional safety and efficacy information. Tumor response (RECIST) was evaluated every 8 weeks. Clinically stable pts with early PD could continue until further PD or clinical deterioration. Results: 126 pts (18 RCC) were treated with 1, 3, or 10 mg/kg. MTD was not reached. Across all doses, the most common AEs (Any/grade 3-4) were fatigue (45.2%/6.3%) and diarrhea (30.2%/0.8%) while the most common drug-related AEs (Any/grade 3-4) were fatigue (20.6%/0.8%), rash (11.9%/0%), pruritus (11.3%/0%), and diarrhea (10.3%/0.8%). There was no apparent relationship between dose and frequency of AEs. One pt died with sepsis while being treated for drug-related grade 4 pneumonitis. The median number of prior treatment regimens in the RCC cohort was 2 (range 1-6). Of the 18 RCC pts, 16 were treated with 10 mg/kg. The median duration of treatment was 7.6+mo. ORR was 5/16 (31.2%) and SD&gt;4mo was 6/16 (37.5%). The median duration of response was 4.0+ mo (3.7-7.4+ mo). Of the 2 RCC pts treated with 1 mg/kg, 1 obtained a CR (12+ mo) and 1 had SD (21+ mo). For evaluable CRPC pts, 1/15 pts (6.7%) obtained a PR (2+ mo) and 3/15 (20%) had SD&gt;4mo. Conclusions: BMS-936558 administered biweekly is tolerable and has encouraging antitumor activity in a previously treated patients with RCC. Data on baseline characteristics, long-term toxicity and response duration will be updated at the meeting. [Table: see text]
Novel Angular Benzophenazines:  Dual Topoisomerase I and Topoisomerase II Inhibitors as Potential Anticancer Agents (2002)

A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j' '). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.
Characterization of Replication-Competent Adenovirus Isolates from Large-Scale Production of a Recombinant Adenoviral Vector (1999)

Replication-deficient adenoviral vectors have been developed for the delivery of DNA sequences encoding a variety of proteins intended for the management of disease through gene therapy. One concern is the occurrence of replication-competent adenovirus (RCA) in the population of replication-deficient adenoviral vectors as a result of recombination or contamination. To address this concern, it is necessary to determine the frequency of occurrence and to fully characterize the molecular structure and biological infectivity of RCA. rAd/p53 is a pIX-deleted p53 gene therapy vector that is designed to lower the RCA occurrence and to deliver the tumor suppressor gene p53 for treatment of various cancers. Multiple preparations of the replication-deficient adenoviral vector rAd/p53 were tested for the presence of RCA, employing a sensitive biological assay. Single plaques from RCA-positive preparations of rAd/p53 were isolated for molecular characterization. All of the RCA isolates displayed a single unique structure that contains the complete E1 sequence of adenovirus type 5 but lacks the p53 sequence. The detailed sequence analysis of the RCA suggests that it is most likely generated as a result of recombination events between the rAd/p53 DNA and the 293 host adenoviral sequence. Results from viral infectivity analysis by flow cytometry demonstrate no substantial difference in infectivity of RCA, rAd/p53, and wild-type adenovirus type 5 in 293 cells.
Release of a product of growth arrest‐specific gene 6 from rat platelets (2000)

A product of growth arrest-specific gene 6 (Gas6) is known to be synthesized by growth-arrested cells. In this study, we found that several rat tissues including platelets contain Gas6 and activation of the platelets with thrombin provoked the release of Gas6. ADP and collagen, which as well as thrombin stimulated release of ATP from platelets, also enhanced the release of Gas6, suggesting that the mechanism of its release was similar to that of ATP release. This study provides the first evidence of growth arrest-independent secretion of Gas6 and suggests the involvement of Gas6 in vascular diseases as well as hemostasis.
A Cultural Revolution (2017)

This chapter argues that between 1965 and 1975 Islam influenced a wide variety of cultural, artistic, and activist movements in African American culture. Although Malcolm X remained the preeminent Muslim figure in this current of Islamic influence, other Islamic figures and organizations were also important, and in many cases multiple, often contradictory Islamic elements were simultaneously impacting individuals and organizations. This chapter examines this influence on African American discourse and naming practices; cultural nationalist organizations; the Black Arts Movement; college activism; and non-college-based activist efforts, such as those of the Black Panther Party and the reparations movement. In addition, black Muslim-led activist activities are also discussed.
Engineering high affinity humanized anti‐p185HER2/anti‐CD3 bispecific F(ab′)2 for efficient lysis of p185HER2 overexpressing tumor cells (1995)

We previously constructed a humanized anti-p185HER2/anti-CD3 bispecific antibody variant, BsF(ab')2 v1 which retargets the cytotoxic activity of human T cells in vitro against human breast tumor cells which overexpress the p185HER2 product of the HER2/neu (c-erbB-2) protooncogene. Subsequently we identified an improved anti-CD3 variant, v9, which binds to T cells with approx. 100-fold higher affinity than the original variant, v1. Here we demonstrate that BsF(ab')2 v9 is more potent than BsF(ab')2 v1 in stimulating the proliferation of both resting peripheral blood lymphocytes (PBL) and IL-2-activated, long-term cultured T lymphocytes (ATL). In addition, at low concentrations (0.01-1 ng/ml) BsF(ab')2 v9 is much more efficient than BsF(ab')2 v1 in directing lysis of p185HER2-overexpressing tumor cells by IL-2 activated PBL. In contrast, at higher concentration BsF(ab')2 v9 and BsF(ab')2 v1 have similar potency in retargeted cytotoxicity. At BsF(ab')2 v9 concentrations of > or = 1 ng/ml the susceptibility of p185HER2-expressing tumor cells to lysis is apparently independent of the level of p185HER2 expression. At lower concentrations of BsF(ab')2 v9 and/or lower ratios of effector to target cells the extent of lysis is reduced, in some cases improving the selectivity of lysis of high p185HER2 expressors over low expressors. Thus selection of a high affinity anti-CD3 arm is likely important in the design of BsF(ab')2 for retargeting the cytotoxicity of T cells to tumors. The dose of BsF(ab')2 v9 in any future clinical evaluation will require optimization to maximize anti-tumor efficacy whilst minimizing potential toxicity against normal tissue expressing p185HER2.
Syngeneic Syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting (2016)

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 d were adoptively transferred into tumor-bearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target (E/T) assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8(+) T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic antitumor immunity was induced. For the first time, TIL of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors.
Two Phases of Rod Photoreceptor Differentiation during Rat Retinal Development (1998)

We have conducted a comprehensive analysis of the relative timing of the terminal mitosis and the onset of rhodopsin expression in rod precursors in the rat retina in vivo. This analysis demonstrated that there are two distinct phases of rod development during retinal histogenesis. For the majority of rod precursors, those born on or after embryonic day 19 (E19), the onset of rhodopsin expression was strongly correlated temporally with cell cycle withdrawal. For these precursors, the lag between the terminal mitosis and rhodopsin expression was measured to be 5.5-6.5 d on average. By contrast, for rod precursors born before E19, the lag was measured to be significantly longer, averaging from 8.5 to 12.5 d. In addition, these early-born rod precursors seemed to initiate rhodopsin expression in a manner that was not correlated temporally with the terminal mitosis. In these cells, onset of rhodopsin expression appeared approximately synchronous with later-born cells, suggesting a synchronous recruitment to the rod cell fate induced by environmental signals. To examine this possibility, experiments in which the early-born precursors were exposed to a late environment were conducted, using a reaggregate culture system. In these experiments, the early-born precursors appeared remarkably uninfluenced by the late environment with respect to both rod determination and the kinetics of rhodopsin expression. These results support the idea that intrinsically distinct populations of rod precursors constitute the two phases of rod development and that the behavior exhibited by the early-born precursors is intrinsically programmed.
Marginal zone macrophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo (2002)

Antigen-presenting cells are localized in essentially every tissue, where they operate at the interface of innate and acquired immunity by capturing pathogens and presenting pathogen-derived peptides to T cells. C-type lectins are important pathogen recognition receptors and the C-type lectin, dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN), is unique in that, in addition to pathogen capture, it regulates adhesion processes such as DC trafficking and T-cell synapse formation. We have isolated a murine homologue of DC-SIGN that is identical to the previously reported murine homologue mSIGNR1. mSIGNR1 is more closely related to the human DC-SIGN homologue L-SIGN than to DC-SIGN itself because mSIGNR1 is specifically expressed by liver sinusoidal endothelial cells, similar to L-SIGN, and not by DCs. Moreover, mSIGNR1 is also expressed by medullary and subcapsular macrophages in lymph nodes and by marginal zone macrophages (MZMs) in the spleen. Strikingly, these MZMs are in direct contact with the bloodstream and efficiently capture specific polysaccharide antigens present on the surface of encapsulated bacteria. We have investigated the in vivo function of mSIGNR1 on MZMs in spleen. We demonstrate here that mSIGNR1 functions in vivo as a pathogen recognition receptor on MZMs that capture blood-borne antigens, which are rapidly internalized and targeted to lysosomes for processing. Moreover, the antigen capture is completely blocked in vivo by the blocking mSIGNR1-specific antibodies. Thus, mSIGNR1, a murine homologue of DC-SIGN, is important in the defense against pathogens and this study will facilitate further investigations into the in vivo function of DC-SIGN and its homologues.