gebhart/patrepeval huggingface dataset:
Patient‐individualized CD8+ cytolytic T‐cell therapy effectively combats minimal residual leukemia in immunodeficient mice (2015)

Adoptive transfer of donor-derived cytolytic T-lymphocytes (CTL) has evolved as a promising strategy to improve graft-versus-leukemia (GvL) effects in allogeneic hematopoietic stem-cell transplantation. However, durable clinical responses are often hampered by limited capability of transferred T cells to establish effective and sustained antitumor immunity in vivo. We therefore analyzed GvL responses of acute myeloid leukemia (AML)-reactive CD8(+) CTL with central and effector memory phenotype in a new allogeneic donor-patient specific humanized mouse model. CTL lines and clones obtained upon stimulation of naive CD45RA(+) donor CD8(+) T cells with either single HLA antigen-mismatched or HLA-matched primary AML blasts, respectively, elicited strong leukemia reactivity during cytokine-optimized short to intermediate (i.e., 2-8 weeks) culture periods. Single doses of CTL were intravenously infused into NOD/scidIL2Rcg(null) mice when engraftment with patient AML reached bone marrow infiltration of 1-5%, clinically defining minimal residual disease status. This treatment resulted in complete regression of HLA-mismatched and strong reduction of HLA-matched AML infiltration, respectively. Most importantly, mice receiving AML-reactive CTL showed significantly prolonged survival. Transferred CTL were detectable in murine bone marrow and spleen and demonstrated sustained AML-reactivity ex vivo. Moreover, injections with human IL-15 clearly promoted CTL persistence. In summary, we show that naive donor-derived CD8(+) CTL effectively combat patient AML blasts in immunodeficient mice. The donor-patient specific humanized mouse model appears suitable to evaluate therapeutic efficacy of AML-reactive CTL before adoptive transfer into patients. It may further help to identify powerful leukemia rejection antigens and T-cell receptors for redirecting immunity to leukemias even in a patient-individualized manner.
An efficient synthesis of hydroxyethylene dipeptide isosteres: the core unit of potent HIV-1 protease inhibitors (1991)

An efficient and stereocontrolled synthesis of hydroxyethylene dipeptide isosteres 1 from commercially available, optically pure D-mannose is described. This synthesis represents a practical and enantioselective entry to a range of other dipeptide isosteres, which are not limited to amino acid derived substituents.
The long‐term but not the short‐term antiviral effectof IFN‐α depends on Flt3 ligand and pDC (2006)

The cooperation between IFN-alpha/beta and FL, the ligand of Fms-like tyrosine kinase 3 (Flt3), plays an important role in the defense against herpes simplex virus type 1 (HSV-1) in neonates. Treatment of neonatal mice with recombinant IFN-alpha has a short-term, FL-independent and a long-term, FL-dependent protective effect against HSV-1. In mice lacking FL, neonatal resistance against HSV-1 is very low and DC numbers in the spleen are reduced. The treatment of these mice with rIFN-alpha at day 6 resulted in an increased resistance against infection with HSV-1 at day 7. In C57BL/6 mice, treatment with rIFN-alpha at birth induced both FL and plasmacytoid DC (pDC), resulting in enhanced resistance against HSV-1 at day 7. In contrast, in mice lacking FL, IFN-alpha treatment at birth did not influence the splenic cell composition and had no effect on viral protection. The transfer of pDC to mice lacking FL enhanced viral resistance. Therefore, the induction and function of pDC, normally controlled by IFN-alpha/beta and FL, are decisive for viral resistance in neonatal mice.
Contrast‐enhanced peripheral magnetic resonance angiography using time‐resolved vastly undersampled isotropic projection reconstruction (2004)

Time-resolved VIPR acquisition was demonstrated to be well suited for distal extremity imaging by providing isotropic spatial resolution, isotropic coverage, and high temporal resolution. The combination of time-resolved VIPR and bolus chase technique provided a novel approach for peripheral run-off examinations.
Hyaluronidases in tissue invasion. (1997)

Hyaluronidases are broadly distributed enzymes with varying substrate specificities, a wide range of pH optima, and different catalytic mechanisms. They may be used by organisms to invade one another. Hyaluronidases have also been invoked as mechanisms for tumor invasion and metastatic spread. In this review, we will concentrate more on the different kinds of hyaluronidases involved in tissue invasion other than cancer metastasis, present some of the rapidly accumulating new data, and address the paradox that both hyaluronidase as well as its hyaluronan substrate are associated with invasion.
Optical properties of human dermis in vitro and in vivo (1993)

Condensed Monte Carlo simulation results have been used for calculating absorption and reduced scattering coefficients from the literature data on the measured total transmittance and total reflectance of samples of the human skin in vitro. The results of several measuring methods have been compared. We have also estimated the range for absorption coefficients and reduced scattering coefficients at 660 and 940 nm from measured intensities at the skin surface as a function of the distance from the location where the light enters the skin by using condensed Monte Carlo simulations for a homogeneous semi-infinite medium. The in vivo values for the absorption coefficients and the reduced scattering coefficients appear to be much smaller than the values from the in vitro measurements, that have been assumed until now. The discrepancies have been discussed in detail. Our in vivo results are in agreement with other in vivo measurements that are available in the literature.
Ability of RecA protein to promote a search for rare sequences in duplex DNA. (1986)

RecA nucleoprotein filaments found homologous targets even when the latter was mixed with 200,000 times as much heterologous duplex DNA. By contrast, mixing of the single-stranded probe with only 100 times as much heterologous single strands markedly reduced the rate of finding homologous duplex molecules. Titration of the reaction with different proportions of homologous single-stranded DNA distinguished a condition under which the search for homology itself was rate limiting from a condition under which some later step was limiting. Less than 1 min was required to scan 6.4 kilobase pairs of duplex DNA for homology to a RecA-coated single strand of the same size, but these experiments revealed that rapid searching by RecA nucleoprotein filaments was largely confined to neighboring duplex molecules. These observations provide guidelines for the use of RecA protein in locating rare sequences in complex mixtures of duplex DNA, and we describe a simple protocol by which rare sequences can be rapidly enriched at least a thousandfold.
Heat Shock Protein 90 Inhibition in Imatinib-Resistant Gastrointestinal Stromal Tumor (2006)

Inhibition of KIT oncoproteins by imatinib induces clinical responses in most gastrointestinal stromal tumor (GIST) patients. However, many patients develop imatinib resistance due to secondary KIT mutations. Heat shock protein 90 (HSP90) protects KIT oncoproteins from proteasome-mediated degradation, and we therefore did preclinical validations of the HSP90 inhibitor, 17-allylamino-18-demethoxy-geldanamycin (17-AAG), in an imatinib-sensitive GIST cell line (GIST882) and in novel imatinib-resistant GIST lines that are either dependent on (GIST430 and GIST48) or independent of (GIST62) KIT oncoproteins. 17AAG (>100 nmol/L) inhibited imatinib-sensitive and imatinib-resistant KIT oncoproteins, with substantially reduced phospho-KIT and total KIT expression after 30 minutes and 6 hours, respectively. KIT signaling intermediates, including AKT and mitogen-activated protein kinase, were inactivated by 17-AAG in the KIT-positive GIST lines, but not in the KIT-negative GIST62. Likewise, cell proliferation and survival were inhibited in the KIT-positive GISTs but not in GIST62. These findings suggest that 17-AAG biological effects in KIT-positive GISTs result mainly from KIT oncoprotein inhibition. The dramatic inactivation of imatinib-resistant KIT oncoproteins suggests that HSP90 inhibition provides a therapeutic solution to the challenge of heterogeneous imatinib resistance mutations in GIST patients.
CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain (2002)

The cannabinoid agonist, HU210 has been evaluated in vivo in nociceptive and inflammatory pain models in the rat. The ED50 for the anti-nociceptive (increasing mechanical withdrawal threshold) effect was 0.1 mg/kg-1 i.p., and for anti-hypersensitivity and anti-inflammatory activity was 5 g/kg-1 i.p. (in the carrageenan model). The selective CB1 antagonist, AM281 (0.5 microg/kg-1 i.p.) reversed effects of HU210 (10 and 30 microg/kg-1 i.p.) in both nociceptive and inflammatory models of hypersensitivity. The selective CB2 antagonist, SR144528 (1 mg/kg-1 i.p.) antagonised effects of HU210 (30 microg/kg-1 i.p.) in the carrageenan induced inflammatory hypersensitivity. The CB2 agonist, 1-(2,3-Dichlorobenzoyl)-5-methoxy-2-methyl-(2-(morpholin-4-yl)ethyl)-1H-indole (GW405833) inhibited the hypersensitivity and was anti-inflammatory in vivo. These effects were blocked by SR144528. These findings suggest that CB1 receptors are involved in nociceptive pain and that both CB1 and CB2 receptors are involved in inflammatory hypersensitivity. Future studies will investigate effects on identified inflammatory cells within the inflamed tissue to further elucidate the role of cannabinoid receptors.
A simulation study of adaptive reception schemes for high-density digital magnetic storage (1991)

At high information densities, digital magnetic recording systems may be seriously hampered by channel imperfections such as intersymbol interference, noise, fading, nonlinearities, crosstalk, and overwrite noise. For such compound disturbance constellations, theoretical analysis of receiver performances becomes difficult. As an alternative, the digitized output signal of an experimental high-density digital videotape recorder is used to compare various promising receiver types by simulation. Apart from adaptive versions of the linear and decision feedback equalizers, adaptive variants of the Viterbi detector are studied, including new ones with resistance to nonlinearities and channel fading. Improvements of up to about 5 dB in effective signal-to-noise ratio over nonadaptive linear equalization are found to be within reach under worst-case operating conditions.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Management of Postmenopausal Hot Flushes With Venlafaxine Hydrochloride: A Randomized, Controlled Trial (2005)

Extended-release venlafaxine, 75 mg per day, is an effective treatment for postmenopausal hot flushes in otherwise healthy women, based on a significant decrease in patient-perceived hot flush score.
Identifying Breast Cancer Bone Metastasis Genes (2007)

Abstract : Bone metastasis is one of the major causes of morbidity and mortality in breast cancer (BC) patients. However, only a few human BC cell lines can efficiently metastasize to bone whereas most BC cell lines cannot. Recently, it was shown that systemic administration of the conditioned medium by a melanoma cell line redirected the metastatic dissemination of a weakly metastatic lung carcinoma cell line to the organ sites that were metastasized by the melanoma cell due to the formation of metastasis-permissive niches by bone marrow-derived cells (BMDCs) in these organ sites. The current project was proposed to test the hypothesis that factors secreted by metastasis-competent BC cells may condition bone marrow for the successful homing and skeletal remodeling of circulating BC cells. Athymic nude mice were treated with media conditioned by metastasis-competent BC cells and then inoculated with nonmetastatic BC cells in arterial circulation. The treatment induced limited bone metastasis. Bone histology analysis is currently being performed.
Graphane: A two-dimensional hydrocarbon (2007)

We predict the stability of an extended two-dimensional hydrocarbon on the basis of first-principles total-energy calculations. The compound that we call graphane is a fully saturated hydrocarbon derived from a single graphene sheet with formula CH. All of the carbon atoms are in $s{p}^{3}$ hybridization forming a hexagonal network and the hydrogen atoms are bonded to carbon on both sides of the plane in an alternating manner. Graphane is predicted to be stable with a binding energy comparable to other hydrocarbons such as benzene, cyclohexane, and polyethylene. We discuss possible routes for synthesizing graphane and potential applications as a hydrogen storage material and in two-dimensional electronics.
En bloc substitution of the Src homology region 2 domain activates the transforming potential of the c-Abl protein tyrosine kinase. (1993)

Src homology region 2 (SH2) domains are present in many proteins involved in signal transduction. In nonreceptor protein tyrosine kinases the SH2 domain has been implicated in regulation of tyrosine kinase activity and in mediating interactions involved in downstream signaling. Different SH2 domains exhibit distinct binding specificities for both phosphotyrosine- and phosphoserine/phosphothreonine-containing proteins. We show that different SH2 domains are not functionally equivalent within the context of the c-ABL1b protooncogene. c-ABL1b, altered by replacement of its SH2 domain with the N-terminal SH2 domain of Ras GTPase-activating protein, exhibited activated transforming capability, caused intracellular tyrosine phosphorylation of p62, and was relocalized from nucleus to cytoplasm. This en bloc substitution apparently uncouples two distinct functions of the SH2 domain so that c-ABL escapes normal regulatory control while it retains the capability to elicit signals that promote transformation. The SH2 domain of the ARG protein tyrosine kinase, which shares high amino acid-sequence homology with the SH2 domain of ABL, was less effective in activating the oncogenic potential of c-ABL. The effects that the N-terminal SH2 domain of Ras GTPase-activating protein has in the context of c-ABL resemble the effects of deleting the SH3 domain. Thus, the SH2 and SH3 domains may have coordinate roles as regulatory control elements within the context of c-ABL.
[Expression of hepatitis C virus genome]. (1993)

Complementary DNAs from HCV genome were expressed and analyzed. C8-2 protein, a part of NS5, and core protein were synthesized in E. coli. Core protein (JCC) was appeared to be very useful for diagnostic probe of HCV infection. Predicted envelope glycoproteins (E1 and E2/NS1) produced in infected insect cells were glycosylated and secreted into the culture media when the signal sequence of rabies virus G protein was introduced. An ELISA was developed using each purified recombinant protein. Anti-E1 antibody was detected in 20% of patients with non-A, non-B chronic liver diseases, whereas anti-E2/NS1 antibody was detected in more than 88%. These results indicate that the immune responses against these glycoproteins are different.
Calcium oscillations in T-cells: mechanisms and consequences for gene expression (2003)

[Ca(2+)](i) (intracellular Ca(2+) concentration) oscillations play a central role in the activation of T-lymphocytes by antigen. Oscillations in T-cells are absolutely dependent on Ca(2+) influx through store-operated CRAC channels (Ca(2+)-release-activated Ca(2+) channels), and evidence suggests that they arise from delayed interactions between these channels and Ca(2+) stores. Their potential functions have been explored by creating controlled [Ca(2+)](i) oscillations with pulses of Ca(2+) entry or pulses of Ins(1,4,5)P(3). Oscillations enhance both the efficiency and specificity of signalling through the Ca(2+)-dependent transcription factors nuclear factor of activated T-cells (NFAT), Oct/Oap and nuclear factor kappa B (NF kappa B) in ways that are consistent with each factor's Ca(2+) dependence and kinetics of activation and deactivation. These studies show how [Ca(2+)](i) oscillations may enhance signalling to the nucleus, and suggest a possible cellular mechanism for extracting information encoded in oscillation frequency.
Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage (2002)

Cerebral vasospasm and ischemic damage are important causes of mortality and morbidity in patients affected by aneurysmal subarachnoid hemorrhage (SAH). Recently, i.p. administration of recombinant human erythropoietin (r-Hu-EPO) has been shown to exert a neuroprotective effect during experimental SAH. The present study was conducted to evaluate further the effect of r-Hu-EPO administration after SAH in rabbits on neurological outcome, degree of basilar artery spasm, and magnitude of neuronal ischemic damage. Experimental animals were divided into six groups: group 1 (n = 8), control; group 2 (n = 8), control plus placebo; group 3 (n = 8), control plus r-Hu-EPO; group 4 (n = 8), SAH; group 5 (n = 8), SAH plus placebo; group 6 (n = 8), SAH plus r-Hu-EPO. r-Hu-EPO, at a dose of 1,000 units/kg, and placebo were injected i.p. starting 5 min after inducing SAH and followed by clinical and pathological assessment 72 h later. Systemic administration of r-Hu-EPO produced significant increases in cerebrospinal fluid EPO concentrations (P < 0.001), and reduced vasoconstriction of the basilar artery (P < 0.05), ischemic neuronal damage (P < 0.001), and subsequent neurological deterioration (P < 0.05). These observations suggest that r-Hu-EPO may provide an effective treatment to reduce the post-SAH morbidity.
Mouse/Human Chimeric Antibodies to a Tumor-Associated Antigen: Biologic Activity of the Four Human IgG Subclasses (1988)

Variable region genes from mouse monoclonal antibody 17-1A (gamma 2a kappa) with specificity for human gastrointestinal malignancies have been paired with human immunoglobulin constant region genes (for heavy and light chains) to produce mouse/human chimeric immunoglobulin molecules (chIgG) for each of the four human IgG subclasses. Mouse 17-1A and the four chIgG bound similarly to two human colon cancer cell lines and had comparable binding affinities. The chIgG1 and chIgG3 molecules mediated lymphocyte and monocyte antibody-dependent cell-mediated cytotoxicity (ADCC) to colon cancer tumor cell lines comparable to that of the parent murine 17-1A. The chIgG2 and chIgG4 molecules were able to mediate ADCC to colon cancer cell lines but were clearly inferior to the chIgG1 and chIgG3 reagents. None of the chIgG antibodies or the murine 17-1A was able to mediate complement lysis of colon cancer cell lines. These studies demonstrate the ability to produce all four human IgG subclass chimeric molecules which retain biologic activity. We have confirmed the subclass preferences of human lymphocyte and monocyte Fc receptors for human IgG subclasses previously determined by studies with monomeric or aggregated IgG. These data may aid in the selection of chimeric antibodies for in vivo trials.
Ostarine increases lean body mass and improves physical performance in healthy elderly subjects: Implications for cancer cachexia patients (2007)

9119 Background: Cancer cachexia results in selective loss of skeletal muscle resulting in weakness, reduced physical activity and a lower quality of life. Cancer cachexia also diminishes response to chemotherapy and survival. Anabolic steroids appear to increase weight and muscle mass in cancer patients, but have the potential for masculinization in women and prostate stimulation in men. A new class of non-steroidal selective androgen receptor modulators (SARMs) is being developed for use in cancer cachexia. SARMs are designed to have predominately anabolic activity in muscle and bone with minimal androgenic effects in most other tissues. We conducted a randomized phase II proof of concept study of ostarine, the first-in-class SARM, in healthy postmenopausal women and elderly men prior to intitiating a phase II study in cancer patients. Methods: Sixty elderly men (mean age 66 years) and 60 postmenopausal women (mean age 63 years) were randomly assigned to ostarine 0.1, 0.3, 1 mg, 3 mg or placebo for three months. The primary end point was change from baseline to three months in total lean body mass (LBM) measured by dual energy x-ray absorptiometry (DXA). The key secondary end point was a stair climb functional performance test that measured speed and power exerted. Evaluations included laboratory safety assessments and additional assessments of androgenic activity including PSA, sebum production and luteinizing hormone. Results: Ostarine treatment resulted in a dose dependent increase in total LBM, with an increase of 1.4 kg compared to placebo (p&lt;0.001) at the 3 mg dose. Increased LBM translated to an improvement in the stair climb test in both speed (+15.5% ± 12.9 faster time, p=0.006) and power (+25.5% ± 20.3 watts, p=0.005). There were no serious adverse events reported. There were no significant changes in PSA, sebum production or luteinizing hormone. Conclusions: Ostarine improves LBM and physical performance in healthy older men and women. Ostarine had no unwanted androgenic side effects. A phase II study is planned to evaluate the safety and efficacy of ostarine in patients with cancer cachexia. No significant financial relationships to disclose.
Serial Monitoring of Circulating Melanoma Cells During Neoadjuvant Biochemotherapy for Stage III Melanoma: Outcome Prediction in a Multicenter Trial (2005)

Serial monitoring of CTCs in blood may be useful for indicating systemic subclinical disease and predicting outcome of patients receiving neoadjuvant BC for metastatic melanoma.
Effectiveness of robust optimization in intensity‐modulated proton therapy planning for head and neck cancers (2013)

CTV-based robust optimization provided significantly more robust dose distributions to targets and organs than PTV-based conventional optimization in H&N using IMPT. Eliminating the use of PTV and planning directly based on CTV provided better or equivalent normal tissue sparing.
Multilocus Phylogenetic Study of the Scheffersomyces Yeast Clade and Characterization of the N-Terminal Region of Xylose Reductase Gene (2012)

Many of the known xylose-fermenting (X-F) yeasts are placed in the Scheffersomyces clade, a group of ascomycete yeasts that have been isolated from plant tissues and in association with lignicolous insects. We formally recognize fourteen species in this clade based on a maximum likelihood (ML) phylogenetic analysis using a multilocus dataset. This clade is divided into three subclades, each of which exhibits the biochemical ability to ferment cellobiose or xylose. New combinations are made for seven species of Candida in the clade, and three X-F taxa associated with rotted hardwood are described: Scheffersomyces illinoinensis (type strain NRRL Y-48827(T) = CBS 12624), Scheffersomyces quercinus (type strain NRRL Y-48825(T) = CBS 12625), and Scheffersomyces virginianus (type strain NRRL Y-48822(T) = CBS 12626). The new X-F species are distinctive based on their position in the multilocus phylogenetic analysis and biochemical and morphological characters. The molecular characterization of xylose reductase (XR) indicates that the regions surrounding the conserved domain contain mutations that may enhance the performance of the enzyme in X-F yeasts. The phylogenetic reconstruction using XYL1 or RPB1 was identical to the multilocus analysis, and these loci have potential for rapid identification of cryptic species in this clade.
STUDY WITH NINE THALIDOMIDE DERIVATIVES IN THE LEPRA REACTION (1978)

ABSTRACT: In our studies, 3 out of the 9 thalidomide derivatives used to treat lepra reaction of lepromatous leprosy were effective. All 3 are known to be teratogenic in animal studies. This suggests that the teratogenic and the lepra reaction suppressive properties may be related.