gebhart/patrepeval huggingface dataset:
HSV-TK Engineered Donor Lymphocytes Add-Backs Reduce Late Mortality and Improve Survival of High Risk Acute Leukemia after Haplo-HSCT: Results of a Phase II Multicenter Trial. (2005)

Abstract The outcome of haplo-SCT is limited by delayed immune reconstitution resulting in a high rate of late mortality and relapse. Here, we report results of a phase II multicenter trial (MM TK007) of early add-backs of donor lymphocytes genetically engineered to express the herpes simplex thymidine kinase (TK) suicide gene after haplo-SCT in inducing immune reconstitution and selective control of GvHD by ganciclovir. Twentysix advanced age pts (median age 51, 17–63) were transplanted for high risk leukemia; disease status at SCT was CR1 (8), CR2 (7), refractory (11). A median of 12.2x106/kg (7.3–16.8) CD34+ selected (Clinimacs) and 1x104/kg (0.8–1.4) CD3+ cells were infused after a myeloablative conditioning. 24/26 pts engrafted with a median time of 14 d (8–21) for ANC &gt;1.0x109/l and 13 d (11–24) for plt &gt;50x109/l. No immune reconstitution and no GvHD were observed in absence of TK-add-back. Sixteen pts received TK-DLI at a median dose of 107/kg with 1st infusion at d +42 and 13 pts obtained CD3+ &gt;100/mcl at a median time of 91 d (61–127) from SCT and 24 d (14–42) from TK-DLI. Transduced cells were documented ex vivo in all pts and represented a median of 48% (10–90) of CD3+ cells. Five pts developed acute GvHD, (grade I to IV) that was always completely abrogated by ganciclovir. In patients in CR at time of SCT who were alive at d +42 and received add-backs of Tk cells, OS rate was 46% at 800 days (intention-to-treat analysis: 38% OS at 800 days post-SCT). Of significance, the cumulative incidence of TRM and relapse showed a 40% probability of mortality with a median time of death of 90 days and last event at day +166. This figure indicate that TK cell add-backs abolish late mortality after CD34+ SCT in adults. In patients in relapse at time of HSCT, a median OS of 201 days was obtained in ITT, with a significant advantage on expected survival without transplantation (60 d) and superior results as compared to haplo EBMT registry (80 d). The 2-year estimation of events of this multicenter phase II study confirm that TK-DLI is an effective tool for promoting immune reconstitution and protecting pts from late infectious mortality after haplo-SCT. We believe that these results are due to the rapid development of a wide T cell repertoire obtained by TK cell infusions. Immunological follow-up showed Th1/Tc1 effector memory T cells, with a wide TCR repertoire in the first 3 months after SCT in all patients. High frequencies of T cells specific for CMV (median: 35 and 93 spots/105 cells with CMV-infected donor and host fibroblasts) and EBV (median: 58 and 41 spots/105 cells with donor and host EBV-LCL) were detected by gIFN ELISpot at time of immunereconstitution, and correlated with complete control of viral infections. Normalization of the T cell repertoire was documented by spectratype, immune-phenotype for naïve and memory T cell subsets and gIFN ELIspot 6 months after treatment. A phase III randomized multicentric study will start in 2006.
TLR4 and MD-2 Expression Is Regulated by Immune-mediated Signals in Human Intestinal Epithelial Cells (2002)

The normal intestinal epithelium is not inflamed despite contact with a high density of commensal bacteria. Intestinal epithelial cells (IEC) express low levels of TLR4 and MD-2 and are lipopolysaccharide (LPS)-unresponsive. We hypothesized that immune-mediated signals regulate the expression of TLR4 and MD-2 in IEC. Expression of TLR4 and MD-2 was examined in normal colonic epithelial cells or intestinal epithelial cell lines. The effect of the cytokines interferon (IFN)-gamma, IFN-alpha, and tumor necrosis factor-alpha (TNF-alpha) on TLR4 and MD-2 expression was examined by reverse transcription-PCR and Western blot. NF-kappaB transcriptional activation and interleukin-8 secretion were used as measures of LPS responsiveness. Native colonic epithelial cells and IEC lines express a low level of TLR4 and MD-2 mRNA. IFN-gamma regulates MD-2 expression in both IEC lines, whereas IFN-gamma and TNF-alpha regulate TLR4 mRNA expression in IEC lines. Pre-incubation with IFN-gamma and/or TNF-alpha sensitizes IEC to LPS-dependent interleukin-8 secretion. To examine MD-2 transcriptional regulation, we cloned a 1-kb sequence proximal to the MD-2 gene translational start site. This promoter directed expression of a reporter gene in endothelial cells and IEC. IFN-gamma positively regulated MD-2 promoter activity in IEC. Co-expression of a STAT inhibitor, SOCS3, blocked IFN-gamma-mediated MD-2 promoter activation. T cell-derived cytokines lead to increased expression of TLR4 and MD-2 and LPS-dependent pro-inflammatory cytokine secretion in IEC. IFN-gamma regulates expression of the critical TLR4 co-receptor MD-2 through the Janus tyrosine kinase-STAT pathway. Th1 cytokines may initiate or perpetuate intestinal inflammation by altering toll-like receptor expression and bacterial reactivity.
[Ca2+]i in single Isolated cardiac cells: a review of recent results obtained with digital imaging microscopy and fora-2 (1988)

The use of fluorescent Ca2+ indicators to observe [Ca2+]i transients in voltage-clamped single cells has many advantages over previous methods, such as the use of aequorin in multicellular preparations, for studying excitation-contraction coupling. In the studies reviewed in this article, [Ca2+]i in single isolated mammalian ventricular myocytes was observed through the use of the fluorescent Ca2+ indicator, fura-2. Individual cells, loaded with fura-2 either by internal perfusion or by exposure to fura-2/AM, were generally studied with the use of inverted microscopes equipped with ultraviolet epifluorescence illumination, intensified silicon intensifier target cameras (ISIT), and (or) a photomultiplier tube. Analysis of subcellular patterns of fura-2 fluorescence was performed by digital analysis of the images obtained with the ISIT camera. Variation of membrane voltage and exposure of cells to ryanodine (which was assumed to selectively block the release of Ca2+ from the sarcoplasmic reticulum) were used to investigate the cellular processes that determine the [Ca2+]i transient. The main results of these studies are the following. (1) In any population of enzymatically isolated heart cells, there are (i) mechanically quiescent cells in which [Ca2+]i is spatially uniform, constant over time, and relatively low; (ii) spontaneously contracting cells, which have a relatively elevated [Ca2+]i, but in which the spatial uniformity of [Ca2+]i is interrupted periodically by spontaneous, propagating waves of high [Ca2+]i; and (iii) cells that are hypercontracted (rounded up) and that have higher levels of [Ca2+]i than the other two types.(ABSTRACT TRUNCATED AT 250 WORDS)
Molecular Linkage Between the Kinase ATM and NF-κB Signaling in Response to Genotoxic Stimuli (2006)

The transcription factor NF-kappaB modulates apoptotic responses induced by genotoxic stress. We show that NF-kappaB essential modulator (NEMO), the regulatory subunit of IkappaB kinase (IKK) (which phosphorylates the NF-kappaB inhibitor IkappaB), associates with activated ataxia telangiectasia mutated (ATM) after the induction of DNA double-strand breaks. ATM phosphorylates serine-85 of NEMO to promote its ubiquitin-dependent nuclear export. ATM is also exported in a NEMO-dependent manner to the cytoplasm, where it associates with and causes the activation of IKK in a manner dependent on another IKK regulator, a protein rich in glutamate, leucine, lysine, and serine (ELKS). Thus, regulated nuclear shuttling of NEMO links two signaling kinases, ATM and IKK, to activate NF-kappaB by genotoxic signals.
Classification of immunoassay (1991)

The immunoassay is an analytical method that depends upon the antigen-antibody reaction. The term immunoassay usually refers to a quantitative method, but in a broader sense, includes characterising methods for analysing the immunological properties of analytes.
7-OH-DPAT-Induced Inhibition of Norepinephrine Release in PC12 Cells (2004)

The purpose of this study was to investigate mechanisms of suppression of norepinephrine release by 7-OH-DPAT, a dopamine D(2)/D(3) receptor agonist, in PC12 cells pretreated with nerve growth factor (NGF). 7-OH-DPAT caused inhibition of basal and K(+)-evoked norepinephrine release, which could be blocked by pretreatment with raclopride, a D(2)/D(3) receptor antagonist. Moreover, dopamine D(2) and D(3 )receptors were identified by immunocytochemistry. Expression of D(2), D(3), and D(4) mRNAs and their proteins were detected using RT-PCR and immunoblotting. Furthermore, 7-OH-DPAT produced no change in cGMP levels; however, 7-OH-DPAT inhibited forskolin-stimulated cAMP accumulation that was antagonized by pretreatment with raclopride. In addition, 7-OH-DPAT inhibited carbachol-induced Ca(2+) transient, conversely, 7-OH-DPAT had no effect on 4-aminopyridine-induced Ca(2+) transient. Taken together, suppression of cAMP accumulation and calcium mobilization by 7-OH-DPAT is involved in the inhibition of norepinephrine release through activation of dopamine D(2)/D(3) receptors.
Behavioral phenotyping of transgenic and knockout animals: a cautionary tale. (2001)

Knockout and transgenic mice are extremely useful for behavioral research, especially for linking specific genes with behaviors. The authors present caveats to be aware of when using such mice in research situations.
Prostaglandin E2 enhances bradykinin-stimulated release of neuropeptides from rat sensory neurons in culture (1994)

Prostaglandins are known to enhance the inflammatory and nociceptive actions of other chemical mediators of inflammation such as bradykinin. One possible mechanism for this sensitizing action is that prostanoids augment the release of neuroactive substances from sensory neurons. To initially test this hypothesis, we examined whether selected prostaglandins could enhance the resting or bradykinin-evoked release of immunoreactive substance P (iSP) and/or immunoreactive calcitonin gene-related peptide (iCGRP) from sensory neurons in culture. Bradykinin alone causes a concentration-dependent increase in the release of iSP and iCGRP from isolated sensory neurons, and this action is abolished in the absence of extracellular calcium. Pretreating the neurons with PGE2 (10 nM to 1 microM) potentiates the bradykinin-evoked release of both iSP and iCGRP by approximately two-to fourfold. At these concentrations, PGE2 alone did not significantly alter peptide release. Exposing the cultures to 1 microM PGF2 alpha is ineffective in altering either resting or bradykinin-evoked peptide release. Sensory neurons in culture contain cyclooxygenase-like immunoreactivity suggesting that the enzyme that converts arachidonic acid to prostaglandins is present. In addition, pretreating cultures with 14C-arachidonic acid yields radiolabeled eicosanoids that cochromatograph with known prostaglandin standards. Preexposing cultures to indomethacin abolishes the production of prostaglandins and attenuates the bradykinin-stimulated release of iSP and iCGRP. This implies that the synthesis of prostaglandins contributes to the bradykinin-evoked release of peptides. The augmentation of bradykinin-induced release of iSP and iCGRP by PGE2 may be one mechanism to account for the inflammatory and hyperalgesic actions of this eicosanoid.
The Evaluation of Subatmospheric Pressure and Hyperbaric Oxygen in Ischemic Full-Thickness Wound Healing (2000)

We evaluated the efficacy of subatmospheric pressure and hyperbaric oxygen (HBO) as adjuncts in the treatment of hypoxic full-thickness wounds in a rabbit model. We hypothesized that subatmospheric pressure and HBO independently are effective in improving wound healing in the ischemic wound model and that when they are used in combination there is an increased positive effect on wound healing. Using a standard ischemic wound model four full-thickness wounds were created on each ear of 41 male New Zealand white rabbits (N = 82 ears). On each rabbit one ear was dressed with the vacuum-assisted closure (VAC) device and connected to suction; the other was dressed identically without the suction and suction tubing. Twenty rabbits were treated with HBO daily for 10 days at 2.0 atmospheres absolute for 90 minutes plus descent and ascent times. Necropsy on all rabbits was performed on postoperative day 10. Four ischemic wound treatment groups were evaluated: Group 1 (N = 21) VAC dressing alone; Group 2 (N = 20) VAC dressing plus HBO; Group 3 (N = 21) VAC dressing to suction alone; and Group 4 (N = 20) VAC dressing to suction and HBO. Using light microscopy a veterinary pathologist blinded to treatment groups quantified peak granulation tissue, granulation tissue gap, and epithelialization tissue gap. Data were analyzed by analysis of variance with significance indicated by P < 0.05. Statistical significance was found in a comparison of VAC dressing to suction and VAC dressing alone for peak granulation tissue and granulation tissue gap both with and without use of HBO. VAC device use appears to increase the rate of healing in a rabbit ischemic wound model. HBO therapy did not significantly affect the rate of healing in this model.
Au-Catalyzed Piperidine Synthesis via Tandem Acyloxy Migration/Intramolecular [3 + 2] Cycloaddition of Enynyl Esters (2011)

An Au-catalyzed tandem protocol involving enynyl ester isomerization and subsequent intramolecular [3 + 2] cyclization has been developed. This strategy provides an efficient approach for the synthesis of polyfunctional piperidines, which are subunits of many bioactive molecules.
Parasympathetic, sympathetic, and sensory interactions in the iris: nerve growth factor regulates cholinergic ciliary ganglion innervation in vivo (1985)

Interactions between peptidergic sensory nerves, noradrenergic sympathetic nerves, and cholinergic parasympathetic fibers were examined in the rat iris. The putative peptide neurotransmitter, substance P (SP), was used as an index of the trigeminal sensory innervation, tyrosine hydroxylase (TH) activity served to monitor the sympathetic fibers, and choline acetyltransferase (CAT) activity was used as an index of the parasympathetic innervation. Destruction of the sympathetic innervation by neonatal administration of 6-hydroxydopamine resulted in increased SP development and a smaller increase in CAT activity in the iris. Moreover, trigeminal ablation resulted in an increase in both TH and CAT activities. Finally, ciliary ganglionectomy resulted in increased SP and a smaller increase in TH activity in the iris. Administration of nerve growth factor (NGF) into the anterior chamber substantially increased both SP and TH activity in the iris and also increased CAT activity to a lesser extent. Moreover, administration of anti-NGF into the anterior chamber prevented both the sympathectomy-induced increases in SP and CAT, and the increases in TH and CAT activities after trigeminal ablation, suggesting that NGF mediated these increases. These observations suggest that the sympathetic, sensory, and parasympathetic innervations of the iris interact by altering availability of NGF elaborated by the iris. Regulation of iris CAT activity was examined in greater detail. Injection of the cholinergic toxin, AF64A, into the anterior chamber concurrently with ablation of the sympathetic and sensory innervations paradoxically increased CAT activity, whereas AF64A alone decreased CAT activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Altered mTOR signalling in nephropathic cystinosis (2016)

Lysosomes play a central role in regulating autophagy via activation of mammalian target of rapamycin complex 1 (mTORC1). We examined mTORC1 signalling in the lysosomal storage disease nephropathic cystinosis (MIM 219800), in which accumulation of autophagy markers has been previously demonstrated. Cystinosis is caused by mutations in the lysosomal cystine transporter cystinosin and initially affects kidney proximal tubules causing renal Fanconi syndrome, followed by a gradual development of end-stage renal disease and extrarenal complications. Using proximal tubular kidney cells obtained from healthy donors and from cystinotic patients, we demonstrate that cystinosin deficiency is associated with a perturbed mTORC1 signalling, delayed reactivation of mTORC1 after starvation and abnormal lysosomal retention of mTOR during starvation. These effects could not be reversed by treatment with cystine-depleting drug cysteamine. Altered mTORC1 signalling can contribute to the development of proximal tubular dysfunction in cystinosis and points to new possibilities in therapeutic intervention through modulation of mTORC-dependent signalling cascades.
Equivalence of hydroxyethyl starch HES 130/0. 4 and HES 200/0. 5 for perioperative volume replacement in major gynaecological surgery (2003)

This clinical trial demonstrated therapeutic equivalence of this novel low-substituted HES 130/0.4 solution and a standard HES 200/0.5 solution for perioperative volume replacement. Moreover, both HES preparations were equally well-tolerated and safe.
MR889, a neutrophil elastase inhibitor, in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled clinical trial (1996)

We investigated whether MR889, a synthetic cyclic thiolic elastase inhibitor, administered for a period of 4 weeks to chronic obstructive pulmonary disease (COPD) patients, is well-tolerated, and whether it modifies biochemical indices of lung destruction. The study was a double-blind, randomized, placebo-controlled clinical trial in COPD patients. Thirty subjects were administered MR889 orally at a dose of 500 mg b.i.d. for 4 weeks, and 30 received placebo following the same schedule. In addition to safety parameters, MR889 efficacy was checked by a pretreatment/postreatment evaluation of levels of plasma elastin-derived peptides and urinary desmosine. There were no statistically significant differences between pretreatment and posttreatment efficacy parameter levels either in the control group or in the treated group. However, in a subset of treated patients with a short disease duration, the level of urinary desmosine dropped significantly with respect to pretreatment values (p = 0.004). We conclude that MR889 is safe to administer to COPD patients for a period of at least 4 weeks. During this time, MR889 does not modify biochemical markers of lung destruction in unselected COPD patients. Nevertheless, a subset of treated patients with fairly short disease duration showed a post-treatment reduction of desmosine urine levels, thus justifying the need for further studies to prove the efficacy of MR889 in modulating indices of lung destruction in COPD.
cDNA cloning and complete sequence of porcine choline acetyltransferase: in vitro translation of the corresponding RNA yields an active protein. (1987)

A cDNA clone encoding the complete sequence of porcine choline acetyltransferase (ChoAcTase; acetyl-CoA: choline O-acetyltransferase, EC 2.3.1.6.) has been identified. A cDNA library, constructed from poly(A)+ RNA of ventral spinal cord, was screened with a mixture of eight oligonucleotides corresponding to the N-terminal sequence of pig brain ChoAcTase. Among five positive clones, one, pChAT-1, was identified as a ChoAcTase cDNA clone based on the following criteria. (i) This clone has an open reading frame coding for a protein of the size expected for ChoAcTase (640 amino acids). (ii) The amino acid composition deduced from the nucleotide sequence of this open reading frame matches that of purified porcine ChoAcTase. (iii) When subcloned in the T7 expression system, the corresponding RNA directs the synthesis in the rabbit reticulocyte lysate of a protein that is specifically immunoprecipitated by antibodies raised against ChoAcTase. (iv) Finally and most important, this corresponding RNA, when translated in the reticulocyte lysate, as well as in the Xenopus oocyte system, directs the synthesis of a protein displaying ChoAcTase activity. This activity is inhibited by the specific ChoAcTase inhibitor 4-(1-naphthylvinyl)pyridine. Comparison of porcine ChoAcTase sequence with that of Drosophila reveals 32% identity between these proteins, when the sequences are suitably aligned. pChAT-1 probe hybridizes with a porcine mRNA species that is at least 7000 nucleotides long, whereas the equivalent rat mRNA species is 3700 nucleotides long.
Use of DNA Encoding Influenza Hemagglutinin as an Avian Influenza Vaccine (1993)

Recently, we demonstrated that direct inoculation of a hemagglutinin 7 (H7)-expressing DNA could vaccinate chickens against a lethal H7 influenza virus challenge. These experiments used a defective-retroviral-based vector to express H7 (p188) (Robinson et al., 1993). Here, we report protective immunizations using a non-retroviral-based vector for H7 expression (pCMV/H7). Unlike the previously used retroviral-based vector, this vector cannot be transmitted as an infectious agent (as a consequence of phenotypic mixing with exogenous or endogenous virus proteins). Vaccination was accomplished by inoculating young, immunocompetent chickens by each of three routes (intravenous, intraperitoneal, and intramuscular) with 100 micrograms of cesium chloride-purified pCMV/H7 DNA in saline. After two immunizations, birds were challenged via the nares with a lethal dose of a highly virulent chicken influenza virus of the H7 subtype. The results of five independent vaccine trials demonstrated protective immunizations in approximately 60% of the pCMV/H7 DNA-inoculated chickens. By contrast, only 3% of the chickens inoculated with control DNA survived the lethal challenge.
A NOTE ON HAUSDORFF MEASURES OF SIERPINSKI CARPETS (2001)

在这份报纸，常规 Sierpinski 地毯作为一个新概念被给。常规 Sierpinski 地毯的 Hausdorff 措施和 Hausdorff 的范围的准确价值为概括 Sierpinski 地毯的所有形式测量也被获得。为我们显示出的任何一条概括 Sierpinski 地毯，那在那里存在一条常规地毯以便他们有一样的 Hausdorff 措施。
The synthesis and conformational analysis of a pair of diastereoisomeric cyclic peptides with cis and transamide bonds, respectively (1993)

N-Protected, conformationally constrained, eight-membered ring containing cyclic dipeptides derived from methyl cyclo-[(R)-cysteinyl-(R)-penicillamine] contain a cis amide bond, whilst the corresponding peptides derved from cyclo-[(R)-cysteinyl-(S)-penicillamine] contain a trans amide bond.
Cold Atmospheric Plasma Treatment Induces Anti-Proliferative Effects in Prostate Cancer Cells by Redox and Apoptotic Signaling Pathways (2015)

One of the promising possibilities of the clinical application of cold plasma, so-called cold atmospheric plasma (CAP), is its application on malignant cells and cancer tissue using its anti-neoplastic effects, primarily through the delivery of reactive oxygen and nitrogen species (ROS, RNS). In this study, we investigated the impact of CAP on cellular proliferation and consecutive molecular response mechanisms in established prostate cancer (PC) cell lines. PC cells showed a significantly reduced cell growth following CAP treatment as a result of both an immediate increase of intracellular peroxide levels and through the induction of apoptosis indicated by annexin V assay, TUNEL assay, and the evaluation of changes in nuclear morphology. Notably, co-administration of N-acetylcysteine (NAC) completely neutralized CAP effects by NAC uptake and rapid conversion to glutathione (GSH). Vitamin C could not counteract the CAP induced effects on cell growth. In summary, relatively short treatments with CAP of 10 seconds were sufficient to induce a significant inhibition of cancer proliferation, as observed for the first time in urogenital cancer. Therefore, it is important to understand the mode of CAP related cell death and clarify and optimize CAP as cancer therapy. Increased levels of peroxides can alter redox-regulated signaling pathways and can lead to growth arrest and apoptosis. We assume that the general intracellular redox homeostasis, especially the levels of cellular GSH and peroxidases such as peroxiredoxins affect the outcome of the CAP treatment.