gebhart/patrepeval huggingface dataset:
ROS Fusion Tyrosine Kinase Activates a SH2 Domain–Containing Phosphatase-2/Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Signaling Axis to Form Glioblastoma in Mice (2006)

Glioblastoma multiforme is the most common and lethal form of primary brain cancer. Diagnosis of this advanced glioma has a poor prognosis due to the ineffectiveness of current therapies. Aberrant expression of receptor tyrosine kinases (RTK) in glioblastoma multiformes is suggestive of their role in initiation and maintenance of these tumors of the central nervous system. In fact, ectopic expression of the orphan RTK ROS is a frequent event in human brain cancers, yet the pathologic significance of this expression remains undetermined. Here, we show that a glioblastoma-associated, ligand-independent rearrangement product of ROS (FIG-ROS) cooperates with loss of the tumor suppressor gene locus Ink4a;Arf to produce glioblastomas in the mouse. We show that this FIG-ROS-mediated tumor formation in vivo parallels the activation of the tyrosine phosphatase SH2 domain-containing phosphatase-2 (SHP-2) and a phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling axis in tumors and tumor-derived cell lines. We have established a fully penetrant preclinical model for adult onset of glioblastoma multiforme in keeping with major genetic events observed in the human disease. These findings provide novel and important insights into the role of ROS and SHP-2 function in solid tumor biology and set the stage for preclinical testing of targeted therapeutic approaches.
Function of micF as an antisense RNA in osmoregulatory expression of the ompF gene in Escherichia coli (1987)

To analyze the function of micF as an antisera RNA in the osmoregulatory expression of the ompF gene in Escherichia coli, we performed two experiments. In the first experiment, two strains were constructed in which the transcription initiation site of the ompF gene and the transcription termination site of the micF gene were separated by 186 and 4,100 base pairs, respectively, on the chromosome. These two strains showed almost the same profile of ompF expression as the wild-type strain in which the two genes are separated by 10(6) base pairs. When a high-copy-number plasmid carrying the micF gene was introduced into these strains, ompF expression was completely repressed, whereas no repression was observed with a low-copy-number plasmid carrying the micF gene. These results indicate that the distance between the two genes on the chromosome is not critical for the function of micF. In the second experiment, expression of the ompF gene was examined by pulse-labeling in both the micF+ and the micF deletion strains. Upon a shift from a low- to a high-osmolarity medium, suppression of OmpF protein synthesis occurred more quickly and more extensively in the micF+ strain than in the micF deletion strain. The steady-state synthesis of the OmpF protein was also completely suppressed in the micF+ strain in the high-osmolarity medium, whereas the suppression was incomplete in the micF deletion strain. From these results we conclude that (i) the micF gene contributes to the fast and complete response of the OmpF synthesis to the medium osmolarity, and that (ii) the distance between the micF and ompF genes on the chromosomes is not critical for the function of the micF gene. The results suggest, rather, that the ratio of the copy numbers of the two genes is critical for the function of the micF gene.
Mitochondrial control of nuclear apoptosis. (1996)

Anucleate cells can be induced to undergo programmed cell death (PCD), indicating the existence of a cytoplasmic PCD pathway that functions independently from the nucleus. Cytoplasmic structures including mitochondria have been shown to participate in the control of apoptotic nuclear disintegration. Before cells exhibit common signs of nuclear apoptosis (chromatin condensation and endonuclease-mediated DNA fragmentation), they undergo a reduction of the mitochondrial transmembrane potential (delta psi m) that may be due to the opening of mitochondrial permeability transition (PT) pores. Here, we present direct evidence indicating that mitochondrial PT constitutes a critical early event of the apoptotic process. In a cell-free system combining purified mitochondria and nuclei, mitochondria undergoing PT suffice to induce chromatin condensation and DNA fragmentation. Induction of PT by pharmacological agents augments the apoptosis-inducing potential of mitochondria. In contrast, prevention of PT by pharmacological agents impedes nuclear apoptosis, both in vitro and in vivo. Mitochondria from hepatocytes or lymphoid cells undergoing apoptosis, but not those from normal cells, induce disintegration of isolated Hela nuclei. A specific ligand of the mitochondrial adenine nucleotide translocator (ANT), bongkreik acid, inhibits PT and reduces apoptosis induction by mitochondria in a cell-free system. Moreover, it inhibits the induction of apoptosis in intact cells. Several pieces of evidence suggest that the proto-oncogene product Bcl-2 inhibits apoptosis by preventing mitochondrial PT. First, to inhibit nuclear apoptosis, Bcl-2 must be localized in mitochondrial but not nuclear membranes. Second, transfection-enforced hyperexpression of Bcl-2 directly abolishes the induction of mitochondrial PT in response to a protonophore, a pro-oxidant, as well as to the ANT ligand atractyloside, correlating with its apoptosis-inhibitory effect. In conclusion, mitochondrial PT appears to be a critical step of the apoptotic cascade.
TCR Peptide Vaccination in Multiple Sclerosis: Boosting a Deficient Natural Regulatory Network that may Involve TCR-Specific CD4+CD25+ Treg Cells (2005)

Vaccination with self peptides contained within T cell receptor (TCR) chains, expressed by pathogenic Th1 cells can induce a second set of regulatory T cells that can reverse paralysis in rodents with experimental encephalomyelitis, and similarly, may have the potential to regulate myelin-reactive Th1 cells in patients with multiple sclerosis (MS). In this review, we discuss our recent discovery that TCR-reactive T cells generally possess classical inhibitory activity associated with Treg cells. CD4+CD25+ TCR-reactive T cells can inhibit CD4+CD25- indicator cells stimulated with anti-CD3/anti-CD28 antibody in a dose-dependent and cell-contact-dependent manner. Additionally, CD4+CD25+ T cells from blood of healthy control donors have significant responses to a pool of discriminatory TCR peptides, including BV10S1P, BV19S20, BV13S7, BV12S2A2T, BV11S1A1T, BV21S3A1T, AV15S1, and BV12S1A1N1. Patients with MS have varying degrees of deficient responses to TCR peptides, and by association, a defect in Treg cell function as well. TCR peptide vaccination using a new tripeptide mixture emulsified in IFA produced strong T cell responses in 100% of MS recipients, a dramatic improvement over previous vaccines given i.d. in saline that induced TCR-reactive T cell responses in about 50% of recipients. Responders to vaccination had a tendency towards reduced MRI lesions, and an early indication of enhanced Treg activity mediated by TCR-reactive T cells that could provide suppression of target as well as bystander T cells. These data provide a strong foundation for future TCR vaccination studies that will critically test the ability of the tripeptide mixture to induce significantly enhanced Treg activity and possible clinical and MRI benefits in vivo.
Iron Loading Enhances Susceptibility to Renal Ischemia in Rats (1994)

Because chronic iron overload can cause organ injury in hemochromatosis and because iron participates in injury during renal ischemia-reperfusion, the effect of mild subacute renal iron loading on the susceptibility to ischemic acute renal failure was evaluated. Male Sprague-Dawley rats were injected with iron nitrilotriacetate (1 mg iron/kg BW i.p. daily) for 5 days. Controls were instead injected with nitrilotriacetate. Seventy-two hours later animals were subjected to 40-min renal artery ischemia. Iron loading produced a 28% increase in kidney iron content without any change in baseline renal function (plasma creatinine) or histology. Ischemic renal injury was far more severe in iron-loaded animals. Plasma creatinine 24 and 48 h after ischemia was significantly higher in iron-loaded rats (3.3 and 3.4 vs. 2.2 and 0.8 mg/dL) and GFR was significantly lower in iron-loaded rats (0.30 vs. 0.78 mL/min). In addition, iron-loaded rats showed a dramatically greater extent of damage by histologic evaluation using a semiquantitative scoring method. Therefore, a small increase in renal iron content greatly increased renal injury after an ischemic insult. These findings may be relevant to human renal disease because there is accumulating evidence of renal iron accumulation in a variety of proteinuric and chronic renal diseases.
Recent Progress in Pharmaceutical Therapies for Castration-Resistant Prostate Cancer (2013)

Since 2010, six drugs have been approved for the treatment of castration-resistant prostate cancer, i.e., CYP17 inhibitor Abiraterone, androgen receptor antagonist Enzalutamide, cytotoxic agent Cabazitaxel, vaccine Sipuleucel-T, antibody Denosumab against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin. All these drugs demonstrate improvement on overall survival, expect for Denosumab, which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone-metastasis-free survival. Besides further CYP17 inhibitors (Orteronel, Galeterone, VT-464 and CFG920), androgen receptor antagonists (ARN-509, ODM-201, AZD-3514 and EZN-4176) and vaccine Prostvac, more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials, including various kinase inhibitors and platinum complexes. Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments. Under these flourishing circumstances, more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients.
Immunohistochemical analysis of integrin αvβ3 expression on tumor‐associated vessels of human carcinomas (1997)

Expression of the αvβ3 integrin is upregulated on sprouting endothelia. Systemic application of antibody or peptidic inhibitors of αvβ3 function disrupts tumor angiogenesis and reduces growth and invasiveness of human tumors in animal models. We systematically investigated αvβ3 expression on tumor-associated vessels of 4 different human epithelial tumors and the corresponding normal tissues by means of immunohistochemistry on frozen sections using the αvβ3-complex specific monoclonal antibody LM609. Variable levels of LM609 staining were found in all carcinoma lesions. A considerable number of tumor tissues (35/50) expressed αvβ3 on more than 50% of their vessels. Inflammatory infiltrates and the possibly hypoxic conditions near necrotic areas of tumors were accompanied by an increased αvβ3 expression. Remarkably, the vasculature in apparently normal tissue also stained for αvβ3. However, the percentages of stained vessels and their staining intensity were lower than in neoplastic tissues. Besides the vascular αvβ3 expression, several extravascular cell types stained positive, in both normal and tumor specimens. Taken together, our findings show a considerable number of colon, pancreas, lung and breast carcinoma lesions with many αvβ3-expressing vessels that could be targets for anti-αvβ3-therapy. Int. J. Cancer 71:320-324, 1997. © 1997 Wiley-Liss Inc.
Amphoteric liposomes enable systemic antigen‐presenting cell–directed delivery of CD40 antisense and are therapeutically effective in experimental arthritis (2009)

Amphoteric liposomes represent a novel carrier concept for systemic and antigen-presenting cell-targeted oligonucleotide delivery with clinical applicability and numerous potential applications, including target validation in vivo and inflammatory disease therapeutics. Moreover, Nov038/CD40-ASO constitutes a potent alternative to monoclonal antibody-based approaches for interfering with CD40-CD40L interactions.
Expanding the Range of Substrate Acceptance of Enzymes: Combinatorial Active‐Site Saturation Test (2005)

Mit CASTing zum Erfolg: Das bekannte Problem, die Substratakzeptanz von Enzymen zu erweitern, lässt sich dadurch lösen, dass fokussierte Mutantenbibliotheken durch Randomisierung von geeignet gewählten Aminosäurepaaren um das aktive Zentrum erzeugt werden (siehe das Beispiel mit der Lipase aus Pseudomonas aeruginosa; die Aminosäurepaare haben jeweils die gleiche Farbe). CAST=combinatorial active-site saturation test.
LUTEINIZING HORMONE RELEASING HORMONE-INDUCED RELEASE OF LUTEINIZING HORMONE FROM PITUITARY EXPLANTS OF COWS KILLED BEFORE OR AFTER OESTRADIOL TREATMENT (1981)

In ovariectomized heifers, oestradiol decreases concentrations of LH in serum for approximately 12 h after which LH is released in a surge comparable in size and duration to the preovulatory surge. Using this model, we measured LH release induced by LH releasing hormone (LH-RH) from pituitary explants taken from ovariectomized heifers before or after an oestradiol-induced LH surge. These changes were related to changes in LH concentrations in serum and pituitary glands and hypothalamic LH-RH content. Twenty Holstein heifers were randomly assigned to one of four treatment groups to be killed 0, 6, 12, or 24 h after the injection of 500 μg oestradiol-17β. Jugular blood was collected at −2, −1 and 0 h then at intervals of 2 h until slaughter. Pituitary glands were collected and ≃2 mm 3 explants were exposed to 4 ng LH-RH/ml medium for 30 min (superfusion) or 4 ng LH-RH/ml medium for 2 h in Erlenmeyer flasks. Levels of LH were measured in the medium. Hypothalami, collected at autopsy, were assayed for LH-RH content. To determine pituitary LH content, an additional 15 ovariectomized heifers were killed, five each at 0, 12 and 24 h after the injection of 500 μg oestradiol. In both groups of heifers, oestradiol reduced serum LH concentrations to ≃ 1 ng/ml, a level which persisted for 12 h, when LH was released in a surge. Pituitary sensitivity to LH-RH was increased at 6 and 12 h after the injection of oestradiol, but was markedly decreased at 24 h, i.e. after the LH surge. Despite this twofold increase in capacity of the pituitary gland to release LH in response to LH-RH, pituitary LH content did not change during 12 h after oestradiol treatment. However, LH content decreased after the LH surge and this decrease was associated with a decrease in pituitary responsiveness to LH-RH. Hypothalamic LH-RH content was not altered by these treatments. We have interpreted our results as evidence that oestradiol exerts a positive feedback effect on the pituitary gland of ovariectomized heifers such that pituitary sensitivity to LH-RH is increased twofold by the time the LH surge is initiated. In addition, oestradiol causes a transitory inhibition of LH-RH release as shown by the fact that serum LH concentrations remained low during the interval from injection of oestradiol until the beginning of the LH surge despite the fact that pituitary sensitivity to LH-RH is increased at this time. Depletion of a readily releasable pool of pituitary LH may be the mechanism by which the LH surge is terminated.
Effect of Posterolateral Scar Tissue on Clinical and Echocardiographic Improvement After Cardiac Resynchronization Therapy (2006)

CRT does not reduce LV dyssynchrony in patients with transmural scar tissue in the posterolateral LV segments, resulting in clinical and echocardiographic nonresponse to CRT.
Early stages in development of the Escherichia coli cell‐division site (1994)

Development of the Escherichia coli cell division site was studied in wild-type cells and in non-septate filaments of ftsZnull and ftsZTs mutant cells. Localized regions of plasmolysis were used as markers for the positions of annular structures that are thought to be related to the periseptal annuli that flank the ingrowing septum during cytokinesis. The results show that these structures are localized at potential division sites in non-septate filaments of FtsZ- cells, contrary to previous reports. The positions of the structures along the long axis of the cells in both wild-type cells and FtsZ- filaments were unaffected by the presence of plasmolysis bays at the cell poles. These results do not agree with a previous suggestion that the apparent association of plasmolysis bays with future division sites was artefactual. They support the view that division sites begin to differentiate before the initiation of septal ingrowth and that plasmolysis bays and the annular attachments that define them, mark the locations of these early events in the division process.
Adaptation and learning in control of voluntary movement by the central nervous system (1988)

In order to control voluntary movements, the central nervous system must solve the following three computational problems at different levels: (1) the determination of a desired trajectory in visual coordinates; (2) the transformation of its coordinates into body coordinates; and (3) the generation of motor command. Concerning these problems, relevant experimental observations obtained in the field of neuroscience are briefly reviewed. On the basis of physiological information and previous models, we propose computational theories and a neural network model which account for these three problems. (1) A minimum torque-change model which predicts a wide range of trajectories in human multi-joint arm movements is proposed as a computational model for trajectory formation. (2) An iterative learning scheme is presented as an algorithm which solves the coordinate transformation and the control problem simultaneously. This algorithm can be regarded as a Newton-like method in function spaces. (3) A neural network model for generation of motor command is proposed. This model contains internal neural models of the motor system and its inverse system. The inverse-dynamics model is acquired by heterosynaptic plasticity using a feedback motor command (torque) as an error signal. The hierarchical arrangement of these neural networks and their global control are discussed. Their applications to robotics are also discussed.
A Plant miRNA Contributes to Antibacterial Resistance by Repressing Auxin Signaling (2006)

Plants and animals activate defenses after perceiving pathogen-associated molecular patterns (PAMPs) such as bacterial flagellin. In Arabidopsis, perception of flagellin increases resistance to the bacterium Pseudomonas syringae, although the molecular mechanisms involved remain elusive. Here, we show that a flagellin-derived peptide induces a plant microRNA (miRNA) that negatively regulates messenger RNAs for the F-box auxin receptors TIR1, AFB2, and AFB3. Repression of auxin signaling restricts P. syringae growth, implicating auxin in disease susceptibility and miRNA-mediated suppression of auxin signaling in resistance.
Duchenne Muscular Dystrophy (1995)

Fifteen subjects with Becker's muscular dystrophy (BMD) were studied prospectively over a 10-yr period to provide a profile of impairment and disability. Proximal lower extremity musculature (particularly the hip and knee extensors), ankle dorsiflexors, and neck flexors showed significantly early weakness. Extensor muscle groups were weaker than flexor muscles at the elbow and knee. The mean manual muscle test (MMT) strength grade for all muscle groups combined was 3.7 +/- 0.8 MMT units. There was a slowly progressive decline in strength, only -0.31 MMT units per decade, and the decline was relatively equal in all muscle groups. There was not side dominance. Severe contractures did not appear to be a problem until after transition to a wheelchair, and scoliosis was rare. Restrictive lung disease occurred as a late complication in a small percentage of cases; however, maximal expiratory pressure was significantly reduced early in the disease. Only two individuals (19%) had severe restrictive lung disease and a history of significant respiratory complications. There was a slight but significant decline in forced vital capacity and maximal expiratory pressure with age and disease duration. The cardiomyopathy in BMD appeared to be disproportionately severe in some cases. Eleven individuals (73%) had abnormal electrocardiograms, and five (25%) had a history of significant cardiovascular complication, with no age or disease duration effect. Functional evaluations and timed motor performance tests showed only mild disability in most individuals. Mean intellectual and neuropsychologic function was within normal limits, but with a large variability in intelligence quotient scores. This report and others suggest a tremendous heterogeneity of severity among males with BMD.
EFFECT OF ETHANOL VAPOR ON GROWTH AND TOXIN PRODUCTION BY CLOSTRIDIUM BOTULINUM IN A HIGH MOISTURE BAKERY PRODUCT (2000)

ABSTRACT To determine the effect of ethanol vapor on toxin production by Clostridium botulinum, studies were done in English style crumpets (a w 0.990, pH 6.5) challenged with 500 spores/g C. botulinum types A and proteolytic B and packaged in high gas barrier bags [ethanol transmission rate (ETR) 0.21 g/m 2 /day @ 25 C]. Crumpets were packaged in air with either commercially available ethanol vapor generators (Ethicap® 2, 4 or 6G) or cotton wool pads saturated with 2, 4 or 6 g of 95% food grade ethanol and stored at 25C. Toxin was detected in all inoculated control crumpets (0% ethanol) after 5 days at ambient temperature (25C). Ethicap® 2G delayed toxicity for 10 days while complete inhibition (&gt;21 days) was observed in all crumpets packaged with 4 or 6G Ethicap® or with 2, 4 or 6 g of ethanol per pad. However, all crumpets were overtly spoiled by this time. Both headspace ethanol and absorption of ethanol by crumpets increased as a function of Ethicap® size/weight of ethanol. Based on these preliminary studies, ethanol vapor would appear to be an effective additional barrier to control the growth and toxin production by C. botulinum in high moisture bakery products and ensure the safety of these products at ambient temperature.
Epidermal growth factor receptor monoclonal antibodies inhibit the growth of lung cancer cell lines. (1992)

The ability of monoclonal antibody (MAb 108), an immunoglobulin G (IgG)2a against the epidermal growth factor receptor (EGF-R), to interact with lung cancer cell lines was investigated. 125I-EGF bound with high affinity to non-small-cell lung cancer (NSCLC) cells, and MAb 108 inhibited specific binding of nine NSCLC cell lines in a dose-dependent manner (IC50 = 0.3-3 micrograms per ml). 125I-MAb 108 bound with high affinity (kd = 2 nM) to a single class of sites (Bmax = 70,000 per cell) using NSCLC neuroendocrine cell line NCI-H460. Specific 125I-MAb 108 binding was inhibited with high affinity by MAb 108 but not by a control antibody IgG using large-cell carcinoma cell line NCI-H1299. 125I-MAb 108 binding was not internalized at 37 degrees C using NSCLC neuroendocrine cell line NCI-H460 and adenocarcinoma cell line NCI-H23. Also, 1 microgram per ml of MAb 108 but not of a control IgG inhibited the clonal growth of NCI-H23 and squamous cell carcinoma cell line NCI-H157 in vitro. Also, MAb 108 inhibited xenograft formation of cell lines NCI-H460, NCI-H157, and NCI-H727 in nude mice in vivo. After a palpable tumor had formed using NCI-H460 cells, injection of 100 micrograms of MAb 108 (intraperitoneally three times weekly) inhibited xenograft volume in nude mice by approximately 50%. These data suggest that MAb 108 may interact with EGF receptors on lung cancer cell lines and inhibit NSCLC proliferation.