gebhart/patrepeval huggingface dataset:
Psoriasis: the future (2001)

The aetiology of psoriasis is still unclear but our knowledge of the psoriatic process has grown substantially over the last two decades. The future will undoubtedly bring advances in our understanding of the pathogenesis of psoriasis and, as a consequence, new therapies. Defining the molecular genetics of psoriasis will enhance our understanding of the disease process and hopefully facilitate the development of a representative animal model. This in itself will be a key step in the development and testing of new therapies. Precise identification of the immunological events involved in psoriasis will allow specific T-cell- and cytokine-targeted, and perhaps less toxic. immunotherapies. Anti-angiogenic agents that are in development for use in oncology may also be effective in psoriasis. The adaptation of current topical therapies such as retinoids and vitamin D analogues to produce more effective and better-tolerated formulations will also play a significant role in our future first-line management of patients. The increased recognition and better management of environmental trigger factors such as psychological distress will become an important factor in future psoriasis care. The development of physical therapies including photodynamic therapy and excimer lasers has the potential to expand the remit of psoriasis therapy. There is little doubt that the future for our patients with psoriasis is bright. However, this will only be achievable by a concerted research effort to understand all facets of this enigmatic disease ranging from the molecular to the environmental.
Inducible production of interleukin-6 by human polymorphonuclear neutrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha (1990)

The recent demonstration of the ability of human polymorphonuclear neutrophils (PMN) to secrete various cytokines in response to the granulocyte activator granulocyte-macrophage colony-stimulating factor (GM-CSF) but not to other cytokines, has led to the identification of PMN as biosynthetically active cells. In this study we have investigated the ability of PMN to secrete interleukin-6 (IL-6), a molecule known to be involved in inflammatory reactions. Using RNA blotting analysis and bioassays, we show that PMN could be induced to synthesize transcripts specific for IL-6, indistinguishable in size from IL-6 mRNA produced by activated human macrophages. Consequently, PMN released IL-6-like activity into their culture supernatants that could be neutralized by monospecific anti-IL-6 antibody. Interleukin-6 secretion by PMN, however, required previous stimulation with GM-CSF or tumor necrosis factor-alpha (TNF-alpha), whereas other cytokines, including interleukin-3 (IL-3), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), interferon gamma (IFN-gamma), and lymphotoxin (LT), failed to induce IL-6 mRNA accumulation and protein secretion by PMN. Similar to GM-CSF and TNF-alpha, other compounds, including the inhibitor of protein synthesis cyclohexemide (CHX), endotoxin (Escherichia coli- derived lipopolysaccharide), and phorbol myristate acetate (PMA) (but not the chemoattractant N-formyl-methionyl-leucyl-phenylalanine [FMLP]), induced detectable levels of IL-6 transcripts in PMN.
A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition (2010)

We have studied a family with severe mental retardation characterized by the virtual absence of speech, autism spectrum disorder, epilepsy, late-onset ataxia, weakness and dystonia. Post-mortem examination of two males revealed widespread neuronal loss, with the most striking finding being neuronal and glial tau deposition in a pattern reminiscent of corticobasal degeneration. Electron microscopic examination of isolated tau filaments demonstrated paired helical filaments and ribbon-like structures. Biochemical studies of tau demonstrated a preponderance of 4R tau isoforms. The phenotype was linked to Xq26.3, and further analysis identified an in-frame 9 base pair deletion in the solute carrier family 9, isoform A6 (SLC9A6 gene), which encodes sodium/hydrogen exchanger-6 localized to endosomal vesicles. Sodium/hydrogen exchanger-6 is thought to participate in the targeting of intracellular vesicles and may be involved in recycling synaptic vesicles. The striking tau deposition in our subjects reveals a probable interaction between sodium/proton exchangers and cytoskeletal elements involved in vesicular transport, and raises the possibility that abnormalities of vesicular targeting may play an important role in more common disorders such as Alzheimer's disease and autism spectrum disorders.
Life table analysis of 879 treatment episodes with slow acting antirheumatic drugs in community rheumatology practice. (1992)

In 596 patients with RA managed over a decade in a community practice setting, 879 slow acting antirheumatic drug (SAARD) treatment episodes were analyzed using 5-year life tables. The probability of continuation of therapy was 50% by 9-24 months for all drugs except for methotrexate (MTX), which was 62% by 5 years [corrected]. MTX treatments were of significantly longer duration than those of all other SAARD (p less than 0.001); terminations for both inefficacy (p less than 0.001) and toxicity (NS) were less likely. These findings concur with recent evidence suggesting that MTX is a superior SAARD in this setting.
Phosphatase-Mediated Intracellular Signaling Contributes to Neuroprotection by Flavonoids ofIris tenuifolia (2014)

A variety of flavonoids are suggested to be useful for the treatment of brain-related disorders, including dementia and depression. An investigation on the characteristics of the extracted compounds of Iris tenuifolia Pall. (IT) is of much interest, as this plant has been used as a traditional medicine. In the present study, we examined the effect of total flavonoids obtained from IT on cultured cortical neurons under oxidative-stress and found that pretreatment with IT flavonoids significantly inhibited H 2 O 2-induced cell death in cortical neurons. Such a survival-promoting effect by IT flavonoids was partially blocked by inhibitors for extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase/Akt (PI3K/Akt) cascades, both of which are known as survival-promoting signaling molecules. Furthermore, the phosphorylation of Src homology-2 (SH2) domain-containing phosphatase2 (Shp2) was induced by IT flavonoids, and the protective effect of IT flavonoids was abolished by NSC87877, an inhibitor for Shp2, suggesting the involvement of Shp2-mediated intracellular signaling in flavonoid-dependent neuroprotection.
Spreading of the immune response from 52 kDaRo and 60 kDaRo to calreticulin in experimental autoimmunity (1998)

Calreticulin (CR) is widely recognized as a new human autoantigen but there are conflicting data concerning its relationship with the Ro(SS-A) ribonucleoprotein (RNP). Recent evidence suggests that CR binds to 52 kDaRo (Ro52) by a protein/protein interaction and binds to hY RNA and rubella virus RNA. Other studies have shown that initiation of immunity to either Ro52 or 60 kDaRo (Ro60) can lead to reciprocal spreading of autoimmunity to Ro60 or Ro52, respectively, and induce anti-La autoantibodies in some strains of mice. These findings support a physical association of these polypeptides in Ro/La complexes. To test the hypothesis that CR is physically associated with Ro52 and/or Ro60 we examined the sera of Ro52-, Ro60- and La-immunized mice for intermolecular spreading to CR. Immune sera from BALB/c and C3H/HeJ mice immunized with recombinant 6xHis-mouse Ro52, 6xHis-human Ro60 or 6xHis-human La were tested for reactivity by ELISA and immunoblotting with a full-length human CR protein expressed as a soluble maltose binding protein fusion protein (CR-MBP). Five of the six Ro52-immunized C3H/HeJ mice sera and all six Ro60-immunized C3H/HeJ mice sera reacted with the CR-MBP (but not a MBP control) on ELISA. In the BALB/c group, the responder rate was lower with one in six of the Ro52-immunized and one in five of the Ro60-immunized mice spreading to CR. In contrast, none of the BALB/c or C3H/HeJ mice which was immunized with La showed evidence of a recruited anti-CR antibody response. Immunoblotting of the different recombinant proteins with immune sera from the C3H/HeJ mice confirmed the specificity of the initial and recruited antibody responses. The spreading of immunity from Ro52 and Ro60 to CR in Ro-immunized mice suggests that a subpopulation of CR or CR-like molecules must associate under certain circumstances with Ro52 and Ro60 polypeptides in vivo, possibly as Ro/CR complexes concentrated in surface membrane blebs of apoptotic cells. The lack of spreading to CR in La-immunized mice suggests that CR may be associated with a subpopulation of Ro particles from which La has already dissociated.
Proximity-based access control for implantable medical devices (2009)

We propose a proximity-based access control scheme for implantable medical devices (IMDs). Our scheme is based on ultrasonic distance-bounding and enables an implanted medical device to grant access to its resources only to those devices that are in its close proximity. We demonstrate the feasibility of our approach through tests in an emulated patient environment. We show that, although implanted, IMDs can successfully verify the proximity of other devices with high accuracy. We propose a set of protocols that support our scheme, analyze their security in detail and discuss possible extensions. We make new observations about the security of implementations of ultrasonic distance-bounding protocols. Finally, we discuss the integration of our scheme with existing IMD devices and with their existing security measures.
Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2 (2000)

Mast cells play a potentially important role in fibroproliferative diseases, releasing mediators including tryptase that are capable of stimulating fibroblast proliferation and procollagen synthesis. The mechanism by which tryptase stimulates fibroblast proliferation is unclear, although recent studies suggest it can activate protease-activated receptor (PAR)-2. We therefore investigated the role of PAR-2 in tryptase-induced proliferation of human fetal lung and adult lung parenchymal and airway fibroblasts and, for comparative purposes, adult dermal fibroblasts. Tryptase (0.7-70 mU/ml) induced concentration-dependent increases in proliferation of all fibroblasts studied. Antipain, bis(5-amidino-2-benzimidazolyl)methane, and benzamidine inhibited tryptase-induced fibroblast proliferation, demonstrating that proteolytic activity is required for the proliferative effects of tryptase. RT-PCR demonstrated the presence of PAR-2 mRNA, and immunohistochemical staining localized PAR-2 to the cell surface of lung fibroblasts. In addition, specific PAR-2 activating peptides, SLIGKV and SLIGRL, mimicked the proliferative effects of tryptase. In contrast, human dermal fibroblasts only weakly stained with the PAR-2 antibody, PAR-2 mRNA was almost undetectable, and fibroblasts did not respond to PAR-2 activating peptides. These results suggest that tryptase induces lung, but not dermal, fibroblast proliferation via activation of PAR-2 and are consistent with the hypothesis that the release of tryptase from activated mast cells may play an important role in the fibroproliferative response observed in asthma, chronic obstructive pulmonary disease, and patients with pulmonary fibrosis.
Hedgehog pathway as a drug target: Smoothened inhibitors in development (2012)

Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian), the transmembrane receptor Patched, the signal transducer Smoothened (Smo), and transcription factors Gli1-3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells) have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain for appropriate patient selection and the optimal combination and sequence of these targeted therapies into current treatment paradigms.
Cultured human trabecular meshwork cells express functional alpha 2A adrenergic receptors. (1996)

Functional alpha 2A-ARs are present on HTM cells where they may affect the outflow pathway during the treatment of glaucoma with alpha 2-AR agonists.
Increase in number of circulating disseminated epithelial cells after surgery for non-small cell lung cancer monitored by MAINTRAC® is a predictor for relapse: A preliminary report (2005)

BACKGROUND: Lung cancer still remains one of the most commonly occurring solid tumors and even in stage Ia, surgery fails in 30% of patients who develop distant metastases. It is hypothesized that these must have developed from occult circulating tumor cells present at the time of surgery, or before. The aim of the present study was to detect such cells in the peripheral blood and to monitor these cells following surgery. METHODS: 30 patients treated for lung cancer with surgery were monitored for circulating epithelial cells (CEC) by taking peripheral blood samples before, 2 weeks and 5 months after surgery and/or radiotherapy (RT) chemotherapy (CT) or combined RT/CT using magnetic bead enrichment and laser scanning cytometry (MAINTRAC(R)) for quantification of these cells. RESULTS: In 86% of the patients CEC were detected before surgery and in 100% at 2 weeks and 5 months after surgery. In the control group, which consisted of 100 normal donors without cancer, 97 % were negative for CEC. A significantly higher number of CEC was found preoperatively in patients with squamous cell carcinoma than in those with adenocarcinoma. In correlation to the extent of parenchymal manipulation 2 weeks after surgery, an increase in numbers of CEC was observed with limited resections (18/21) whereas pneumonectomy led to a decrease (5/8) of CEC, 2 weeks after surgery. The third analysis done 5 months after surgery identified 3 groups of patients. In the group of 5 patients who received neo- or adjuvant chemo/radiotherapy there was evidence that monitoring of CEC can evaluate the effects of therapy. Another group of 7 patients who underwent surgery only showed a decrease of CEC and no signs of relapse. A third group of 11 patients who had surgery only, showed an increase of CEC (4 with an initial decrease after surgery and 7 with continuous increase). In the group with a continuous increase during the following 24 months, 2 early relapses in patients with stage Ia adenocarcinoma were observed. The increase of CEC preceded clinical detection by six months. CONCLUSION: We consider, therefore, that patients with adenocarcinoma and a continuous increase of CEC after complete resection for lung cancer are at an increased risk of early relapse.
RHAMNOLIPIDS PRODUCED BY PSEUDOMONAS AERUGINOSA GROWN ON n-PARAFFIN (MIXTURE OF C12, C13 AND C14 FRACTIONS) (1971)

Two kinds of glycolipids (R-l and R-2) were produced in the culture media by several strains of Pseudomonas aeruginosa when grown on n paraffin (mixture of C12, C13. and C14 fractions). These compounds were isolated through the extraction of the culture broth with ethylacetate and the chromatography on silicic acid column. On the basis of chemical analysis, these lipids were characterized as 2-O-α-L-rhamnopyranosyl-α-L-rhamnopyranosyl-β- hydroxydecanoyl-β-hydroxydecanoate (R-l) and L-α-rhamnopyranosyl-β- hydroxydecanoyl-β-hydroxydecanoate (R-2). Bactericidal activity of R-2 which is postulated to be a precursor of R-1 was remarked against grampositive bacteria. Further, these compounds also demonstrated mycoplasmacidal and antiviral activities in vitro.
Increased β-Carotene Production in Recombinant Escherichia coli Harboring an Engineered Isoprenoid Precursor Pathway with Mevalonate Addition (2007)

When pT-LYCm4 containing lycopene synthetic genes was co-transformed with pSUcrtY or pSHcrtY containing crtY gene of Pantoea ananatis (P. ananatis) or Pantoea agglomerans (P. agglomerans), beta-carotene productions of 36 and 35 mg/L were obtained, respectively. No lycopene was detected in the beta-carotene production culture. pT-HB, constructed by addition of P. ananatis crtY gene into pT-LYCm4, was used for co-transformation with pSdxs and pSSN12Didi, which increased isopentenyl diphosphate and dimethylallyl diphosphate synthesis. beta-Carotene production significantly increased 1.5-fold (51 mg/L) with the amplification of the dxs gene through pSdxs and 4-fold (135 mg/L) with the mevalonate bottom pathway of pSSN12Didi in the presence of 3.3 mM mevalonate. The pT-DHB, constructed by integrating the dxs gene into pT-HB, was used for cotransformation of Escherichia coli (E. coli) harboring pSSN12Didi, resulting in beta-carotene production of 141 mg/L. Recombinant E. coli harboring pT-DHB and pSSN12Didi was used to maximize beta-carotene production by adjusting the available amounts of glycerol, a carbon source, and mevalonate, the precursor of the mevalonate bottom pathway. When recombinant E. coli was given 16.5 mM mevalonate and 2.5% (w/v) glycerol, beta-carotene production of 503 mg/L in concentration and 49.3 mg/g DCW in content was obtained at 144 h, which was the highest level of carotenoid production in E. coli ever reported in the literature.
Expanded adipose-derived stem cells for the treatment of complex perianal fistula including Crohn's disease (2008)

A Phase IIb study comparing ASC and fibrin glue therapy with fibrin glue therapy alone showed that ASCs were effective at inducing healing in complex perianal fistulas.
Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: electrophysiologic and anatomic correlation. (1988)

In this report we describe electrophysiologic and histologic findings in hearts and endocardially resected preparations from patients with sustained ventricular tachycardias in the chronic phase of myocardial infarction. We recorded simultaneously from 64 endocardial sites during tachycardia in 72 patients that were operated on for medically intractable ventricular tachycardias. Two other patients underwent heart transplantation, and mapping was performed on the explanted isolated heart connected to a Langendorff perfusion set-up. During operation 139 tachycardias with different morphologies could be induced. Although the majority of evidence supports the concept of a reentrant mechanism for these tachycardias, we found that 105 tachycardias appeared to arise at a focal area of less than 1.4 cm2. In only three cases macroreentry around the infarction scar could be detected. Of 21 tachycardias in which the "origin" appeared to be focal, earliest subendocardial activation was preceded by discrete electrograms of low amplitude (presystolic activity). In three tachycardias presystolic activity was detected at several sites, permitting reconstruction of its route. Histology of the endocardial resected preparation in one of these cases revealed separate zones of viable myocardial fibers in areas in which presystolic activity was recorded. These zones were located intramurally and subendocardially, supporting the concept that reentry occurred via isolated bundles of surviving myocytes at the border of the infarct and the larger subendocardial muscle mass. Conduction velocity through the isolated tracts was on the order of 25 cm/sec. Similar reentrant pathways were found in the two isolated hearts. Extracellular and intracellular recordings were made from 20 endocardial preparations that were excised from areas in which tachycardia originated. Preparations were superfused in a tissue bath. These experiments showed that action potentials were usually close to normal, but occasionally action potentials with reduced amplitude and slow upstrokes were found. In addition, there were cells that exhibited both fast and slow upstrokes, depending on the direction of the wavefront. Histology of seven resected preparations and the isolated hearts showed subendocardially as well as intramurally located zones of viable myocardium. Fractionation of extracellular electrograms and slow conduction were found in areas where surviving muscle fibers and strands of fibrous tissue were interwoven, and in zones where muscle fibers were oriented in parallel but isolated by strands of connective tissue.(ABSTRACT TRUNCATED AT 400 WORDS)
Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis (2008)

Although good evidence suggests that many agents are effective in preventing osteoporotic fractures, the data are insufficient to determine the relative efficacy or safety of these agents.
Local Complement-Targeted Intervention in Periodontitis: Proof-of-Concept Using a C5a Receptor (CD88) Antagonist (2012)

When excessively activated or deregulated, complement becomes a major link between infection and inflammatory pathology including periodontitis. This oral inflammatory disease is associated with a dysbiotic microbiota, leads to the destruction of bone and other tooth-supporting structures, and exerts an adverse impact on systemic health. We have previously shown that mice deficient either in complement C5a receptor (C5aR; CD88) or TLR2 are highly and similarly resistant to periodontitis, suggesting that a cross-talk between the two receptors may be involved in the disease process. In this paper, we show that C5aR and TLR2 indeed synergize for maximal inflammatory responses in the periodontal tissue and uncover a novel pharmacological target to abrogate periodontitis. Using two different mouse models of periodontitis, we show that local treatments with a C5aR antagonist inhibited periodontal inflammation through downregulation of TNF, IL-1β, IL-6, and IL-17 and further protected against bone loss, regardless of the presence of TLR2. These findings not only reveal a crucial cooperation between C5aR and TLR2 in periodontal inflammation but also provide proof-of-concept for local targeting of C5aR as a powerful candidate for the treatment of human periodontitis.