gebhart/patrepeval huggingface dataset:
Systematic review of the clinical effectiveness of neuromodulation in the treatment of faecal incontinence (2013)

Emerging data for SNS suggest maintenance of its initial therapeutic effect into the long term. The clinical effectiveness of PTNS is comparable to that of SNS at 12 months, although there is no evidence to support its continued effectiveness after this period. PTNS may be a useful treatment before SNS. The clinical effectiveness of TTNS is still uncertain owing to the paucity of available evidence. A consensus to standardize the use of outcome measures is recommended in order that further reports can be compared meaningfully.
The cyclosporin‐erythromycin interaction: impaired first pass metabolism in the pig (1991)

1. The pharmacokinetic interaction between cyclosporin (CsA) and erythromycin has been studied in the weanling pig model. 2. Blood CsA and metabolite-1 (M1) concentrations were monitored by high performance liquid chromatography in portal, hepatic and jugular venus blood before and after treatment with erythromycin stearate for 7 days. 3. Erythromycin significantly increased maximum concentration (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC) of CsA in the peripheral circulation. This was accompanied by a significant reduction in the hepatic extraction ratio calculated from portal and hepatic Cmax and AUC data. 4. The extraction ratio appears to be concentration-dependent in that values derived from Cmax (high concentrations) were greater than those from AUC (average concentrations). 5. Time to Cmax (tmax) and t1/2 of CsA were essentially unchanged and no significant changes were observed in peripheral M1 kinetics apart from a small increase in tmax. 6. The pharmacokinetic changes observed in the pig suggest that the CsA-erythromycin interaction is caused by inhibition of hepatic metabolism and the impact of inhibition is greatest during first-pass when CsA concentrations are at their highest.
Steroid Receptor Coactivator-1 Upregulates Integrin α5 Expression to Promote Breast Cancer Cell Adhesion and Migration (2011)

Metastatic breast cancer remains a lethal disease with poorly understood molecular mechanisms. Steroid receptor coactivator-1 (SRC-1 or NCOA1) is overexpressed in a subset of breast cancers with poor prognosis. It potentiates gene expression by serving as a coactivator for nuclear receptors and other transcription factors. We previously reported that SRC-1 promotes breast cancer metastasis without affecting primary mammary tumor formation. Herein, we found that SRC-1 deficiency in mouse and human breast cancer cells substantially reduced cell adhesion and migration capabilities on fibronectin and significantly extended the time of focal adhesion disassembly and reassembly. In agreement with this phenotype, SRC-1 expression positively correlated with integrin α(5) (ITGA5) expression in estrogen receptor-negative breast tumors whereas SRC-1 deficiency decreased ITGA5 expression. Furthermore, ITGA5 reduction in SRC-1-deficient/insufficient breast cancer cells or knockdown of ITGA5 in SRC-1-expressing breast cancer cells was associated with a disturbed integrin-mediated signaling. Critical downstream changes included reduced phosphorylation and/or dampened activation of focal adhesion kinase, paxillin, Rac1, and Erk1/2 during cell adhesion. Finally, we found that SRC-1 enhanced ITGA5 promoter activity through an AP-1 (activator protein)-binding site proximal to the transcriptional initiation site; both SRC-1 and c-Jun were recruited to this promoter region in breast cancer cells. These results show that SRC-1 can promote breast cancer metastasis by directly enhancing ITGA5 expression and thus promoting ITGA5-mediated cell adhesion and migration. Therefore, targeting ITGA5 in SRC-1-positive breast cancers may result in inhibition of SRC-1-promoted breast cancer metastasis.
The endogenous Toll–like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer (2009)

The innate immune system is crucial for initiation and amplification of inflammatory responses. During this process, phagocytes are activated by PAMPs that are recognized by PRRs. Phagocytes are also activated by endogenous danger signals called alarmins or DAMPs via partly specific, partly common PRRs. Two members of the S100 protein family, S100A8 and S100A9, have been identified recently as important endogenous DAMPs. The complex of S100A8 and S100A9 (also called calprotectin) is actively secreted during the stress response of phagocytes. The association of inflammation and S100A8/S100A9 was discovered more than 20 years ago, but only now are the molecular mechanisms involved in danger signaling by extracellular S100A8/S100A9 beginning to emerge. Taking advantage of mice lacking the functional S100A8/S100A9 complex, these molecules have been identified as endogenous activators of TLR4 and have been shown to promote lethal, endotoxin-induced shock. Importantly, S100A8/S100A9 is not only involved in promoting the inflammatory response in infections but was also identified as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. This proinflammatory action of S100A8/S100A9 involves autocrine and paracrine mechanisms in phagocytes, endothelium, and other cells. As a net result, extravasation of leukocytes into inflamed tissues and their subsequent activation are increased. Thus, S100A8/S100A9 plays a pivotal role during amplification of inflammation and represents a promising new therapeutic target.
Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family (2004)

Although several genes have been implicated in the development of the early-onset autosomal dominant form of Alzheimer's disease (AD), the genetics of late-onset AD (LOAD) is complex. Loci on several chromosomes have been linked to the disease, but so far only the apolipoprotein E gene has been consistently shown to be a risk factor. We have performed a large-scale single-nucleotide polymorphism (SNP)-based association study, across the region of linkage on chromosome 12, in multiple case-control series totaling 1,089 LOAD patients and 1,196 control subjects and report association with SNPs in the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene. Subsequent analysis of GAPD paralogs on other chromosomes demonstrated association with two other paralogs. A significant association between LOAD and a compound genotype of the three GAPD genes was observed in all three sample sets. Individually, these SNPs make differential contributions to disease risk in each of the casecontrol series, suggesting that variants in functionally similar genes may account for series-to-series heterogeneity of disease risk. Our observations raise the possibility that GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis.
Specific CD8+ T‐lymphocytes control dissemination of measles virus (2009)

Measles continues to be an important cause of childhood mortality in developing countries. Measles virus (MV) is lymphotropic and infects high percentages of B- and T-lymphocytes in lymphoid tissues. Cellular immunity is considered crucial for viral clearance; however, MV-specific T-lymphocytes generated during primary infection also constitute a potential target for MV infection. We therefore aimed to identify T-lymphocyte subsets that can clear MV infection without becoming infected. To this end, we infected human EBV transformed B-lymphoblastic cell lines (B-LCL) with a recombinant MV strain expressing enhanced GFP, and co-cultured these with non-infected B-LCL resulting in rapid viral spread. MV-specific CD8(+) T-cell clones efficiently suppressed MV dissemination in autologous and HLA-matched, but not in HLA-mismatched B-LCL. In contrast, CD4(+) T-cell clones could not control MV dissemination but became a target for MV infection themselves. Furthermore, PBMC collected 6-9 months after acute measles and stimulated with autologous MV-infected B-LCL also efficiently suppressed MV dissemination; this was mediated by the fraction containing CD8(+) T-lymphocytes. In conclusion, we have developed a powerful tool to study cellular immunity against measles, and demonstrate that control of MV dissemination is mediated by virus-specific CD8(+) rather than by CD4(+) T-lymphocytes.
State-of-the-art of battery state-of-charge determination (2005)

From the early days of its discovery, humanity has depended on electricity, a phenomenon without which our technological advancements would not have been possible. With the increased need for mobility, people moved to portable power storage—first for wheeled applications, then for portable and finally nowadays wearable use. Several types of rechargeable battery systems, including those of lead–acid, nickel–cadmium, nickel–metal hydride, lithium ion and lithium-ion polymer exist in the market. The most important of them will be discussed in this review. Almost as long as rechargeable batteries have existed, systems able to give an indication about the state-of-charge (SoC) of a battery have been around. Several methods, including those of direct measurements, book-keeping and adaptive systems (Bergveld et al 2002 Battery Management Systems, Design by Modelling (Philips Research Book Series) vol 1 (Boston: Kluwer)) are known in the art for determining the SoC of a cell or battery of cells. An accurate SoC determination method and an understandable and reliable SoC display to the user will improve the performance and reliability, and will ultimately lengthen the lifetime of the battery. However, many examples of poor accuracy and reliability can be found in practice (Bergveld et al 2002, cited above). This review presents an overview on battery technology and the state-of-the-art of SoC methods. The goal of all the presented SoC indication methods is to design an SoC indication system capable of providing an accurate SoC indication under all realistic user conditions, including those of spread—in both battery and user behaviour, a large temperature and current range and ageing of the battery.
In Vivo Administration of CD4-Specific Monoclonal Antibody: Effect on Provirus Load in Rhesus Monkeys Chronically Infected with the Simian Immunodeficiency Virus of Macaques (1995)

Since monoclonal antibodies (MAb) specific for CD4 are potent inhibitors of HIV and SIV replication in vitro, we explored their potential usefulness in vivo as an AIDS therapy. The anti-CD4 MAb 5A8 binds to domain 2 of the CD4 molecule and inhibits virus replication and virus-induced cell fusion at a postvirus binding step. Administration of this MAb to normal rhesus monkeys coats all circulating and lymph node CD4 cells and induces neither CD4 cell clearance nor measurable immunosuppression. In the present study, monkeys chronically infected with the simian immunodeficiency virus of macaques (SIVmac) had stable levels of SIVmac provirus in PBMC prior to treatment as measured by a quantitative polymerase chain reaction technique. Six infected monkeys treated with anti-CD4 MAb demonstrated a significant decrease in SIVmac provirus level after 9 days. Of these monkeys, 3 had > 800 CD4 cells/microliter and developed strong antimouse Ig responses that prevented further treatment. The remaining 3 monkeys had < 800 CD4 cell/microliter and failed to develop antimouse Ig antibody responses. When treatment was continued for 12-21 days in these monkeys, a sustained or further decrease in SIVmac provirus load occurred over the extended treatment period. Four monkeys that received a control MAb of irrelevant specificity for 9-22 days showed either no significant change or a transient increase in SIVmac provirus. Thus, the passive administration of anti-CD4 MAb may exert a specific antiviral effect in controlling immunodeficiency virus infection in vivo.
Spore-forming bacteria and their utilisation as probiotics (2012)

In this review article, the beneficial application of bacterial spore formers as probiotics in the food industry is discussed based on the knowledge gleaned from current publications. The summary of new scientific results provides evidence of the advantages of the utilisation of Bacillus or Clostridium strains in the food industry. Both bacteria are able to produce a very stable duration form: the endospore. Compared to the widely used lactic acid bacteria, bacterial spores offer the advantage of a higher survival rate during the acidic stomach passage and better stability during the processing and storage of the food product. In many food products, germination of the spores does not occur. Hence the product quality of the food is not affected because of their inactive metabolism. Besides the possible utilisation and functional properties, an overview of the fast-developing knowledge about the mechanisms of the beneficial health effects of spore-forming bacteria is provided.
Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models (2004)

Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar levels of EGFR expression, the antitumor activity of erlotinib is robust both as monotherapy and in combination with chemotherapies.
Analytical Methods for the Assessment of Protein Formulations and Delivery Systems (1994)

The characterization of a protein drug is a complex undertaking, requiring the use of a wide range of methods to establish the properties of the drug substance. The development of a formulation, and especially a novel delivery system, begins with the information and analytical methods from the characterization and initially extends that information by evaluating the ranges of storage conditions or processing operations under which the protein remains in its initial state in terms of the rates of degradation over these ranges. The complexity of protein molecules means that there are many potential degradation pathways, each with their individual dependences on such parameters as pH, ionic strength, temperature and so on. Further, each protein represents a unique combination of such pathways and dependences. It is therefore critical that a broad array of methods be used to evaluate the effects of processing or storage to assure optimal maintenance of the safety and efficacy of the drug. This chapter surveys the methods that are commonly used, in terms of their principles, utility and limitations in the study of protein degradation.
A CMOS Chopper Offset-Stabilized Opamp (2007)

In this paper, an offset-stabilized operational amplifier is described. The amplifier employs a chopper amplifier in a low frequency path to cancel the offset of a wide-bandwidth amplifier. A sample-and-hold circuit is used to reduce the chopper ripple, and the low frequency path is also offset-stabilized to further reduce the residual offset. The amplifier has less than 1.5 offset at a 16-kHz chopper frequency, a unity gain frequency of 1.3 MHz with a 50-pF load, and draws 700 from a 5-V supply. The amplifier was realized in a 0.7 CMOS process, and has an effective chip area of 3.6.
When Does 2 Plus 2 Equal 5? A Review of Antimicrobial Synergy Testing (2014)

In this age of emerging antibiotic resistance, limited therapeutic options exist for treating multidrug-resistant organisms. Combination therapy is commonly employed to manage these infections despite little laboratory guidance as to the efficacy of this approach. Synergy testing methods have been used to assess the interaction of antibiotic combinations in vitro. This review will discuss the four primary methods used to assess synergy, as well as the data that exist for testing of cystic fibrosis. In the final analysis, this review concludes that there is not enough evidence to endorse synergy testing for routine clinical use.
ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells (2003)

The involvement of P2Y receptors, which are activated by extracellular nucleotides, in proliferative regulation of human lung epithelial cells is unclear. Here we show that extracellular ATP and UTP stimulate bromodeoxyuridine (BrdU) incorporation into epithelial cell lines. The nucleotide efficacy profile [ATP = ADP > UDP >or= UTP > adenosine >or= 2-methylthioadenosine-5'-diphosphate, with alpha,beta-methylene adenosine 5'-triphosphate, 2',3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate, AMP, UMP, and ATPalphaS inactive] and PCR analysis indicate involvement of P2Y2 and P2Y6 receptors. The signal transduction pathway, which, via the P2Y2 receptor, transmits the proliferative activity of ATP or UTP in A549 cells downstream of phospholipase C, depends on Ca2+/calmodulin-dependent protein kinase II and nuclear factor-kappaB, but not on protein kinase C. Signaling does not involve the mitogen-activated protein kinases extracellular signal-regulated kinases-1 and -2, the phosphatidylinositol 3-kinase pathway, or Src kinases. Thus nucleotides regulate proliferation of human lung epithelial cells by a novel pathway. The stimulatory effect of UTP, but not ATP, in A549 cells is attenuated by preincubation with interleukin-1beta and interleukin-6, but not tumor necrosis factor-alpha. This indicates an important role for the pyrimidine-activated P2Y receptor in the inflammatory response of lung epithelia. ATP antagonizes the antiproliferative effect of the anticancer drugs paclitaxel and etoposide, whereas it enhances the activity of cisplatin about fourfold. Thus pathways activated by extracellular nucleotides differentially control proliferation of lung epithelial tumor cells.
Ig‐Therasorb Immunoadsorption for Selective Removal of Human Immunoglobulins in Diseases Associated with Pathogenic Antibodies of All Classes and IgG Subclasses, Immune Complexes, and Fragments of Immunoglobulins (1998)

Therasorb immunoadsorption (IA), by selectively eliminating pathogenic substances from the circulation, allows for successful therapy of previously insufficiently treatable diseases. Molecules (specific polyclonal sheep antibodies) coupled to a matrix (Sepharose CL 4B) selectively bind plasma components in extracorporeal circulation. This procedure has been established in the treatment of various diseases. Examples are familial hypercholesterolemia (LDL-Therasorb) and selected autoimmune diseases (Ig-Therasorb). Ig-Therasorb IA has been performed in a variety of clinical indications, primarily in the treatment of autoimmune diseases. In most cases, Ig-Therasorb IA has been applied in patients who have failed to respond to conventional therapy with a high rate of clinical improvement. In defined groups of patients with autoimmune diseases and alloantibodies, immunoadsorption can now be considered an established therapeutic means. The fast and efficient removal of immunoglobulins obviously exceeds the efficiency of conventional plasma exchange by far. Autoimmune diseases could be induced by balanced and nonbalanced immunity. The importance of autoantibodies remains unclear, but the efficacy of Ig-Therasorb IA suggests a key role for them. In addition to the established indications for removal of immunoglobulins, there may be a number of promising new indications.
Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts (2015)

Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
The5ESSSwitching System: Operational Software (1985)

The operational software of the 5ESS™ switching system has been designed to meet specific objectives for capacity, functionality, and reliability. It has also been designed to accommodate changing technology, changing system applications, and an ever-increasing feature application set. Structured programming techniques, high-level languages, and modular design techniques have been used to obtain these objectives. Specifically, the operational software architecture is organized as a set of functional software components utilizing the advantages of a generalized operating system and database manager to achieve a high degree of hardware independence. A primary cause for hardware churning is the introduction of new peripheral units in support of new feature applications. The peripheral control software shields the majority of the operational software from these changes. Standardized and locally well-defined interfaces to the operations support systems provide information to the customer for the administration and maintenance of the switching system.