gebhart/patrepeval huggingface dataset:
Lead compounds for the development of SARS-CoV-2 3CL protease inhibitors (2021)

We report the identification of three structurally diverse compounds - compound 4, GC376, and MAC-5576 - as inhibitors of the SARS-CoV-2 3CL protease. Structures of each of these compounds in complex with the protease revealed strategies for further development, as well as general principles for designing SARS-CoV-2 3CL protease inhibitors. These compounds may therefore serve as leads for the basis of building effective SARS-CoV-2 3CL protease inhibitors.
Heart-Specific Targeting of β -Galactosidase by the Ventricle-Specific Cardiac Myosin Light Chain 2 Promoter Using Adenovirus Vectors (1998)

Adenoviruses are attractive vectors for gene transfer into cardiac muscle. However, their promiscuous tissue tropism, which leads to an ectopic expression of the transgene, is a considerable limitation. To restrict expression to cardiomyocytes, we have constructed two recombinant adenoviruses (Ad-MLC2-250betagal and Ad-MLC2-2100betagal) containing the beta-galactosidase reporter gene under the control of the 250- or 2100-bp rat ventricle-specific cardiac myosin light chain-2v promoter (MLC-2v). Our in vitro and in vivo data have evidenced that the 2100-bp promoter allows stronger beta-galactosidase activity than the 250-bp promoter and that the deleted promoter allows a weak beta-galactosidase expression in skeletal muscle-derived cells in vitro. In contrast to the in vitro results, the highly deleted MLC-2v promoter of 250 pb conserved its heart specificity in in ovo and in vivo when introduced into the adenovirus genome, indicating that the specificity of this promoter is neither altered by the inverted terminal repeat nor by the enhancer of the Ela promoter, both of which located in the 5' flanking region of the promoter. Systemic injections of both recombinant adenoviruses into chicken embryos showed beta-galactosidase expression mainly in the right ventricle of the heart. We have confirmed the cardiac specificity of both promoters in mammalian species after injection of both recombinant adenoviruses into the heart of adult rats in vivo. The comparison of both promoters in vitro and in vivo has shown that the 250-bp MLC-2v promoter is 80% less active than the 2100-bp MLC-2v promoter and has enabled us to conclude that the MLC-2v promoter of 2100 bp is the most appropriate for efficient expression of a reporter gene or a therapeutic cardiac gene (e.g., SERCA2a or minidystrophin gene).
Migration of gonocytes into the mammalian gonad and their differentiation (1970)

Abstract The migration of the germ cells into the mammalian gonad and their subsequent differentiation has been the subject of many investigations and controversies. However, sufficient facts have accumulated which led Witschi (1962) to state that ‘the formerly controversial subject of the origin and unbroken continuity of the germ cell lines can now be considered settled’. Histo-chemical techniques for alkaline phosphatase have made it possible to selectively stain and identify primordial germ cells (McKay, Hertig, Adams &amp; Danziger 1953; Chiquoine 1954; Mintz 1959). The path and development of the germ cells has been described in detail in histological investigation (for review see Brambell 1956; Mintz 1960; Franchi, Mandl &amp; Zuckerman 1962) and recently labelling techniques have made the continuity of the germ cell line ‘visible’ (Rudkin &amp; Griech 1962; Peters, Levy &amp; Crone 1962; Kennelly &amp; Foote 1966; Borum 1966; Peters &amp; Crone 1967).
Changes in PSA kinetics predict metastasis‐free survival in men with PSA‐recurrent prostate cancer treated with nonhormonal agents (2011)

This hypothesis generating analysis suggests that within-subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with MFS in men with biochemically recurrent prostate cancer. If validated in prospective trials, changes in PSA kinetics may represent a reasonable intermediate end point for screening new agents in these patients.
Fibromyalgia and psychiatric disorders. (2007)

Fibromyalgia (FM) is a common and polymorphic syndrome, characterized by long-lasting, widespread musculoskeletal pain, in the presence of 11 or more tender points located at specific anatomical sites. A heterogeneous series of disturbances, mainly involving autonomic, neuroendocrine and neuropsychic systems, is usually present. Even if subjective, the chronic psychophysical suffering state of FM adversely affects the patient's quality of life, performance and mood. Cognitive behavioural therapy and antidepressant drugs are useful in FM treatment, suggesting a close link between the syndrome and psychiatric, psychological and behavioural factors. Our aim was to evaluate the personality profiles of FM patients, as well as the aggregation and relationships between FM and psychiatric disorders (PD), reviewing the available evidences in current literature on this comorbidity. Personality variables associated with psychological vulnerability are frequent in FM patients. Personality disorders are rarely reported. Compared with controls, FM patients show a significantly higher prevalence of depressive and anxiety disorders, reported in 20-80% and 13-63.8% of cases, respectively. This high variability may depend on the psychosocial characteristics of patients, since most of the studies were performed on tertiary care consulting patients, however, even referring to the lower percentages, the occurrence of PD is significantly higher in FM subjects compared to the general population (7%). Moreover, elevated frequencies of PD have been detected in relatives of FM patients. The FM/PD aggregation suggests a common physiopathology, and alterations of neurotransmitter systems may constitute the shared underlying factor.
POPULATION VARIABILITY IN THE PHARMACOKINETICS OF TERFENADINE: THE CASE FOR A PSEUDO-POLYMORPHISM WITH CLINICAL IMPLICATIONS (1994)

Terfenadine is nearly completely first pass biotransformed. Unmetabolized terfenadine plasma concentrations have been associated with altered cardiac repolarization. During previous drug interaction studies, 2 subjects were found to have quantifiable concentrations of unmetabolized terfenadine with accompanying electrocardiographic repolarization changes while on terfenadine alone. To determine whether these subjects were representative of the population, 150 healthy volunteers (109 males, 41 females, ages 19-49) were screened for their ability to metabolize terfenadine after achieving steady-state. Blood was obtained at known times of maximum terfenadine concentration after dosing. Eleven subjects had quantifiable concentrations of terfenadine demonstrating wide intersubject variability in terfenadine metabolism. Further studies to determine whether such subjects are more susceptible to untoward terfenadine-associated events are underway.
Multimarker Approach to Risk Stratification in Non-ST Elevation Acute Coronary Syndromes (2002)

Troponin, CRP, and BNP each provide unique prognostic information in patients with ACS. A simple multimarker strategy that categorizes patients based on the number of elevated biomarkers at presentation allows risk stratification over a broad range of short- and long-term major cardiac events.
Nonobvious Obstructive Meibomian Gland Dysfunction (2010)

This review presents the rationale and supporting data for a recent paradigm shift in our understanding of meibomian gland dysfunction (MGD). The historical understanding of MGD has been that of an infectious hypersecretory disorder with obvious signs of inflammation, hypersecretion, and purulent excreta. The current understanding of MGD now includes the polar concept of a less obvious or nonobvious type of hyposecretory obstructive MGD, where inflammation and other signs of pathology may be absent unless special examination techniques are employed. A new term, nonobvious obstructive MGD (NOMGD), is used to describe what may be the most common form of obstructive MGD. Obstructive MGD is an area of growing importance because obstructive MGD is now recognized to be the most common cause of evaporative dry eye, and because NOMGD seems to be the precursor to obvious obstructive MGD, it is also an important area to understand. The prevalence of NOMGD seems to be very high but currently significantly underdiagnosed. This review presents the relevant anatomy and physiology, concepts of obstructive MGD, the usual absence of inflammation in obstructive MGD, nomenclature and classification of obstructive and NOMGD, clinical diagnosis of NOMGD emphasizing the necessity for diagnostic expression, the use of a new instrument for diagnostic expression providing a standardized method of assessing meibomian gland functionality, the complementary roles of the aqueous and lipid layers, and the specific treatment of NOMGD, emphasizing that the success of treatment of all forms of obstructive MGD is dependent on the relief of the obstruction.
Qualitative analysis of Adenomatous Polyposis Coli promoter: Hypermethylation, engagement and effects on survival of patients with esophageal cancer in a high risk region of the world, a potential molecular marker (2009)

Observing similar level of APC promoter hypermethylation in patients with SCCE in this high risk region and comparing it with other parts of the world could support the hypothesis that a common molecular mechanism might be involved in tumorigenesis of SCCE. In addition, the higher rate of two-year survival for patients with unmethylated APC promoter as well as its relationship with tumor differentiation would suggest that this tumor suppressor could be an appropriate candidate molecular marker for evaluating tumor malignancy and predicting survival of patients subsequent to treatment.
Towards A Genetic Dissection Of The Basis Of Triplet Decoding, And Its Natural Subversion: Programmed Reading Frame Shifts And Hops (1991)

We have made rapid progress in recent years in identifying the genetic causes of many human diseases. However, despite this recent progress, our mechanistic understanding of these diseases is often incomplete. This is a problem because it limits our ...Read More
SPARC is a key Schwannian-derived inhibitor controlling neuroblastoma tumor angiogenesis. (2002)

Neuroblastoma (NB), a common pediatric neoplasm, consists of two main cell populations: neuroblastic/ganglionic cells and Schwann cells. NB tumors with abundant Schwannian stroma display a more benign clinical behavior than stroma-poor tumors. Recent studies suggest that Schwann cells influence NB tumor growth via secreted factors that induce differentiation, suppress proliferation, and inhibit angiogenesis. Two angiogenesis inhibitors, pigment epithelium-derived factor and tissue inhibitor of metalloproteinase-2, have been detected in Schwann cell secretions. Here, we isolated another Schwann cell-derived secreted inhibitor of angiogenesis, a 43-kDa protein identified as SPARC (secreted protein acidic and rich in cysteine), an extracellular matrix protein. We found SPARC to be critical for the antiangiogenic phenotype of cultured Schwann cells. We also show that purified SPARC potently inhibits angiogenesis and significantly impairs NB tumor growth in vivo. SPARC may be an effective candidate for the treatment of children with clinically aggressive, Schwannian stroma-poor NB tumors.
Ghrelin Increases Energy Intake in Cancer Patients with Impaired Appetite: Acute, Randomized, Placebo-Controlled Trial (2004)

There is a pressing need for more effective appetite-stimulatory therapies for many patient groups including those with cancer. We have previously demonstrated that the gastric hormone ghrelin potently enhances appetite in healthy volunteers. Here, we performed an acute, randomized, placebo-controlled, cross-over clinical trial to determine whether ghrelin stimulates appetite in cancer patients with anorexia. Seven cancer patients who reported loss of appetite were recruited from oncology clinics at Charing Cross Hospital. The main outcome measures were energy intake from a buffet meal during ghrelin or saline infusion and meal appreciation as assessed by visual analog scale. A marked increase in energy intake (31 +/- 7%; P = 0.005) was observed with ghrelin infusion compared with saline control, and every patient ate more. The meal appreciation score was greater by 28 +/- 8% (P = 0.02) with ghrelin treatment. No side effects were observed. The stimulatory effects of ghrelin on food intake and meal appreciation seen in this preliminary study suggest that ghrelin could be an effective treatment for cancer anorexia and possibly for appetite loss in other patient groups.
Amino Acid Sequence Deduced from a Rat Kidney cDNA Suggests It Encodes the Zn-Peptidase Aminopeptidase N (1989)

We have isolated and characterized rat kidney cDNA clones encoding a 140-kDa glycoprotein that exhibits characteristics of a cell surface Zn-peptidase. Structural features predicted for this putative kidney Zn-peptidase (KZP) are most consistent with properties previously determined for the Zn-peptidase aminopeptidase N. The deduced amino acid sequence of rat KZP is almost identical to the NH2-terminal sequence of aminopeptidase N purified from rabbit. The overall amino acid composition predicted for rat KZP is remarkably similar to that previously determined for rabbit and pig aminopeptidase N. The predicted Mr of rat kidney KZP approximates the Mr of the unglycosylated form of aminopeptidase N. The topology predicted for KZP is identical to that observed for aminopeptidase N: a short cytoplasmic domain at the NH2 terminus immediately precedes an uncleaved signal/anchor domain; a stalk region connects this membrane anchor to the extracellular, hydrophilic bulk of the protein containing catalytic sites required for Zn-peptidase activity. In addition, mRNA encoding KZP is present in tissues known to exhibit aminopeptidase N activity. Taken together with the observation that only a single gene homologous to KZP DNA is present in the rat and human genomes, these results suggest that we have established the primary structure of rat kidney aminopeptidase N.
Poorly controlled postoperative pain: prevalence, consequences, and prevention (2017)

This review provides an overview of the clinical issue of poorly controlled postoperative pain and therapeutic approaches that may help to address this common unresolved health-care challenge. Postoperative pain is not adequately managed in greater than 80% of patients in the US, although rates vary depending on such factors as type of surgery performed, analgesic/anesthetic intervention used, and time elapsed after surgery. Poorly controlled acute postoperative pain is associated with increased morbidity, functional and quality-of-life impairment, delayed recovery time, prolonged duration of opioid use, and higher health-care costs. In addition, the presence and intensity of acute pain during or after surgery is predictive of the development of chronic pain. More effective analgesic/anesthetic measures in the perioperative period are needed to prevent the progression to persistent pain. Although clinical findings are inconsistent, some studies of local anesthetics and nonopioid analgesics have suggested potential benefits as preventive interventions. Conventional opioids remain the standard of care for the management of acute postoperative pain; however, the risk of opioid-related adverse events can limit optimal dosing for analgesia, leading to poorly controlled acute postoperative pain. Several new opioids have been developed that modulate μ-receptor activity by selectively engaging intracellular pathways associated with analgesia and not those associated with adverse events, creating a wider therapeutic window than unselective conventional opioids. In clinical studies, oliceridine (TRV130), a novel μ-receptor G-protein pathway-selective modulator, produced rapid postoperative analgesia with reduced prevalence of adverse events versus morphine.
Xanthomonas citri : breaking the surface (2003)

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Biotransformation of Rosamicin Antibiotic into 10,11-Dihydrorosamicin with Enhanced In Vitro Antibacterial Activity Against MRSA (2014)

A biotransformation approach using microbes as biocatalysts can be an efficient tool for the targeted modification of existing antibiotic chemical scaffolds to create previously uncharacterized therapeutic agents. By employing a recombinant Streptomyces venezuelae strain as a microbial catalyst, a reduced macrolide, 10,11-dihydrorosamicin, was created from rosamicin macrolide. Its chemical structure was spectroscopically elucidated, and the new rosamicin analog showed 2-4-fold higher antibacterial activity against two strains of methicillin-resistant Staphylococcus aureus compared with its parent rosamicin. This kind of biocatalytic approach is able to expand existing antibiotic entities and can also provide more diverse therapeutic resources.
Radiographic progression in rheumatoid arthritis: A long-term rospective study of 109 patients (1998)

The progression of radiographic damage in RA followed mathematical functions of time. The identification of progression type may be used in the prediction of outcome in patients with RA.
A technology simulation methodology for AC-performance optimization of SiGe HBTs (2002)

A methodology for simultaneous calibration of SiGe HBT process and device simulation is presented and applied to SiGe BiCMOS HBTs with peak cut-off frequencies ranging from 100 GHz to 200 GHz. Predictive simulation capability is demonstrated for critical HBT AC device characteristics through comparison with experimental devices.
Association of the factor VIII light chain with von Willebrand factor. (1988)

Coagulation factor VIII (fVIII) is isolated from porcine blood as a set of three heterodimers because of proteolytic cleavages in the middle, or B region, of the parent single-chain molecule. A single 80-kDa COOH-terminal fragment, the light chain (fVIIILC), is associated with one of three forms of heavy chain (fVIIIHCs) by a calcium-dependent linkage. The purified heterodimers were dissociated using EDTA and fVIIILC, and fVIIIHCs were isolated by high pressure liquid chromatography under nondenaturing conditions. The association of fVIII, fVIIILC, and fVIIIHCs with multimeric human von Willebrand factor (vWF) was studied using analytical velocity sedimentation. A previous study using this method with an intact, single heterodimeric species of fVIII has shown that one molecule of fVIII can bind to each subunit of vWF (Lollar, P., and Parker, C.G. (1987) J. Biol. Chem. 262, 17572-17576). fVIIILC bound vWF as judged by the increase in the plateau height and sedimentation coefficient of the fVIIILC.vWF complex compared to vWF at 42,000 x g and by the decrease in the plateau height of the 4.8 S fVIIILC boundary sedimenting at 240,000 x g. Titration of a fixed concentration of fVIIILC with vWF yielded a stoichiometry of one fVIIILC molecule per subunit of vWF. Proteolytic cleavage by thrombin to remove an acidic 41-residue NH2-terminal peptide from fVIIILC completely abolished its binding to vWF. In contrast, no binding of fVIIIHCs to vWF was observed. Additionally, intact fVIII bound to vWF was completely dissociated after proteolysis by thrombin. These data are consistent with the hypothesis that a critical step in blood coagulation is the release of all regions of fVIII from vWF following a single proteolytic cleavage of fVIIILC.
Novel Antitumor Prodrugs Designed for Activation by Matrix Metalloproteinases-2 and -9 (2004)

Enzyme prodrug monotherapy takes advantage of the selectivity and specificity of enzymes that are differentially active in the immediate environment of tumor cells. Matrix metalloproteinases-2 and -9 (MMP-2 and -9, respectively) are cell-surface Zn-dependent endoproteases associated with diverse processes throughout tumor formation and progression. These enzymes have demonstrated high ratios of tumor- to nontumor-associated activity and may represent candidates for antitumor prodrug activation. Our MMP targeting strategy was to prepare and evaluate two classes of enzyme prodrugs, peptides and sequence-similar peptidomimetics, and determine which would be substrates for the enzymes and thus suitable for further in vitro and in vivo evaluation. We selected representatives of three structurally and mechanistically distinct classes of compounds for delivery, doxorubicin, several auristatins (novel synthetic members of the dolastatin class of tubulin polymerization inhibitors), and CBI-TMI (a duocarmycin class minor groove binder). The drugs were acylated on available amines with the broadly recognized MMP substrate P3-P1' sequence acetyl L-prolyl-L-leucyl-glycyl-L-leucine, or with a peptidomimetic analogue. From a panel of four peptides and four peptidomimetics, two compounds, both peptides, were found to be substrates, with specific activities in the range of 1-20 nmol min(-1) mg(-1). For MMP-9, complete conversion took place in 4-16 h; proteolysis by MMP-2 was considerably slower. Cleavage occurred, as predicted, at the Gly-Leu bond to liberate a leucyl drug, and no other intermediates or cleavage products were observed. Although the MMP-9 proteolysis products were equipotent with the parent leucyl drugs, the prodrugs were not differentially active against MMP-2 or -9-expressing versus nonexpressing cell lines during a 4 h exposure. Our data can be interpreted in light of the current understanding of the structural and mechanistic factors governing MMP-2 and -9 proteolysis.
Immune aging, dysmetabolism, and inflammation in neurological diseases (2015)

As we age, the immune system undergoes a process of senescence accompanied by the increased production of proinflammatory cytokines, a chronic subclinical condition named as "inflammaging". Emerging evidence from human and experimental models suggest that immune senescence also affects the central nervous system and promotes neuronal dysfunction, especially within susceptible neuronal populations. In this review we discuss the potential role of immune aging, inflammation and metabolic derangement in neurological diseases. The discovery of novel therapeutic strategies targeting age-linked inflammation may promote healthy brain aging and the treatment of neurodegenerative as well as neuropsychiatric disorders.
Blind source extraction of heart sound signals from lung sound recordings exploiting periodicity of the heart sound (2008)

A novel approach for separating heart sound signals (HSSs) from lung sound recordings is presented. The approach is based on blind source extraction (BSE) with second-order statistics (SOS), which exploits the quasi-periodicity of the HSSs. The method is evaluated on both synthetic periodic signals of known period mixed with temporally white Gaussian noise (WGN) as well as on real quasi periodic HSSs mixed with lung sound signals (LSSs). Qualitative evaluation involving comparison of the power spectral densities (PSDs) of the extracted signals, by the proposed method and by the JADE algorithm, and that of the original signal is performed for the case of real data. Separation results confirm the utility of the proposed approach, although departure from strict periodicity may impact performance.