gebhart/patrepeval huggingface dataset:
Safety profile: transdermal testosterone treatment of women after oophorectomy (2001)

Purpose: To evaluate the safety of two doses of testosterone (T) administered by investigational transdermal matrix patch to women with impaired sexual function after surgical menopause. Methods: Seventy-five women, aged 31–56 years, 1 to 10 years after TAH-BSO, received oral conjugated equine estrogens and, in random order, placebo, 150 μg T, and 300 μg T per day transdermally for 12 weeks each. Results: Serum-free and bioavailable T increased to normal values with both T treatments. Dihydrotestosterone and total T increased to above normal with 300 μg T treatment, a finding related to higher than normal SHBG levels in women on oral estrogen. The hormones DHEA-S, estradiol, estrone, LH, FSH, and other safety parameters, hirsutism and acne scores, total cholesterol, HDL, LDL, triglycerides, hematocrit, platelets, WBC, bilirubin, AST, GGT, albumin, fasting glucose, insulin, heart rate, blood pressure, and hot flush frequency were not significantly affected by T treatment. Facial depilation rates (times/month) were similar for baseline (0.5), placebo (0.8) and 150 μg T (0.7) and rose slightly for 300 μg T (1.4). Adverse events during T and placebo treatments were comparable. One woman withdrew because of a skin reaction to the placebo patch; three others withdrew because of adverse events possibly or probably related to treatment. Conclusion: Testosterone patches of 150 μg and 300 μg per day were well tolerated and raised T levels without affecting other sex hormones, lipids, blood counts, liver function, carbohydrate metabolism, vital signs, or hot flushes. No clinically significant virilization occurred. Longer, larger prospective clinical trials are planned.
Theories of schizophrenia: a genetic-inflammatory-vascular synthesis (2005)

A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons.
Mast cells and inflammation. (2002)

Mast cells have long been recognized as potent producers of a large panel of biologically highly active mediators such as biogenic amines, arachidonic acid metabolites, cytokines and chemokines, but most of their biological functions have been elusive and speculative. By taking advantage of mast cell-deficient mice, the role of mast cells in a variety of experimental settings can now be studied in detail and such approaches have dramatically altered and enlarged our knowledge about mast cell biology and function. Herein we will focus on the role of mast cells in inflammatory reactions of diverse origin, such as delayed type hypersensitivity, atopy, immune complex-mediated inflammation and innate immune responses. From the current standpoint, there is no doubt that the most outstanding and beneficial feature of mast cells is their recently discovered ability to induce a life-saving inflammatory response rapidly upon encountering microbes and microbial constituents. Nevertheless, the picture is also emerging that mast cells are deeply involved in the induction and maintenance of a variety of severe allergic and autoimmune diseases. However, a deeper understanding of their activation and immune-modulatory capacity might open a new window for the development of curative strategies.
Whole-genome haplotyping approaches and genomic medicine (2014)

Genomic information reported as haplotypes rather than genotypes will be increasingly important for personalized medicine. Current technologies generate diploid sequence data that is rarely resolved into its constituent haplotypes. Furthermore, paradigms for thinking about genomic information are based on interpreting genotypes rather than haplotypes. Nevertheless, haplotypes have historically been useful in contexts ranging from population genetics to disease-gene mapping efforts. The main approaches for phasing genomic sequence data are molecular haplotyping, genetic haplotyping, and population-based inference. Long-read sequencing technologies are enabling longer molecular haplotypes, and decreases in the cost of whole-genome sequencing are enabling the sequencing of whole-chromosome genetic haplotypes. Hybrid approaches combining high-throughput short-read assembly with strategic approaches that enable physical or virtual binning of reads into haplotypes are enabling multi-gene haplotypes to be generated from single individuals. These techniques can be further combined with genetic and population approaches. Here, we review advances in whole-genome haplotyping approaches and discuss the importance of haplotypes for genomic medicine. Clinical applications include diagnosis by recognition of compound heterozygosity and by phasing regulatory variation to coding variation. Haplotypes, which are more specific than less complex variants such as single nucleotide variants, also have applications in prognostics and diagnostics, in the analysis of tumors, and in typing tissue for transplantation. Future advances will include technological innovations, the application of standard metrics for evaluating haplotype quality, and the development of databases that link haplotypes to disease.
[The role of the tryptophan-62 residue in the structure and function of lysozyme]. (1977)

The thermostability and thermodinamics of formation of the enzyme-substrate complex of two oxidation products of chicken egg lysozyme with the tryptophane-62 residue modified to N'-formylkinurenine (with 2.5% activity) and kinurenine (with 27.5% activity) have been studied. In thermostability and pH effect on the substrate binding the lysozyme oxidation products do not differ from native lysozyme. The data obtained and thermodynamical characteristics of the enzyme-substrate complex formation suggest that the chemical nature of the 62 residue does not significantly affect the conformational properties of lysozyme, however, having a strongly pronounced effect on the binding of substrate and hence the total enzyme activity.
Phase I evaluation and pharmacokinetics of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193). (1985)

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, TCAR, Riboxamide, NSC 286193) is a novel C-nucleoside with antitumor activity against several murine tumor models, including Lewis lung carcinoma. The mechanism whereby this compound exerts its antineoplastic effects is most likely related to a state of guanine nucleotide depletion whereby the anabolite, thiazole-4-carboxamide adenine dinucleotide, potently inhibits inosine-5'-monophosphate dehydrogenase. This Phase I study was designed to determine the maximally tolerated dose of Tiazofurin administered on a 5-day, every-28-day schedule. Tiazofurin levels were measured using a high-pressure liquid chromatography assay, and pharmacokinetic studies were performed in patients treated at each dose level. Nineteen patients received a total of 24 courses of the drug in doses ranging from 550 to 2200 mg/sq m. The dose-limiting toxicities were pleuropericarditis and a general illness best described as a "viral-like" syndrome (manifested by severe malaise, headaches, myalgias, fever, nausea, vomiting, and diarrhea). Other toxicity included myelosuppression, hyperuricemia, elevated serum creatine phosphokinase and serum glutamic oxaloacetic transaminase, conjunctivitis, mucositis, and desquamation of the palms of the hands. Plasma clearance of Tiazofurin followed a biexponential pattern with a harmonic mean terminal half-life of 7.6 h. The mean volume of distribution at steady state was 30 liters/sq m, and the mean plasma clearance was 3 liters/h/sq m. The total cumulative urinary excretion ranged from 15 to 49%. The maximally tolerated dose of Tiazofurin on a 5-day schedule was 1650 mg/sq m. The recommended dose for Phase II evaluations is 1100 mg/sq m for 5 days. However, exploration of other schedules which might allow administration of more Tiazofurin combined with biochemical studies including thiazole-4-carboxamide adenine dinucleotide measurements would be desirable.
Nonlocality and anomalous critical current dependence on the magnetic flux in mesoscopic SNS junctions (1998)

We show that in {\em ballistic} mesoscopic SNS junctions the period of critical current vs. magnetic flux dependence (magnetic interference pattern), $I_c(\Phi)$, changes {\em continuously and non-monotonically} from $\Phi_0$ to $2\Phi_0$ as the length-to-width ratio of the junction grows, or temperature drops. In {\em diffusive} mesoscopic junctions the change is even more drastic, with the first zero of $I_c(\Phi)$ appearing at $3\Phi_0$. The effect is a manifestation of nonlocal relation between the supercurrent density and superfluid velocity in the normal part of the system, with the characteristic scale $\xi_T = \hbar v_F/2\pi k_BT$ (ballistic limit) or $\tilde{\xi}_T = \sqrt{\hbar D/2\pi k_BT}$ (diffusive limit), the normal metal coherence length, and arises due to restriction of the quasiparticle phase space near the lateral boundaries of the junction. It explains the $2\Phi_0$-periodicity recently observed by Heida et al. (Phys. Rev. B {\bf 57}, R5618 (1998)). We obtained explicit analytical expressions for the magnetic interference pattern for a junction with an arbitrary length-to-width ratio. Experiments are proposed to directly observe the $\Phi_0\to 2\Phi_0$- and $\Phi_0\to 3\Phi_0$-transitions.
Magnitude of Sustained Multiple Risk Factors for Ischemic Heart Disease in Japanese Employees (2001)

A case-control study was performed to clarify the cause of ischemic heart disease (IHD), such as acute myocardial infarction and angina pectoris, in Japanese employees. Among 122,051 workers from 31 industries, 94 cases of IHD were the subjects of the study, and a total of 191 age-matched subjects from the same department, but who did not develop IHD, served as the controls. Compared with the control group, body mass index, blood pressure, fasting plasma glucose, serum total cholesterol and serum triglyceride were significantly higher, and cigarette consumption and serum uric acid also tended to be higher, in the patient group from at least 10 years prior to onset. The frequency of moderate-drinkers tended to be lower in the case group. Electrocardiograms showed that, compared with the control group, the frequency of myocardial ischemia was higher in the case group from 9 years prior to onset and further rapidly increased from 3 years prior. The frequency of subjects with arrhythmia was the same as the control group until 3 years before onset and increased rapidly from 2 years prior. The frequency of subjects with multiple risk factors, particularly obesity, hypertension, hyperlipidemia and hyperglycemia, was consistently higher in the case group compared with the control group from 10 years prior to onset. Conditional logistic regression analysis demonstrated that having more than one risk factor greatly increased the risk; in particular, the combination of 3 or more factors increased the relative risk to 10.56 (95% confidence interval: 3.30-33.78). These findings suggest that a long duration of multiple risks is involved in the onset of IHD in Japanese employees, and that annual ECG monitoring as part of the medical examination was important in the prognosis.
The EcoCyc and MetaCyc databases (2000)

EcoCyc is an organism-specific Pathway/Genome Database that describes the metabolic and signal-transduction pathways of Escherichia coli, its enzymes, and-a new addition-its transport proteins. MetaCyc is a new metabolic-pathway database that describes pathways and enzymes of many different organisms, with a microbial focus. Both databases are queried using the Pathway Tools graphical user interface, which provides a wide variety of query operations and visualization tools. EcoCyc and MetaCyc are available at http://ecocyc.PangeaSystems.com/ecocyc/
Primary Human Lymphocytes Transduced with NY-ESO-1 Antigen-Specific TCR Genes Recognize and Kill Diverse Human Tumor Cell Lines (2005)

cDNAs encoding TCR alpha- and beta-chains specific for HLA-A2-restricted cancer-testis Ag NY-ESO-1 were cloned using a 5'RACE method from RNA isolated from a CTL generated by in vitro stimulation of PBMC with modified NY-ESO-1-specific peptide (p157-165, 9V). Functionality of the cloned TCR was confirmed by RNA electroporation of primary PBL. cDNA for these alpha- and beta-chains were used to construct a murine stem cell virus-based retroviral vector, and high titer packaging cell lines were generated. Gene transfer efficiency in primary T lymphocytes of up to 60% was obtained without selection using a method of precoating retroviral vectors onto culture plates. Both CD4(+) and CD8(+) T cells could be transduced at the same efficiency. High avidity Ag recognition was demonstrated by coculture of transduced lymphocytes with target cells pulsed with low levels of peptide (<20 pM). TCR-transduced CD4 T cells, when cocultured with NY-ESO-1 peptide pulsed T2 cells, could produce IFN-gamma, GM-CSF, IL-4, and IL-10, suggesting CD8-independent, HLA-A2-restricted TCR activation. The transduced lymphocytes could efficiently recognize and kill HLA-A2- and NY-ESO-1-positive melanoma cell lines in a 4-h (51)Cr release assay. Finally, transduced T cells could efficiently recognize NY-ESO-1-positive nonmelanoma tumor cell lines. These results strongly support the idea that redirection of normal T cell specificity by TCR gene transfer can have potential applications in tumor adoptive immunotherapy.
HUMAN EMBRYONIC STEM CELLS: TECHNOLOGICAL CHALLENGES TOWARDS THERAPY (2006)

1. Human embryonic stem cells (hESC) hold promise for overcoming many diseases because they provide a potential source for many of the slow-growing cell types needed for effective tissue repair, such as the dopaminergic neural cells for Parkinson's disease or the pancreatic islet cells needed to relieve diabetic patients of their daily insulin injections. 2. Human embryonic stem cells can be characterized by several surface antigen markers, transcription factors and enzymes, as well as their ability to differentiate into cells representative of the three germ layers, both in vivo and in vitro. 3. Significant progress has been made in defining the feeder-free and serum-free conditions needed for the culture of hESC. The fibroblast growth factor-2 and transforming growth factor-b signalling pathways appear to be important in maintaining self-renewal and preventing differentiation, respectively. 4. Several important quality controls, including karyotyping, immunogenicity and murine viral assays, will have to be established to monitor the production of hESC for therapeutic purposes. 5. Methods of expansion and differentiation of hESC are still in their infancy and the efficiency of these processes needs to be significantly enhanced.
Modification of work function of Ti by self-assembled monolayer molecules on SiO2∕p-Si (2005)

A method was used to change the work function of Ti (ϕTi) using self-assembled monolayer (SAM) molecules of dipolar, aminopropyl triethoxy silane, a change attributed to the change in the electrical potential at the Ti∕SAM interface. The SAM was deposited on SiO2∕Si followed by Ti electrode evaporation to form a Ti∕SAM∕SiO2∕p-Si stack for capacitance-voltage (C–V) analyses. The binding of SAM on the SiO2 surface was confirmed using Fourier-transform infrared spectroscopy, and the surface coverage of SAM was determined by the change in the flat-band voltages VFB with deposition time. After 1h of deposition time, an independence of the total capacitance Ctotal and VFB was indicative of saturated surface coverage of SAM on the SiO2 surface. A relationship between the fraction x (where 0&amp;lt;x&amp;lt;1 and x=1 correspond to a monolayer) of the SiO2 surface covered with SAM, at saturated surface coverage, and the dielectric permittivity of SAM (KSAM) was found to be x=0.15KSAM+0.09; if KSAM is assumed to be 3, x is estimated to be 0.54. The ϕTi on the bare SiO2 surface as well as on the SiO2 surface covered with SAM at saturated surface coverage were determined from VFB versus total equivalent oxide thickness plots. The maximum change in ϕTi from Ti∕SiO2∕p-Si to Ti∕SAM∕SiO2∕p-Si configuration was found to be 0.2V.
ALTERATIONS IN ENDOTHELIN B RECEPTOR SITES IN CAVERNOSAL TISSUE OF DIABETIC RABBITS: POTENTIAL RELEVANCE TO THE PATHOGENESIS OF ERECTILE DYSFUNCTION (1997)

The autoradiographic and immunohistochemical findings in this study suggest that ET-1 may have a role in the pathophysiology of diabetic ED. This peptide may be released in an autocrine fashion causing cavernosal smooth muscle cell (CSMC) contraction and/or proliferation.
Specific amplification by PCR of rearranged genomic variable regions of immunoglobulin genes from mouse hybridoma cells. (1995)

We have designed a novel strategy for the isolation of the rearranged genomic fragments encoding the L-VH-D-JH and L-V kappa/lambda-J kappa/lambda regions of mouse immunoglobulin genes. This strategy is based on the PCR amplification of genomic DNA from mouse hybridomas using multiple specific primers chosen in the 5'-untranslated region and in the intron downstream of the rearranged JH/J kappa/lambda sequences. Variable regions with intact coding sequences, including full-length leader peptides (L) can be obtained without previous DNA sequencing. Our strategy is based on a genomic template that produces fragments that do not need to be adapted for recombinant antibody expression, thus facilitating the generation of chimeric and isotype-switched immunoglobulins.
PKC-ε-dependent survival signals in diabetic hearts (2005)

Diabetes mellitus is complicated by the development of a primary cardiomyopathy, which contributes to the excess morbidity and mortality of this disorder. The protein kinase C (PKC) family of isozymes plays a key role in the cardiac phenotype expressed during postnatal development and in response to pathological stimuli. Hyperglycemia is an activating signal for cardiac PKC isozymes that modulate a myriad of cell events including cell death and survival. The epsilon-isozyme of the PKC family transmits a powerful survival signal in cardiac muscle cells. Accordingly, to test the hypothesis that endogenous activation of cardiac PKC-epsilon will protect against hyperglycemic cell injury and left ventricular dysfunction, diabetes mellitus was induced using streptozotocin in genetically engineered mice with cardiac-specific expression of the PKC-epsilon translocation activator [psiepsilon-receptors for activated C kinase (psiepsilon-RACK)]. The results demonstrate a striking PKC-epsilon cardioprotective phenotype in diabetic psiepsilon-RACK (epsilon-agonist) mice that is characterized by inhibition of the hyperglycemia apoptosis signal, attenuation of hyperglycemia-mediated oxidative stress, and preservation of parameters of left ventricular pump function. Hearts of diabetic epsilon-agonist mice exhibited selective trafficking of PKC-epsilon to membrane and mitochondrial compartments, phosphorylation/inactivation of the mitochondrial Bad protein, and inhibition of cytochrome c release. We conclude that activation of endogenous PKC-epsilon in hearts of diabetic epsilon-agonist mice promotes the survival phenotype, attenuates markers of oxidative stress, and inhibits the negative inotropic properties of chronic hyperglycemia.
Use of Prednisone With Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer (2014)

Abiraterone acetate, a prodrug of the CYP17A1 inhibitor abiraterone that blocks androgen biosynthesis, is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) in combination with prednisone or prednisolone 5 mg twice daily. This review evaluates the basis for the effects of prednisone on mineralocorticoid-related adverse events that arise because of CYP17A1 inhibition with abiraterone. Coadministration with the recommended dose of glucocorticoid compensates for abiraterone-induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone. Consequently, 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate, analogous to use of glucocorticoid replacement therapy for certain endocrine disorders. We searched PubMed to identify safety concerns regarding glucocorticoid use, placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer. In general, glucocorticoid-related adverse events, including bone loss, immunosuppression, hyperglycemia, mood and cognitive alterations, and myopathy, appear dose related and tend to occur at doses and/or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC. Although glucocorticoids are often used to manage tumor-related symptoms or to prevent treatment-related toxicity, available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC. Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone, the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens.
Multilocus Sequence Typing Subtypes of Poultry Clostridium perfringens Isolates Demonstrate Disease Niche Partitioning (2011)

Clostridium perfringens is a ubiquitous and versatile pathogenic bacterium and is implicated in the etiology of the poultry diseases necrotic enteritis (NE) and poultry gangrene (PG). In this study, multilocus sequence typing was used to investigate genotypic relationships among 139 C. perfringens isolates from 74 flocks. These isolates had multiple disease, host, and environmental origins. The results indicated a polymorphic yet highly clonal population, with 79.6% of all isolates partitioning into one of six clonal complexes or two dominant sequence types, ST-9 and ST-31. The most prolific clonal complex, CC-1, contained 27.3% of all isolates and was not clearly associated with one particular disease. The subtypes CC-4 and ST-31 were highly associated with NE and represented 9.4% and 7.2% of the total isolates, respectively. No PG-associated and NE-associated C. perfringens isolates shared the same sequence type or clonal complex. NE-associated subtypes were more clonal and appeared more evolutionarily divergent than PG-associated subtypes, which tended to cluster in the more ancestral lineages alongside isolates from asymptomatic chickens and turkeys. Toxin gene screening identified cpb2 throughout these isolates and correlated the presence of netB with NE pathology. Previous investigations into the genetic basis of C. perfringens pathogenicity have focused on toxins and other variable genetic elements. This study presents the first sequence-based comparison of C. perfringens isolates recovered in clinical cases of PG and NE and demonstrates that niche specialization is observable in the core genomes of poultry-associated C. perfringens isolates, a concept with both epidemiological and evolutionary significance.