gebhart/patrepeval huggingface dataset:
Inhaled insulin – a new therapeutic option in the treatment of diabetes mellitus (2003)

The beneficial effects of maintaining an optimal glucose control on chronic complications of diabetes have been firmly established in patients with both Type 1 and 2 diabetes mellitus. Effective glucose control usually requires multiple daily injections of subcutaneous insulin. Limitations of these intensive regimens include inconvenience and poor patient adherence and acceptability. As a consequence, several alternative methods for insulin delivery have been developed with the aim of eliminating the pain, inconvenience and disruption of lifestyle associated with the need for insulin injections. Recent evidence suggests that intrapulmonary insulin delivery may be an effective, non-invasive alternative to subcutaneous regular insulin. In fact, clinical trials in the last few years have shown that intrapulmonary insulin was as good as subcutaneous insulin in controlling glucose levels in patients with both Type 1 and 2 diabetes mellitus. It was well-tolerated and, so far, there is no evidence of an increased risk of hypoglycaemia or adverse bronchopulmonary effects. Although the bio-availability of inhaled insulin is lower than that of subcutaneous insulin, the former has a more physiological pharmacokinetic profile than the latter. Inhaled insulin currently represents the most viable alternative insulin delivery method to preprandial subcutaneous injection.
Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation (2009)

Adequate recovery of hematopoietic stem cell (HSC) niches after cytotoxic conditioning regimens is essential to successful bone marrow transplantation. Yet, very little is known about the mechanisms that drive the restoration of these niches after bone marrow injury. Here we describe a profound disruption of the marrow microenvironment after lethal total body irradiation of mice that leads to the generation of osteoblasts restoring the HSC niche, followed by a transient, reversible expansion of this niche. Within 48 hours after irradiation, surviving host megakaryocytes were observed close to the endosteal surface of trabecular bone rather than in their normal parasinusoidal site concomitant with an increased stromal-derived factor-1 level. A subsequent increase in 2 megakaryocyte-derived growth factors, platelet-derived growth factor-beta and basic fibroblast growth factor, induces a 2-fold expansion of the population of N-cadherin-/osteopontin-positive osteoblasts, relative to the homeostatic osteoblast population, and hence, increases the number of potential niches for HSC engraftment. After donor cell engraftment, this expanded microenvironment reverts to its homeostatic state. Our results demonstrate the rapid recovery of osteoblastic stem cell niches after marrow radioablation, provide critical insights into the associated mechanisms, and suggest novel means to manipulate the bone marrow microenvironment to promote HSC engraftment.
Development of a highly efficient gene targeting system for using the disruption of a polyketide synthase gene as a visible marker (2005)

We cloned a polyketide synthase gene (pks12) from Fusarium graminearum, a devastating fungal pathogen of cereals. Transformation-mediated gene disruption led to an easily detectable albino phenotype of the disruptants. We used the disruption of the pks12 gene as a visible marker for transformation-mediated homologous recombination and optimized the transformation procedure to achieve a high rate of homologous recombination. In combination with the published genomic sequence data and the generation of expressed sequence tags (ESTs) for F. graminearum, this is a useful tool to investigate this important plant pathogen on a molecular level. Optimized transformation of F. graminearum resulted in at least 93% homologous recombination events when the homologous genomic DNA fragment in the vector had a size of approximately 800bp and was linearized in the middle. Using a genomic sequence of approximately 500bp in the transformation vector, 70% of the transformants still exhibited homologous recombination. On the contrary, no more than 10% homologous recombination events were observed when less than 400bp DNA fragments were used. We co-transformed F. graminearum with two different vectors. One vector harboured a DNA insert homologous to the pks12 gene, while the other vector consisted of the same vector backbone carrying the selection marker specific for F. graminearum. About 70% of the transformants had a disrupted pks12 gene, and all of these showed an integration of the second vector into the pks disruption vector. Therefore, the time-consuming construction of a single transformation vector can be avoided; furthermore, it is now easily feasible to express a gene construct at a defined and mutated genomic site.
Effect of Semen Characteristics on Pregnancy Rate in a Gamete Intrafallopian Transfer Program (1993)

The aim of this study was to evaluate the influence of sperm morphology, swim-up concentration, and insemination volume on pregnancy outcome in patients undergoing gamete intrafallopian transfer (GIFT) treatment in whom the male partner had a morphology of less than 14%. Only patients who received four oocytes were entered into this study (n = 103). In all cases the swim-up procedure time was standardized to 1 h and the insemination concentration was standardized to 500,000 per oviduct. There was no significant difference in pregnancy rate when normal morphology, swim-up concentration, or insemination volume were used as predictors. In the P pattern group (< 4% normal forms) only four of the 28 (14%) patients had ongoing pregnancies, whereas in the G pattern group (5% to 14% normal forms) 16 out of 75 (21%) had ongoing pregnancies (P vs G, p > 0.05; not significant). The fertilization rate among excess oocytes in the P pattern group was 18% but was 39% (p < .0001) in the G pattern group. When an attempt was made to compensate for low morphology by increasing insemination concentration no significant difference in the pregnancy rate between the P and G pattern groups in the GIFT program was recorded. This was not the case when the in vitro fertilization rate was used as an endpoint. Insemination volume and swim-up concentration played no role in pregnancy rate.
A Polymer-Based Antibody–Vinca Drug Conjugate Platform: Characterization and Preclinical Efficacy (2015)

Antibody-drug conjugates (ADC) are an emerging drug class that uses antibodies to improve cytotoxic drug targeting for cancer treatment. ADCs in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly to an antibody at a 4:1 or less stoichiometric ratio. Herein, we report a novel, polyacetal polymer-based platform for creating ADC that use poly-1-hydroxymethylethylene hydroxymethyl-formal (PHF), also known as Fleximer. The high hydrophilicity and polyvalency properties of the Fleximer polymer can be used to produce ADC with high drug loading without compromising physicochemical and pharmacokinetic properties. Using trastuzumab and a vinca drug derivative to demonstrate the utility of this platform, a novel Fleximer-based ADC was prepared and characterized in vivo. The ADC prepared had a vinca-antibody ratio of 20:1. It exhibited a high antigen-binding affinity, an excellent pharmacokinetic profile and antigen-dependent efficacy, and tumor accumulation in multiple tumor xenograft models. Our findings illustrate the robust utility of the Fleximer platform as a highly differentiated alternative to the conjugation platforms used to create ADC currently in clinical development.
Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution (2013)

The genetic and morphological development of colorectal cancer is a paradigm for tumorigenesis. However, the dynamics of clonal evolution underpinning carcinogenesis remain poorly understood. Here we identify multipotential stem cells within human colorectal adenomas and use methylation patterns of nonexpressed genes to characterize clonal evolution. Numerous individual crypts from six colonic adenomas and a hyperplastic polyp were microdissected and characterized for genetic lesions. Clones deficient in cytochrome c oxidase (CCO(-)) were identified by histochemical staining followed by mtDNA sequencing. Topographical maps of clone locations were constructed using a combination of these data. Multilineage differentiation within clones was demonstrated by immunofluorescence. Methylation patterns of adenomatous crypts were determined by clonal bisulphite sequencing; methylation pattern diversity was compared with a mathematical model to infer to clonal dynamics. Individual adenomatous crypts were clonal for mtDNA mutations and contained both mucin-secreting and neuroendocrine cells, demonstrating that the crypt contained a multipotent stem cell. The intracrypt methylation pattern was consistent with the crypts containing multiple competing stem cells. Adenomas were epigenetically diverse populations, suggesting that they were relatively mitotically old populations. Intratumor clones typically showed less diversity in methylation pattern than the tumor as a whole. Mathematical modeling suggested that recent clonal sweeps encompassing the whole adenoma had not occurred. Adenomatous crypts within human tumors contain actively dividing stem cells. Adenomas appeared to be relatively mitotically old populations, pocketed with occasional newly generated subclones that were the result of recent rapid clonal expansion. Relative stasis and occasional rapid subclone growth may characterize colorectal tumorigenesis.
Superoxide-dependent formation of hydroxyl radicals and lipid peroxidation in the presence of iron salts. Detection of ‘catalytic’ iron and anti-oxidant activity in extracellular fluids (1982)

Synovial fluid from rheumatoid patients and normal cerebrospinal fluid contains micromolar concentrations of non-protein-bound iron salts that can promote lipid peroxidation and also the superoxide-dependent formation of hydroxyl radicals from hydrogen peroxide. These iron catalysts of oxygen radical reactions cannot be detected by conventional assays unless interfering high-molecular-weight substances, probably proteins, are removed by ultrafiltration or inactivated by exposure to low pH values. The bleomycin assay for ;catalytic' iron [Gutteridge, Rowley & Halliwell (1981) Biochem. J.199, 263-265] does not suffer from these artifacts.
Double-Blind Report on the Efficacy of Lactic Acid-Producing Enterococcus SF68 in the Prevention of Antibiotic-Associated Diarrhoea and in the Treatment of Acute Diarrhoea (1989)

A multicentre double-blind, placebo-controlled clinical trial, involving 123 patients at 10 centres, was carried out to assess the efficacy of a preparation of lactic acid-producing Enterococcus SF 68 in the prevention of antibiotic-associated diarrhoea and in the treatment of acute diarrhoea. In the prevention study, 45 patients being treated with antibiotics were given, concurrently, one capsule twice daily of either Enterococcus SF68 or placebo. Acute diarrhoea was present in 78 patients who were given the same treatment but three times daily. All treatments were continued for 7 days. Enterococcus SF 68 was shown to be effective in reducing the incidence of antibiotic-associated diarrhoea in comparison with placebo (8.7% compared with 27.2%, respectively). Patients with acute enteritis showed a significantly faster resolution of bowel abnormalities during treatment with Enterococcus SF68 compared with placebo.
Synergistic effect of nonspecific immunostimulation and antibiotics in experimental peritonitis. (1987)

To assess the role of combined immunomodulator and antibiotic therapy in sepsis, glucan--a beta 1,3 polyglucose--and gentamicin were administered in a model of murine peritonitis. ICR/HSD mice received one of four treatment regimens: 5% dextrose; gentamicin 0.02 mg intramuscularly (sub-MIC) 2 hours before peritonitis; glucan 0.1 mg intraperitoneally 24 hours before peritonitis; combined glucan-gentamicin treatment. All animals were challenged with 1 X 10(8) Escherichia coli intraperitoneally. Long-term survival was significantly enhanced in the combined therapy group (56%, p less than 0.05) when compared with D5W (0%), gentamicin alone (0%), or glucan alone (9%). Macrophage secretory activity, as assayed by interleukin-1 (IL-1) production, was significantly enhanced by combined therapy when compared with the other three treatment groups. Combined therapy significantly reduced E. coli bacteremia at 8 hours after inoculation, when compared with the other three groups. Availability of host neutrophils was assessed by peripheral counts and bone marrow proliferation assay. Combined glucan-gentamicin significantly enhanced bone marrow proliferation when compared with the other three groups and this enhancement correlated with increased circulating neutrophils. Combined immunomodulator and antibiotic therapy had synergistic effects on survival in E. coli peritonitis. This combined therapy enhanced macrophage secretory activity and bone marrow proliferation. Clinical use of immunomodulators may alter conventional use and dosage of antibiotics.
Molecular model for DNA recognition by the family of basic-helix-loop-helix-zipper proteins. (1992)

The basic-helix-loop-helix-zipper (bHLH-Zip) motif is a conserved region of approximately 70 amino acids that mediates both sequence-specific DNA binding and protein dimerization. This motif is found in protein sequences from many eukaryotic organisms and is contained in the protein sequence of the oncogene myc and its partner max, and a shortened version of the motif (bHLH) is found in the muscle determination factor myoD and its partner E12. An evaluation of the conserved amino acids that define the motif coupled with the published mutagenic studies of this region has led to our formulation of a molecular model for the binding of this motif as a dimer to specific sequences of DNA. This model has the dimeric protein interacting with an abutted, dyad-symmetric DNA sequence. Helix 2 of each monomer is modeled as a coiled-coil extension of the C-terminal "leucine zipper." Helix 1 does not interact with helix 1 from its partner in the dimer but with the hydrophobic surface created when the helix 2 regions of the dimer interact with each other as a coiled-coil. Sequence-specific interactions are proposed between the basic region and the invariant cis elements that all bHLH-Zip proteins bind.
Can machine learning be secure? (2006)

Machine learning systems offer unparalled flexibility in dealing with evolving input in a variety of applications, such as intrusion detection systems and spam e-mail filtering. However, machine learning algorithms themselves can be a target of attack by a malicious adversary. This paper provides a framework for answering the question, "Can machine learning be secure?" Novel contributions of this paper include a taxonomy of different types of attacks on machine learning techniques and systems, a variety of defenses against those attacks, a discussion of ideas that are important to security for machine learning, an analytical model giving a lower bound on attacker's work function, and a list of open problems.
[Use of fragmin in program hemodialysis of patients with terminal chronic renal failure]. (2005)

The subjects of the study were 60 patients at the end stage of chronic renal failure of various origins, who were on program hemodialysis (PHD) in Dialysis Center of City hospital #20. The main group consisted of 25 patients, who were administered fragmin (Pfizer, USA), a low-molecular heparin, for hypocoagulation during the procedure of hemodialysis. The drug was administered in a bolus dose of 5000 aXa ICU into the arterial line after connecting it to a fistula needle. The control group (35 patients) received unfranctionated heparin (UFH) in a conventional way (a bolus of 2000 to 2500 IU before the beginning of the procedure, followed by 1200 to 1500 IU/h in a continuous infusion, stopped 1 hour prior to the end of the dialysis). The following parameters were measured at the beginning and the end of the procedure: the number of thrombocytes, hemoglobin and hematocrit levels, activated partial thromboplastin time, activated coagulation time, antithrombin III level, and anti-Xa factor activity. Standard regimen of UFH administration allowed satisfactory hypocoagulation, but the necessary dose was hard to select. A bolus dose of fragmin led to adequate hypocoagulation in all the patients: there were no fibrin or blood clots in the lines or the dialyzer, or hemorrhage from the sites of puncture after the procedure. Anti-Xa-factor activity grew after a bolus injection of fragmin. By the end of the procedure the inhibitory activity of fragmin towards Xa-factor remained at the level of 0.44 +/- 0.7 IU/ml. The results show that a single dose of fragmin is effective and safe during a standard procedure of hemodialysis lasting up to 5 hours.
Sleep apnea: epidemiology, pathophysiology, and relation to cardiovascular risk (2007)

Several studies have shown the occurrence of an independent association between obstructive sleep apnea syndrome (OSAS) and cardiovascular disease, including arterial hypertension, ischemic heart disease, and stroke. The pathogenesis of the cardiovascular complications of OSAS is still poorly understood, however. Several mechanisms are likely to be involved, including sympathetic overactivity, selective activation of inflammatory molecular pathways, endothelial dysfunction, abnormality in the process of coagulation, and metabolic dysregulation. The latter may involve insulin resistance and disorders of lipid metabolism. The aim of this review, which reports the data presented at a workshop jointly endorsed by the European Society of Hypertension and by the European Union COST action on OSAS (COST B26), is to critically summarize the evidence available to support an independent association between OSAS and cardiovascular disease.
Structural Basis for Recognition of Phosphorylated High Mannose Oligosaccharides by the Cation-dependent Mannose 6-Phosphate Receptor (1999)

Mannose 6-phosphate receptors (MPRs) play an important role in the targeting of newly synthesized soluble acid hydrolases to the lysosome in higher eukaryotic cells. These acid hydrolases carry mannose 6-phosphate recognition markers on their N-linked oligosaccharides that are recognized by two distinct MPRs: the cation-dependent mannose 6-phosphate receptor and the insulin-like growth factor II/cation-independent mannose 6-phosphate receptor. Although much has been learned about the MPRs, it is unclear how these receptors interact with the highly diverse population of lysosomal enzymes. It is known that the terminal mannose 6-phosphate is essential for receptor binding. However, the results from several studies using synthetic oligosaccharides indicate that the binding site encompasses at least two sugars of the oligosaccharide. We now report the structure of the soluble extracytoplasmic domain of a glycosylation-deficient form of the bovine cation-dependent mannose 6-phosphate receptor complexed to pentamannosyl phosphate. This construct consists of the amino-terminal 154 amino acids (excluding the signal sequence) with glutamine substituted for asparagine at positions 31, 57, 68, and 87. The binding site of the receptor encompasses the phosphate group plus three of the five mannose rings of pentamannosyl phosphate. Receptor specificity for mannose arises from protein contacts with the 2-hydroxyl on the terminal mannose ring adjacent to the phosphate group. Glycosidic linkage preference originates from the minimization of unfavorable interactions between the ligand and receptor.
PEP4 gene of Saccharomyces cerevisiae encodes proteinase A, a vacuolar enzyme required for processing of vacuolar precursors. (1986)

The proteinase A structural gene of Saccharomyces cerevisiae was cloned by using an immunological screening procedure that allows detection of yeast cells which are aberrantly secreting vacuolar proteins (J. H. Rothman, C. P. Hunter, L. A. Valls, and T. H. Stevens, Proc. Natl. Acad. Sci. USA, 83:3248-3252, 1986). A second cloned gene was obtained on a multicopy plasmid by complementation of a pep4-3 mutation. The nucleotide sequences of these two genes were determined independently and were found to be identical. The predicted amino acid sequence of the cloned gene suggests that proteinase A is synthesized as a 405-amino-acid precursor which is proteolytically converted to the 329-amino-acid mature enzyme. Proteinase A shows substantial homology to mammalian aspartyl proteases, such as pepsin, renin, and cathepsin D. The similarities may reflect not only analogous functions but also similar processing and intracellular targeting mechanisms for the two proteins. The cloned proteinase A structural gene, even when it is carried on a single-copy plasmid, complements the deficiency in several vacuolar hydrolase activities that is observed in a pep4 mutant. A strain carrying a deletion in the genomic copy of the gene fails to complement a pep4 mutant of the opposite mating type. Genetic linkage data demonstrate that integrated copies of the cloned proteinase A structural gene map to the PEP4 locus. Thus, the PEP4 gene encodes a vacuolar aspartyl protease, proteinase A, that is required for the in vivo processing of a number of vacuolar zymogens.
Developments in chemotherapy of breast cancer (2000)

BACKGROUND Breast carcinoma is moderately sensitive to multiple antitumor agents. Cytotoxic combination regimens developed in the 1970s were shown to produce higher response rates and longer durations of response and survival than single-agent therapy. These regimens became the standard of care for the management of metastatic, hormone-refractory breast carcinoma, and more recently, for primary breast carcinoma. Randomized trials also have demonstrated that amthracycline-containing combinations were more effective than combinations without anthracyclines. The development of several new cytotoxic agents and novel antitumor strategies prompted this review. METHODS The author conducted a computerized literature search of MEDLINE and CANCERLIT and also reviewed the abstracts of major oncology meetings (ASCO, American Association for Cancer Research, ESMO, and San Antonio Breast Cancer Symposium) over the past 10 years. RESULTS Effective new cytotoxic drugs include the taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and capecitabine. The identification of specific molecular abnormalities (HER-2/neu or epidermal growth factor receptor [EGFR] overexpression) led to the development of targeted therapeutic intervention (monoclonal antibodies and tyrosine kinase inhibitors). Trastuzumab, a monoclonal antibody against the HER-2/neu oncoprotein, produced objective regression in 15–20% of patients with HER-2/neu–overexpressing breast carcinoma and improved the efficacy of paclitaxel. Other productive directions of therapeutic research include inhibition of intracellular signaling, interference with tumor angiogenesis, cell cycle regulation, and the development of vaccines. CONCLUSIONS Expanded understanding of the biology of breast carcinoma led to the development of rational therapeutic interventions, many of which are currently under active clinical development. Cancer 2000;88:3073–9. © 2000 American Cancer Society.