gebhart/patrepeval huggingface dataset:
Reduced SMAD7 Leads to Overactivation of TGF-β Signaling in MDS that Can Be Reversed by a Specific Inhibitor of TGF-β Receptor I Kinase (2010)

Even though myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, the molecular alterations that lead to marrow failure have not been well elucidated. We have previously shown that the myelosuppressive TGF-β pathway is constitutively activated in MDS progenitors. Because there is conflicting data about upregulation of extracellular TGF-β levels in MDS, we wanted to determine the molecular basis of TGF-β pathway overactivation and consequent hematopoietic suppression in this disease. We observed that SMAD7, a negative regulator of TGF-β receptor I (TBRI) kinase, is markedly decreased in a large meta-analysis of gene expression studies from MDS marrow-derived CD34(+) cells. SMAD7 protein was also found to be significantly decreased in MDS marrow progenitors when examined immunohistochemically in a bone marrow tissue microarray. Reduced expression of SMAD7 in hematopoietic cells led to increased TGF-β-mediated gene transcription and enhanced sensitivity to TGF-β-mediated suppressive effects. The increased TGF-β signaling due to SMAD7 reduction could be effectively inhibited by a novel clinically relevant TBRI (ALK5 kinase) inhibitor, LY-2157299. LY-2157299 could inhibit TGF-β-mediated SMAD2 activation and hematopoietic suppression in primary hematopoietic stem cells. Furthermore, in vivo administration of LY-2157299 ameliorated anemia in a TGF-β overexpressing transgenic mouse model of bone marrow failure. Most importantly, treatment with LY-2157199 stimulated hematopoiesis from primary MDS bone marrow specimens. These studies demonstrate that reduction in SMAD7 is a novel molecular alteration in MDS that leads to ineffective hematopoiesis by activating of TGF-β signaling in hematopoietic cells. These studies also illustrate the therapeutic potential of TBRI inhibitors in MDS.
Medication practice in hospitals: are nanosimilars evaluated and substituted correctly? (2017)

Evaluation of NBCD similars for substitution and interchange by hospital pharmacists is rarely based on scientific and clinical criteria but rather on cost aspects only, which does not ensure safe, efficacious and cost-effective use of such drugs.
A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40 (1995)

CD40 is a member of the tumor necrosis factor receptor (TNF-R) family that regulates B-lymphocyte proliferation, immunoglobulin class-switching, and apoptosis through poorly defined signal transduction mechanisms. Using a yeast two-hybrid method, cDNAs were obtained that encode a novel protein, CD40-associated protein-1 (CAP-1), which binds specifically to the cytosolic domain of CD40 but not TNF-R1, TNF-R2, or Fas. The CAP-1 protein contains a C-terminal domain that shares strong amino acid sequence homology with a unique domain found recently in two putative signal transducing proteins that bind to the TNF-R2 cytosolic tail, TRAF1 and TRAF2. This C-terminal region of CAP-1 was sufficient to mediate binding to CD40 and homodimerization of CAP-1 proteins. The N-terminal portion of CAP-1 contains a RING finger motif and three zinc finger-like domains similar to those found in several regulatory proteins that interact with DNA or RNA. CAP-1 thus represents a new member of a family of potential signal transducing proteins that contain a conserved domain (the TRAF domain), bind to the cytosolic regions of particular members of TNF-R family proteins, and that can form homo- and heterotypic dimers.
Multiple cytokines induce the tyrosine phosphorylation of Shc and its association with Grb2 in hemopoietic cells. (1993)

The identification and characterization of proteins that become tyrosine-phosphorylated in response to growth factor stimulation is critical to furthering our understanding of the signal transduction pathways involved in regulating cell proliferation and differentiation. In this report we demonstrate that interleukin-3, erythropoietin, and steel factor all induce the tyrosine phosphorylation of the SH2 containing protein, p52shc. These studies were carried out with various human and murine cell lines to document that this is a common event in hemopoietic cells. We also show that upon tyrosine phosphorylation, p52shc becomes associated with the adaptor protein, Grb2. The formation of this complex may directly link tyrosine phosphorylation events to Ras activation in hemopoietic progenitors and may be a critical step in stimulating these cells to transit through G1 into S phase.
Glycosaminoglycans in cervical connective tissue during pregnancy and parturition. (1993)

Besides collagenolysis during pregnancy, the glycosaminoglycans are also important regulators of cervical function. The different clinical features of the human cervix are characterized not only by variation in the total glycosaminoglycan content but also by changes in the proportions of the different glycosaminoglycans.
Human cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein. (1991)

Cytotoxic T lymphocytes (CTL) against the circumsporozoite (CS) protein of malaria sporozoites protect against malaria in rodents. Although there is interest in developing human vaccines that induce CTL against the Plasmodium falciparum CS protein, humans have never been shown to produce CTL against any Plasmodium species protein or other parasite protein. We report that when peripheral blood mononuclear cells (PBMC) from three of four volunteers immunized with irradiated P. falciparum sporozoites were stimulated in vitro with a recombinant vaccinia virus expressing the P. falciparum CS protein or a peptide including only amino acids 368-390 of the P. falciparum CS protein [CS-(368-390)], the PBMC lysed autologous Epstein-Barr virus-transformed B cells transfected with the P. falciparum CS protein gene or incubated with CS-(368-390) tricosapeptide. Activity was antigen specific, genetically restricted, and dependent on CD8+ T cells. In one volunteer, seven peptides reflecting amino acids 311-400 were tested, and, as in B10.BR mice, CTL activity was only associated with the CS-(368-390) peptide. Development of an assay for studying human CTL against the CS and other malaria proteins and a method for constructing target cells by direct gene transfection provide a foundation for studying the role of CTL in protection against malaria.
Classification of cytokines according to the receptor code. (1997)

A simple classification of cytokines is presented. It is based on voluminous information available from published papers of many outstanding researchers of the cytokines and their receptors and/or summarized by experts in this field. The cytokines are divided into 7 families according to their receptor code. Such arrangement of apparently different cytokines may explain the biological significance of pleiotropy and redundancy. Furthermore, it may stimulate the development of the comprehensive classification of cytokines together with classical hormones, neuromediators, neuromodulators and related substances that participate in complex biological communication system.
Carbon nanotube based biomimetic membranes: mimicking protein channels regulated by phosphorylation (2007)

Membranes based on an array of aligned carbon nanotubes were used to mimic biological protein channels by functionalizing the open tips of the nanotubes with a synthetic peptide to obtain a biomimetic system where phosphorylation regulates the flow.
The energy of an array of dislocations: Implications for strain relaxation in semiconductor heterostructures (1990)

Abstract An exact closed-form formula is given for the energy of an array of dislocations, arranged periodically on the interface between an epitaxial layer and its substrate, when these are modelled as elastically isotropic with the same elastic constants. In the course of the formulation, the exact equivalence of equilibrium theories originating in the work of Frank and van der Merwe and of Matthews and Blakeslee is established. The new formula allows the exact assessment of arrays of dislocations in equilibrium, for layers thicker than critical. This demonstrates that previous approximations may be seriously in error.
Anti‐epidermal growth factor receptor‐antibody therapy for treatment of breast cancer (2002)

Recent studies demonstrated that tumors overexpressing the epidermal growth factor receptor (EGF-R, erbB-1) are associated with poor clinical outcome. This led to the development of a variety of monoclonal antibodies targeting the extracellular domain of this receptor tyrosine kinase. The aim of our study was the evaluation of anti-EGF-R antibody EMD 55900 therapy for treatment of breast cancer. On the basis of 299 tumor specimens derived from breast cancer patients, we investigated EGF-R expression and generated a collective of primary xenotransplants in athymic nude mice. The animals received therapy in 2 treatment schedules to investigate the therapeutic response in early stages of tumor formation as well as on well established tumors. Using 6 different tumors with EGF-R expression levels between 10-300 fmol/mg total protein, we found a therapeutic effect when the EGF-R expression of the tumors was at least 40 fMol/mg. On the basis of these experimental data and our EGF-R expression analysis of breast cancer specimens, we conclude that up to 15% of breast cancer patients could benefit from this monotherapy with EMD 55900.
Mechanical Arm Trainer for the Treatment of the Severely Affected Arm After a Stroke (2008)

Arm trainer training did not lead to a superior primary outcome over electrical stimulation training. However, "good performers" on the secondary outcome seemed to benefit more from the arm trainer training.
Inflammation, Pravastatin, and the Risk of Coronary Events After Myocardial Infarction in Patients With Average Cholesterol Levels (1998)

Evidence of inflammation after MI is associated with increased risk of recurrent coronary events. Therapy with pravastatin may decrease this risk, an observation consistent with a nonlipid effect of this agent.
Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction (2008)

The rules for the conserved reaction of alphabeta T cell receptors (TCRs) with major histocompatibility complex (MHC) proteins plus peptides are poorly understood, probably because thymocytes bearing TCRs with the strongest MHC reactivity are lost by negative selection. Thus, only TCRs with an attenuated ability to react with MHC appear on mature T cells. Also, the interaction sites between TCRs and MHC may be inherently flexible and hence difficult to spot. We reevaluated contacts between TCRs and MHC in the solved structures of their complexes with these points in mind. Relatively conserved amino acids in the TCR complementarity-determining regions (CDR) 1 and CDR2 are often used to bind exposed areas of the MHC alpha-helices. These areas are exposed because of small amino acids that allow somewhat flexible binding of the TCRs. The TCR amino acids involved are specific to families of variable (V) regions and to some extent different rules may govern the recognition of MHCI versus MHCII.
An update on migraine: current understanding and future directions (2017)

Migraine is a common brain disorder with high disability rates which involves a series of abnormal neuronal networks, interacting at different levels of the central and peripheral nervous system. An increase in the interest around migraine pathophysiology has allowed researchers to unravel certain neurophysiological mechanisms and neurotransmitter involvement culminating in the recent development of novel therapies, which might substantially change the clinical approach to migraine patients. The present review will highlight the current aspects of migraine pathophysiology, covering an understanding of the complex workings of the migraine state and the brain regions responsible for them. We will further discuss the therapeutic agents which have appeared in the most recent years for migraine care, from calcitonin gene-related peptide (CGRP) receptor antagonists, gepants; through serotonin 5-HT<sub>1F</sub> receptor agonists, ditans, and CGRP or CGRP receptor monoclonal antibodies to invasive and non-invasive neuromodulation techniques.
Rhinitis (2000)

The nasal airway, which includes the nasal cavity and the nasopharynx, begins at the nasal vestibule and extends through the nasopharynx (Fig. 1). The epithelium is a ciliated, pseudostratified, columnar mucosa except for the squamous epithelium lining the vestibule and anterior third of the nasal airway. The mucosa of the nasal airway is contiguous with that of the paranasal sinuses and eustachian tubes. The blood flow to the nasal mucosa is one of the highest for any tissue of the body, with the flow controlled by a combination of resistance and capicitance vessels. The latter permit pooling of blood in the submucosa, resulting in swelling or congestion. The microcirculation is fenestrated to facilitate the transfer of water from the vascular space to the mucosa. The high blood flow and fenestrated vessels facilitate heating and humidification of the airstream.
Effects on platelet function of removal of platelet sialic acid by neuraminidase. (1975)

A number of investigators have implicated sialic acid on the surface of platelets in platelet function. In this study we have quantitated the amount of sialic acid removed by purified neuraminidase from the surface of washed platelets of man, rabbit, or pig and examined the effects of this removal. Purified neuraminidase did not induce the release of platelet granule contents. Platelets were pre-labeled with 14C-serotonin for measurement of the release reaction or with 51Cr for determination of adherence to a collagen-coated surface or damaged aortic surface, and for in vivo platelet survival studies. Washed, neuraminidase-treated platelets were resuspended in Tyrode's solution containing 0.35 per cent albumin or in citrated platelet-free plasma from the same species. Both resuspending fluids contained apyrase. Aggregating agents tested were ADP, acid-soluble collagen, thrombin, ristocetin (with human platelets), polylysine, and serotonin (with rabbit platelets). With all of these agents except polylysine, aggregation of neuraminidase-treated human or rabbit platelets was slightly enhanced compared with control platelets; aggregation of pig platelets was unchanged. When release-inducing agents were used, neuraminidase-treated platelets released more of their 14C-serotonin than control platelets. The extent to which rabbit platelets adhered to a collagen-coated surface or to the damaged surface of everted rabbit aorta was unchanged by pretreatment of platelets with neuraminidase. Therefore it seems unlikely that sialic acid is involved in platelet adherence to collagen. When more than 15 per cent of total sialic acid had been removed from rabbit platelets, they were completely cleared from the circulation within 1 hour of their injection into rabbits. When 8 to 10 per cent of total sialic acid had been removed, the platelets were not cleared immediately from the circulation but were cleared more quickly than control platelets. Thus, although removal of up to 65 per cent of platelet sialic acid has only a slightly enhancing effect on platelet aggregation and release in vitro, removal of as little as 8 to 10 per cent results in the recognition of platelets as "foreign" in vivo.
Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence (2014)

Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.).
Gallium nitride based microcavity light emitting diodes with 2λ effective cavity thickness (2007)

Gallium nitride based microcavity light emitting diodes less than 400nm thick emitting at a peak wavelength of 455nm have been fabricated. The epitaxial structure was grown by metal organic chemical vapor deposition, and the device was fabricated using a laser lift-off process. Cavity thinning was carried out using inductively coupled plasma etching until a cavity length of roughly 2λ (∼375nm, corresponding to a cavity order of 4 for λ=455nm in GaN) was achieved. Devices are presented that show perfectly detuned angular emission and perfectly resonant emission between the cavity length and emission wavelength.
Detection of circulating immune complexes in MRL mice with different forms of glomerulonephritis. (1990)

Serum levels of circulating immune complexes (CIC) in MRL mice were determined using the 125I-C1q binding test and a conglutinin enzyme assay. The serum 125I-C1q and conglutinin binding capacity were correlated to the development of different forms of glomerulonephritis (GN) detected by light microscopy. The study was carried out with a total of 132 MRL/MpJ-lpr/lpr and MRL/MpJ(-)+/+ mice of different age groups. From the age of 3 months on an enormous elevation of C1q- and conglutinin-binding CIC occurred in MRL/MpJ-lpr/lpr mice, while in MRL/MpJ(-)+/+ mice the mean values of CIC remained low in all age groups studied. The results corresponded to histopathological glomerular findings. In lpr/lpr-mice, from the age of 3 months on, extremely severe proliferative forms of GN occurred. In most cases of +/+(-)mice examined comparatively mild glomerular lesions were found. In serum samples of Han:NMRI and C3H/He mice an increase of conglutinin-binding material was found in certain age groups, while the levels of 125I-C1q binding activity remained low in mice of all age groups studied.
The mechanism of tamoxifen in breast cancer prevention (2001)

Background: Disruption of the balance between apoptosis and proliferation is considered to be an important factor in the development and progression of tumor. In this study we determined the in vivo cell kinetics along the spectrum of apparently normal epithelium, hyperplasia, preinvasive lesions and invasive carcinoma, in breast tissues affected by fibrocystic changes in which preinvasive and/or invasive lesions developed, as a model of breast carcinogenesis. Materials and method: A total of 32 areas of apparently normal epithelium and 135 ductal proliferative and neoplastic lesions were studied. More than one epithelial lesion per case was analyzed. The apoptotic index (AI) and the proliferative index (PI) were expressed as the percentage of TUNEL (TdT-mediated dUTP-nick end-labelling) and Ki-67 positive cells, respectively. The proliferative/apoptotic index (P/A) was calculated for each case. Results: Statistical analysis demonstrated significant differences among the tissue groups for both indices (P < 0.0001). The Als and PIs were significantly higher in hyperplasia than in apparently normal epithelium (P = 0.04 and P = 0.0005, respectively), in atypical hyperplasia than in hyperplasia (P = 0.01 and P = 0.04, respectively) and in invasive carcinoma than in in situ carcinoma (P = 0.0001 and P < 0.0001, respectively). The two indices were similar in atypical hyperplasia and in in situ carcinoma. The P/A index increased significantly from normal epithelium to hyperplasia (P = 0.01) and from preinvasive lesions to invasive carcinoma (P = 0.04), whereas it was decreased (NS) from hyperplasia to preinvasive lesions. A strong positive correlation between the Als and the Pls was found (r = 0.83; P < 0.0001).
Effect of glucagon-like peptide 1(7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes. (2000)

Although it is well established that glucagon-like peptide 1(7-36) amide (GLP-1) is a potent stimulator of insulin secretion, its effects on insulin action and glucose effectiveness are less clear. To determine whether GLP-1 increases insulin action and glucose effectiveness, subjects with type 2 diabetes were studied on two occasions. Insulin was infused during the night on both occasions to ensure that baseline glucose concentrations were comparable. On the morning of study, either GLP-1 (1.2 pmol x kg(-1) x min(-1)) or saline were infused along with somatostatin and replacement amounts of glucagon. Glucose also was infused in a pattern mimicking that typically observed after a carbohydrate meal. Insulin concentrations were either kept constant at basal levels (n = 6) or varied so as to create a prandial insulin profile (n = 6). The increase in glucose concentration was virtually identical on the GLP-1 and saline study days during both the basal (1.21 +/- 0.15 vs. 1.32 +/- 0.19 mol/l per 6 h) and prandial (0.56 +/- 0.14 vs. 0.56 +/- 0.10 mol/l per 6 h) insulin infusions. During both the basal and prandial insulin infusions, glucose disappearance promptly increased after initiation of the glucose infusion to rates that did not differ on the GLP-1 and saline study days. Suppression of endogenous glucose production also was comparable on the GLP-1 and saline study days during both the basal (-2.7 +/- 0.3 vs. -3.1 +/- 0.2 micromol/kg) and prandial (-3.1 +/- 0.4 vs. -3.0 +/- 0.6 pmol/kg) insulin infusions. We conclude that when insulin and glucagon concentrations are matched, GLP-1 has negligible effects on either insulin action or glucose effectiveness in people with type 2 diabetes. These data strongly support the concept that GLP-1 improves glycemic control in people with type 2 diabetes by increasing insulin secretion, by inhibiting glucagon secretion, and by delaying gastric emptying rather than by altering extrapancreatic glucose metabolism.
RNA SILENCING SYSTEMS AND THEIR RELEVANCE TO PLANT DEVELOPMENT (2005)

RNA silencing refers to a broad range of phenomena sharing the common feature that large, double-stranded RNAs or stem-loop precursors are processed to ca. 21-26 nucleotide small RNAs, which then guide the cleavage of cognate RNAs, block productive translation of these RNAs, or induce methylation of specific target DNAs. Although the core mechanisms are evolutionarily conserved, epigenetic maintenance of silencing by amplification of small RNAs and the elaboration of mobile, RNA-based silencing signals occur predominantly in plants. Plant RNA silencing systems are organized into a network with shared components and overlapping functions. MicroRNAs, and probably trans-acting small RNAs, help regulate development at the posttranscriptional level. Small interfering RNAs associated with transgene- and virus-induced silencing function primarily in defending against foreign nucleic acids. Another system, which is concerned with RNA-directed methylation of DNA repeats, seems to have roles in epigenetic silencing of certain transposable elements and genes under their control.
MicroRNAs: potential therapeutic targets in diabetic complications of the cardiovascular and renal systems (2014)

Diabetes mellitus is a serious health problem that can lead to several pathological complications in numerous organs and tissues. The most important and most prevalent organs affected by this disease are the heart and the kidneys, and these complications are the major causes of death in patients with diabetes. MicroRNAs (miRNAs), short non-coding RNAs, have been found to be functionally important in the regulation of several pathological processes, and they are emerging as an important therapeutic tool to avoid the complications of diabetes mellitus. This review summarizes the knowledge on the effects of miRNAs in diabetes. The use of miRNAs in diabetes from a clinical perspective is also discussed, focusing on their potential role to repair cardiovascular and renal complications.