gebhart/patrepeval huggingface dataset:
Immunotherapy of melanoma (2013)

Melanoma is considered one of the immunogenic - if not the most immunogenic - malignancies. This is based on several observations.1.Spontaneous remissions occur occasionally.2.In about 5% of melanomas no primary tumour is found. The genetic aberrations of these tumours closely resemble those of cutaneous melanomas, and therefore are suggestive of spontaneous regressions of the primary tumours.3.Both primary tumours and metastases often have brisk lymphocytic infiltrates, a phenomenon that is correlated with better outcome.4.Studies of isolates of these tumour-infiltrating T lymphocytes have revealed that a proportion of these cells recognise melanoma antigens.5.Melanomas respond to immunotherapy. These observations have led to over 30 years of research on immunotherapy for melanoma; many of these efforts have failed, with only a few exceptions: interleukin-2 (IL-2) and to a lesser degree interferon-a (IFN-〈). Recently, new developments in immunotherapy have revolutionised this treatment modality. Anti-CTLA4 has received approval from the Food and Drugs Administration (FDA) and the European Medicines Agency (EMA) for the treatment of stage IV melanomas based on the improvement in overall survival in phase III trials, and more recently blockade of PD1/PDL1 interactions has shown objective clinical responses in a stage IV melanoma in early-phase clinical trials. In addition, several independent single-institution phase I/II trials using adoptive cell therapy have shown a consistently high response rate, including durable complete remissions in a substantial percentage of treated patients. Now, for the first time, immunotherapy has moved beyond the treatment of melanoma as both CTLA4 and PD1 blockade have been shown to induce objective responses in other tumour types as well. This chapter will discuss the mechanism of action, clinical efficacy and side effects of IL-2, the novel treatments consisting of the immune checkpoint blockade drugs anti-CTLA4 and anti-PD1 and adoptive cell therapy.
Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. (1975)

The mouse, dog, and monkey toxicity data on 30 drugs was retrospectively analyzed in comparison with the actual clinical dose schedules used in man. Animal dose schedules were converted to the human schedule and comparisons were made of the human dose versus the large animal toxic dose low, toxic dose high, and lethal dose, the lethal doses for 10% and 90% of normal mice, and the optimal dose in tumor-bearing mice. If the starting dose in Phase 1 clinical trials had been selected by calculating one-third of the toxic dose low (in mg/sq m) in the most sensitive large animal species, 5 of the 30 drugs would have produced significant toxicity in the first patient. The lethal doses for 10 and 90% of normal mice and the optimal dose in L1210-bearing mice were found to offer good quantitative prediction of human toxicity. Determination of a safe and practical starting dose for Phase 1 studies should take into account not only dog and monkey data but also toxicology data in normal and tumor-bearing mice.
Production of a standard closed fracture in laboratory animal bone (1984)

To develop a technique for the production of a standard closed experimental fracture, a new apparatus was designed and tested on 40 male Sprague-Dawley rats. First, the femur was treated with an intramedullary Steinmann pin. The femoral diaphysis was then fractured by means of a blunt guillotine driven by a dropped weight. Radiographically, this technique resulted in a highly reproducible transverse fracture. There was minimal comminution and minimal angulation of the intramedullary pin. Histologically, there was minimal soft tissue damage. Mechanical testing showed that all fractures healed. Pin removal was accomplished with ease and without disturbance of the healed fracture site. The apparatus is simple to use and inexpensive to build. Through its use, a highly reproducible closed fracture model is established.
Transforming Growth Factor-β Stimulates Bone Matrix Apposition and Bone Cell Replication in Cultured Fetal Rat Calvariae* (1990)

Transforming growth factor-β (TGFβ) stimulates the expression of extracellular matrix proteins and may be a local regulator of bone growth. The aims of this research were to localize the effect of TGFjS on bone matrix formation and to determine if this effect was dependent on increased cell replication, using histomorphometry and autoradiography of bone organ cultures. Half-calvariae of 21-day-old fetal rats were cultured with native or recombinant TGFβ1 for 24 h and labeled either with [3H]proline for 0–24 or 24–48 h or with [3H]thymidine for the last 6 h of culture. Bones were fixed in glutaraldehyde, embedded in glycol methacrylate, and processed for autoradiography. Bone matrix formation was assessed as the matrix apposition rate per day and the percentage of [3H]proline-labeled bone surface. Cell replication was evaluated based on the number and percentage of [3H]thymidine labeled cells in the osteoblast cell zone, the osteoprogenitor cell zone, and the pericranial fibroblastic periosteum. Both native and recombinant TGFβ at 1-30 ng/ml increased bone matrix formation by 25-40% (P < 0.05). At 30 ng/ml, TGFβ had a generalized mitogenic effect as cell replication increased by approximately 2-fold in all cell zones of the pericranial periosteum. TGFβ had specific effects on bone cell differentiation. The number of unlabeled cells lining the bone surface increased, and the number of osteoclasts on bone decreased. Inhibition of cell replication by hydroxyurea only partially blocked the stimulatory effect of TGFβ on bone matrix formation, suggesting that TGFβ may have independent effects on cell replication and differentiated bone cell function. In summary, TGFβ had a generalized mitogenic effect on the pericranial periosteum and specific stimulatory and inhibitory effects on bone cell differentiation and function. (Endocrinology126: 421–426, 1990)
Tutorial on automated Patterson interpretation to find heavy atoms (1992)

Abstract The algorithms employed for automatic location of heavy atoms via the Patterson function in the programs SHELXS-86 and SHELXS-90 are discussed, and are illustrated in the form of two tutorial exercises. As a small molecule crystallographer participating in a macromolecular computing school, I have tried to choose a topic of importance to both small molecule and macromolecular crystallographers, namely the location of heavy atoms via the Patterson function. In the case of heavy atom derivatives of proteins this Patterson would be calculated using the isomorphous difference structure factors. At least a quarter of organic and inorganic structures are solved by the heavy atom method, and the preparation of heavy atom derivatives is almost obligatory for proteins if no suitable search model is available for molecular replacement. Despite this, there is a striking lack of user-friendly computer programs, general for all space groups and types of problem, for the automatic location of heavy atoms, in sharp contrast to the situation in small-molecule direct methods. This seems to be simply an historical accident; the necessary theory has be well understood for at least 40 years, and the computer resources required are modest.
LNA and α-L-LNA: Towards Therapeutic Applications (2003)

LNA and alpha-L-LNA are promising candidates for the development of efficient oligonucleotide-based therapeutic agents. Here, we report dose-dependent inhibition of HIV-1 Tat-dependent trans activation by a 12-mer chimeric alpha-L-LNA/DNA oligomer. This oligomer exhibits a dose-dependency similar to that of the corresponding 12-mer chimeric LNA/2'-O-Me-RNA oligomer. In addition, we show that incorporation of alpha-L-LNA or LNA monomers into each of the two binding arms of a "10-23" DNAzyme markedly increases cleavage of the target RNA.
Caspase-dependent Cleavage of Signaling Proteins during Apoptosis (1998)

Caspases are activated during apoptosis and cleave specific proteins, resulting in the irreversible commitment to cell death. The signal transduction proteins MEKK1, p21-activated kinase 2, and focal adhesion kinase are caspase substrates that contribute to the cell death response when cleaved. Thirty additional signaling proteins were screened for their ability to be cleaved during apoptosis. Twenty-two of these proteins were not affected in Jurkat cells stimulated to undergo apoptosis by Fas ligation, exposure to ultraviolet-C or incubation with etoposide. Ras GTPase-activating protein was found to be a caspase substrate whose cleavage followed the same time course as that for activation of caspase activity and the cleavage of MEKK1 and focal adhesion kinase. Four additional proteins, Cbl, Cbl-b, Raf-1, and Akt-1, were cleaved later in the apoptotic response. These signaling proteins were similarly cleaved in U937 cells undergoing apoptosis. Cleavage of the proteins was blocked by caspase inhibitors in Jurkat cells or in U937 cells expressing BclxL, demonstrating that the cleavage was dependent on caspase activation. Cleavage of Raf-1 and Akt correlated with the loss of extracellular signal-regulated kinase and Akt activities in apoptotic cells. Neither c-Jun N-terminal kinase nor p38 mitogen-activated protein kinase was cleaved in cells undergoing apoptosis, and the activation of the c-Jun N-terminal kinase and p38 mitogen-activated protein kinase pathways was not compromised in apoptotic cells. These results indicate that caspase-dependent cleavage of specific proteins induces the turn off of survival pathways, such as the extracellular signal-regulated kinase and phosphatidylinositol-3 kinase/Akt pathways, that could otherwise interfere with the apoptotic response.
Habituation of Odor Responses in the Rat Anterior Piriform Cortex (1998)

Simultaneous recordings of main olfactory bulb (MOB) and anterior piriform cortex (aPCX) neuron responses to repeated and prolonged odor pulses were examined in freely breathing, urethan-anesthetized rats. Comparisons of odor responses were made between multi-unit recordings of MOB activity and single-unit extracellular and intracellular recordings of Layer II/III aPCX neurons. Odor stimuli consisted of either 2-s pulses repeated at 30-s intervals or a single, prolonged 50-s stimulus. Respiration rate was monitored throughout. MOB and aPCX neuron responses to odor were quantified both through firing frequency and through the temporal patterning of firing over the respiratory cycle. The results demonstrate that aPCX neurons habituate significantly more (faster) than MOB neurons with both repeated and prolonged stimulation paradigms. This enhanced habituation is expressed as both a decrease in aPCX firing despite maintained odor-evoked MOB input and as a decrease in aPCX respiratory cycle entrainment despite maintained MOB cyclic input. Intracellular aPCX recordings suggest that several mechanisms may be involved in this experience-induced change in aPCX function, including 1) decreased excitatory driveof aPCX neurons, 2) decreased excitability of aPCX neurons,and/or 3) enhancement in odor-evoked inhibition of aPCX neurons. These studies provide the initial basis for understanding the mechanisms of nonassociative plasticity in olfactory cortex.
Phagocytosis (1995)

Phagocytosis is the process of recognition and engulfment of microorganisms or tissue debris that accumulate during infection, inflammation or wound repair. This ingestion, which is performed most efficiently by migrating, bone marrow-derived cells called 'professional phagocytes', is essential for successful host defense. Ingestion results when an invading microorganism is recognized by specific receptors on the phagocyte surface and requires multiple, successive interactions between the phagocyte and the target. Each of these interactions results in a signal transduction event, which is confined to the membrane and cytoskeleton around the ligated receptor and which is required for successful phagocytosis. Many molecules found at sites of inflammation or infection stimulate phagocytosis, so that efficient ingestion is confined to the site of infection or inflammation, which in turn limits the proinflammatory and tissue-destructive processes that accompany phagocytosis. This review summarizes current understanding of this critical component of host defense and of its regulation.
Effects of Tau Domain-Specific Antibodies and Intravenous Immunoglobulin on Tau Aggregation and Aggregate Degradation (2014)

Tau pathology, including neurofibrillary tangles, develops in Alzheimer's disease (AD). The aggregation and hyperphosphorylation of tau are potential therapeutic targets for AD. Administration of anti-tau antibodies reduces tau pathology in transgenic "tauopathy" mice; however, the optimal tau epitopes and conformations to target are unclear. Also unknown is whether intravenous immunoglobulin (IVIG) products, currently being evaluated in AD trials, exert effects on pathological tau. This study examined the effects of anti-tau antibodies targeting different tau epitopes and the IVIG Gammagard on tau aggregation and preformed tau aggregates. Tau aggregation was assessed by transmission electron microscopy and fluorescence spectroscopy, and the binding affinity of the anti-tau antibodies for tau was evaluated by enzyme-linked immunosorbent assays. Antibodies used were anti-tau 1-150 ("D-8"), anti-tau 259-266 ("Paired-262"), anti-tau 341-360 ("A-10"), and anti-tau 404-441 ("Tau-46"), which bind to tau's N-terminus, microtubule binding domain (MBD) repeat sequences R1 and R4, and the C-terminus, respectively. The antibodies Paired-262 and A-10, but not D-8 and Tau-46, reduced tau fibrillization and degraded preformed tau aggregates, whereas the IVIG reduced tau aggregation but did not alter preformed aggregates. The binding affinities of the antibodies for the epitope for which they were specific did not appear to be related to their effects on tau aggregation. These results confirm that antibody binding to tau's MBD repeat sequences may inhibit tau aggregation and indicate that such antibodies may also degrade preformed tau aggregates. In the presence of anti-tau antibodies, the resulting tau morphologies were antigen-dependent. The results also suggested the possibility of different pathways regulating antibody-mediated inhibition of tau aggregation and antibody-mediated degradation of preformed tau aggregates.
SACRAL NERVE ROOT NEUROMODULATION: AN EFFECTIVE TREATMENT FOR REFRACTORY URGE INCONTINENCE (1998)

Sacral root neuromodulation is an appealing modality for treatment of urge incontinence refractory to conventional pharmacotherapy. The relative simplicity of the technique, promising results and low complication rate make this therapy a likely alternative.
Nucleotide sequence of the human placental alkaline phosphatase gene. Evolution of the 5′ flanking region by deletion/substitution. (1988)

Three closely related alkaline phosphatase (ALP) genes reside on the long arm of chromosome 2 in man. One of these genes (the placental ALP-1) encodes the classic heat-stable placental alkaline phosphatase. Another gene (the placental ALP-2) is closely related to the placental ALP-1 and may encode the so-called placental ALP-like enzyme of the testis and thymus. The third member of this gene family (the intestinal ALP gene) encodes the intestinal alkaline phosphatase. The expression of the placental ALP-1 and intestinal ALP genes is highly tissue-specific in spite of nearly 90% sequence similarity within their exons. To help determine the basis for this tissue specificity, the nucleotide sequence of the placental ALP-1 gene and some of its 5' flanking region has been determined and analyzed by comparison with placental ALP-2 and intestinal ALP gene sequences. The placental ALP-1 gene transcription unit has 4087 bases between the major cap site and the most distal of several reported 3' ends. The protein coding region is divided by 10 short introns varying in size from 74 to 241 nucleotides. Three of these introns bisect regions of the gene that encode residues conserved between the active site of the Escherichia coli enzyme and the human placental ALP. This result suggests that the human alkaline phosphatase genes have evolved in an intron-independent fashion. A comparison of the placental ALP-1 5' flanking sequence (up to -540) with the analogous sequence of the intestinal ALP gene revealed several deletion/substitutions which could be important in determining the tissue-specific expression of these genes.
Dislocation engineering in strained mos materials (2005)

Strain in electronic devices is receiving renewed interest due to the advantageous effects of strain on carrier mobility, and therefore drive current. However, the physics of strain incorporation, by definition, introduces the physics of strain relief. At typical CMOS process temperatures, semiconductors become ductile, and therefore dislocation nucleation and glide are the most common means of plastic relaxation. To obtain the highest levels of strain, dislocation nucleation and propagation must be avoided. It can be advantageous to create alternative lattice constants for creating strain in other regions, in which case plastic deformation is purposely created in the structure and dislocation sites must be managed. If the goal for the particular device is to create completely relaxed lattice constants, we show global and local methods to control threading dislocation densities. We also show methods to achieve the opposite, i.e. larger values of strain, higher than the level expected in equilibrium. By understanding the nature of dislocation nucleation and propagation, we can overcome future dislocation engineering challenges for new materials systems such as III-V MISFIT heterostructures
Effects of Androgens on the Insulin-Like Growth Factor System in an Androgen-Responsive Human Osteoblastic Cell Line (1999)

Although androgens have significant effects on bone metabolism, the mediators of their effects are still unclear. As the insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have important effects on osteoblast proliferation and differentiation, we examined androgen effects on the IGF system in a conditionally immortalized human fetal osteoblastic cell line, hFOB/AR-6, which displays a mature osteoblastic phenotype and physiological levels of functional androgen receptors. The nonaromatizable androgen, 5alpha-dihydrotestosterone (5alphaDHT), and testosterone, but not dehydroepiandrosterone, increased IGF-I messenger RNA (mRNA) levels up to 4-fold in a dose (10(-12)-10(-6) M)- and time (2-72 h)-dependent fashion. These changes were prevented by the specific androgen receptor antagonist, hydroxyflutamide. In addition, 5alpha-DHT decreased IGFBP-4 mRNA and protein levels by 2- and 4-fold, respectively, and increased IGFBP-2 and -3 mRNA and protein levels by 6- and 7-fold (for mRNA) and 3- and 5-fold (for protein), respectively. hFOB/AR-6 cells expressed the type-I IGF receptor, but this was not regulated by 5alphaDHT. 5alphaDHT and IGFBP-3 specifically increased hFOB/AR-6 cell proliferation, and a monoclonal antibody specific for IGF-I blocked this effect. Thus, androgens increase the expression of IGF-I, IGFBP-2, and IGFBP-3, but decrease levels of the inhibitory IGFBP-4 in an androgen-responsive human osteoblastic cell line. Our data are consistent with the hypothesis that the effects of androgen on bone cells may be mediated at least in part by increases in IGF-I production and by differential regulation of IGFBPs.
Ley para la Reforma del Estadoy Transición a la Democracia(una visión escéptica) (2007)

Del análisis de las condiciones de aprobación, y del carácter de la agenda de la LPRE, todo parece indicar que el resultado de esa ley podría constituirse en el oxígeno que el gobierno de Felipe Calderón requiere para lograr la legitimidad social y política que no obtuvo del proceso electoral. Si revisamos la astucia del estado mexicano para renovar sus fuentes de legitimidad fuera de los cánones de los procesos electorales, el hecho se repite en diversos momentos históricos. Lo ilustro con las coyunturas históricas más recientes.
Binding of Phosphates to Aminocyclodextrin Biomimetics (1999)

Aminocyclodextrins (ACDs) in which the primary face is perfacially substituted with amino pendant groups provide three potential biomimetic binding domains: the hydrophobic cavity, the cationic annulus, and the corona formed by the pendant tendrils. Binding of phosphate monoester dianions and diester monoanions by ACDs and native CDs is compared to that of neutral guest molecules. Binding to ACDs can be understood in terms of cooperativity between binding domains in which electrostatic and hydrophobic forces may be additive or compromised. Unexpectedly, slow chemical exchange is observed, in particular for dianionic aryl ester guest molecules. The substantial kinetic barriers for dissociation of these pseudorotaxane complexes are explained by the unfavorable passage of the anionic phosphate headgroup through the relatively hydrophobic ACD cavity.
A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2) (1999)

A novel human organic transporter, OATP2, has been identified that transports taurocholic acid, the adrenal androgen dehydroepiandrosterone sulfate, and thyroid hormone, as well as the hydroxymethylglutaryl-CoA reductase inhibitor, pravastatin. OATP2 is expressed exclusively in liver in contrast to all other known transporter subtypes that are found in both hepatic and nonhepatic tissues. OATP2 is considerably diverged from other family members, sharing only 42% sequence identity with the four other subtypes. Furthermore, unlike other subtypes, OATP2 did not transport digoxin or aldosterone. The rat isoform oatp1 was also shown to transport pravastatin, whereas other members of the OATP family, i.e. rat oatp2, human OATP, and the prostaglandin transporter, did not. Cis-inhibition studies indicate that both OATP2 and roatp1 also transport other statins including lovastatin, simvastatin, and atorvastatin. In summary, OATP2 is a novel organic anion transport protein that has overlapping but not identical substrate specificities with each of the other subtypes and, with its liver-specific expression, represents a functionally distinct OATP isoform. Furthermore, the identification of oatp1 and OATP2 as pravastatin transporters suggests that they are responsible for the hepatic uptake of this liver-specific hydroxymethylglutaryl-CoA reductase inhibitor in rat and man.
Siblings with severe pyruvate kinase deficiency and a complex genotype (2016)

Siblings presented as neonates with severe jaundice and transfusion-dependent hemolytic anemia. Next-generation sequencing revealed both to have three heterozygous mutations in the gene encoding erythrocyte pyruvate kinase (PKLR), plus a heterozygous splice mutation in the beta-spectrin gene (SPTB). In addition, both have a different 5th mutation in a gene encoding other erythrocyte membrane proteins. The asymptomatic parents and all three asymptomatic siblings have different sets of these mutations. © 2016 Wiley Periodicals, Inc.