gebhart/patrepeval huggingface dataset:
mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. (2001)

The mammalian target of rapamycin (mTOR) is a central regulator of G1 cell cycle protein synthesis that precedes commitment to normal cellular replication. We have studied the effect of cell cycle inhibitor-779 (CCI-779), a rapamycin ester that inhibits mTOR function, on the proliferation of a panel of breast cancer cell lines. Six of eight lines studied were sensitive (IC(50)< or = 50 nM) and two lines were resistant (IC(50)>1.0 microM) to CCI-779. Sensitive lines were estrogen dependent (MCF-7, BT-474, T-47D), or lacked expression of the tumor suppressor PTEN (MDA-MB-468, BT-549), and/or overexpressed the Her-2/neu oncogene (SKBR-3, BT-474). Resistant lines (MDA-MB-435, MDA-MB-231) shared none of these properties. CCI-779 (50 nM) inhibited mTOR function in both a sensitive and a resistant line. In nu/nu mouse xenografts, CCI-779 inhibited growth of MDA-MB-468 (sensitive) but not MDA-MB-435 resistant tumors. Treatment of sensitive lines with CCI-779 resulted in a decrease in D-type cyclin and c-myc levels and an increase in p27(kip-1) levels. There was good correlation between activation of the Akt pathway and sensitivity to CCI-779. Amplification of mTOR-regulated p70S6 kinase, which is downstream of Akt, may also have conferred CCI-779 sensitivity to MCF-7 cells. Taken together, the data suggest that mTOR may be a good target for breast cancer therapy, especially in tumors with Akt activation resulting from either growth factor dependency or loss of PTEN function.
Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model (2006)

These findings support the MSW hypothesis and suggest comparable antistaphylococcal effects of clinically achievable AUC24/MIC90s of daptomycin and vancomycin but slightly better prevention against the selection of resistant S. aureus by daptomycin.
Adaptive antenna systems (1967)

A system consisting of an antenna array and an adaptive processor can perform filtering in both the space and the frequency domains, thus reducing the sensitivity of the signal-receiving system to interfering directional noise sources. Variable weights of a signal processor can be automatically adjusted by a simple adaptive technique based on the least-mean-squares (LMS) algorithm. During the adaptive process an injected pilot signal simulates a received signal from a desired "look" direction. This allows the array to be "trained" so that its directivity pattern has a main lobe in the previously specified look direction. At the same time, the array processing system can reject any incident noises, whose directions of propagation are different from the desired look direction, by forming appropriate nulls in the antenna directivity pattern. The array adapts itself to form a main lobe, with its direction and bandwidth determined by the pilot signal, and to reject signals or noises occurring outside the main lobe as well as possible in the minimum mean-square error sense. Several examples illustrate the convergence of the LMS adaptation procedure toward the corresponding Wiener optimum solutions. Rates of adaptation and misadjustments of the solutions are predicted theoretically and checked experimentally. Substantial reductions in noise reception are demonstrated in computer-simulated experiments. The techniques described are applicable to signal-receiving arrays for use over a wide range of frequencies.
The anti‐apoptotic genes Bcl‐XL and Bcl‐2 are over‐expressed and contribute to chemoresistance of non‐proliferating leukaemic CD34+ cells (2002)

In acute myeloid leukaemia (AML), cell kinetic quiescence has been postulated to contribute to drug resistance. As the anti-apoptotic genes Bcl-2 and Bcl-X(L) have been implicated in cell cycle regulation, we investigated the expression of these genes in non-proliferating (Q) and proliferating (P) AML and normal CD34+ progenitor cells. Using reverse transcription polymerase chain reaction, Bcl-X(L) and Bcl-2 were overexpressed in Q versus P AML cells, whereas no difference in Bcl-XS and Bax expression was found. Furthermore, the Bcl-X(L)/X(S) but not the Bcl-2/Bax ratio was higher in Q AML compared with normal CD34+ Q cells (P = 0.001). An inverse correlation between Bcl-2 expression of leukaemic Q cells and their ability to enter the cell cycle was found. Treatment with all-trans retinoic acid (ATRA) reduced Bcl-2 and Bcl-X(L) expression in the leukaemic Q cells, and enhanced their chemosensitivity to cytosine arabinoside (ara-C). These findings demonstrate overexpression of the anti-apoptotic proteins Bcl-X(L) and Bcl-2 in quiescent CD34+ AML cells and suggest their involvement in the chemoresistance. The observed inverse correlation between Bcl-2 and proliferation suggests a role for Bcl-2 in the cell cycle regulation of AML. These findings could be used in the development of therapies that selectively induce apoptosis in quiescent leukaemic progenitor cells.
Assays for Controlling Host-Cell Impurities in Biopharmaceuticals (2005)

the manufacture of biopharmaceuticals is purification of the drug substance. The downstream process must remove all contaminants, including host cell material such as DNA and cellular protein. Trace amounts of host-cell DNA and proteins can be copurified along with the drug substance. Such contaminants are obviously undesirable because of possible consequences if they are injected into patients along with it. They could potentially cause allergic reactions (proteins) or even transfection of cells (DNA) resulting in tumors. Because of those potential negative effects, regulatory authorities have released several guidance documents about what levels of impurities are acceptable. Residual DNA in final bulk products should be generally lower than 100 pg per therapeutic dose (1). Other references suggest that higher levels may be acceptable (2). The 100pg limit requires a purification process that is very effective and robust in removing DNA — as well as analytical methods that are extremely sensitive and reliable to prove it. Host-cell proteins in the drug substance should be “below detectable levels using a highly sensitive analytical method” (1). As a rule, that amount should not exceed a level of about 100 ppm. But no exact limit is set for proteins; therefore, the specification for proteins must be determined case by case. According to the European Agency for the Evaluation of Medicinal Products, EMEA (3), two different strategies can be used to ensure that a drug substance is within the allowable limits of contamination with DNA or hostcell proteins. You can either validate that a process removes sufficient amounts of such contaminants or perform routine final product testing to determine whether they are present. With the validation approach, known amounts of DNA are spiked into a downstream process. The various steps within that process are then examined to determine their capability to remove the contamination. This approach is most commonly used for DNA. Robustness and consistency in DNA removal also must be shown by measuring the amounts contaminating several batches of product. Routine testing determines host-cell DNA and proteins in each product batch as part of the lotrelease data. No matter which approach is used, the assays and methods involved in determination of residual DNA and proteins must fulfill ICH validation requirements (4, 5). Obviously those techniques must be sensitive enough to determine very low levels of contamination (e.g., in the ppm range). Here we describe some common analytical methods used.
The Stomach Divalent Ion-sensing Receptor SCAR Is a Modulator of Gastric Acid Secretion (2001)

Divalent cation receptors have recently been identified in a wide variety of tissues and organs, yet their exact function remains controversial. We have previously identified a member of this receptor family in the stomach and have demonstrated that it is localized to the parietal cell, the acid secretory cell of the gastric gland. The activation of acid secretion has been classically defined as being regulated by two pathways: a neuronal pathway (mediated by acetylcholine) and an endocrine pathway (mediated by gastrin and histamine). Here, we identified a novel pathway modulating gastric acid secretion through the stomach calcium-sensing receptor (SCAR) located on the basolateral membrane of gastric parietal cells. Activation of SCAR in the intact rat gastric gland by divalent cations (Ca(2+) or Mg(2+)) or by the potent stimulator gadolinium (Gd(3+)) led to an increase in the rate of acid secretion through the apical H+,K+ -ATPase. Gd(3+) was able to activate acid secretion through the omeprazole-sensitive H+,K+ -ATPase even in the absence of the classical stimulator histamine. In contrast, inhibition of SCAR by reduction of extracellular cations abolished the stimulatory effect of histamine on gastric acid secretion, providing evidence for the regulation of the proton secretory transport protein by the receptor. These studies present the first example of a member of the divalent cation receptors modulating a plasma membrane transport protein and may lead to new insights into the regulation of gastric acid secretion.
Regulation of cell motile behavior by crosstalk between cadherin- and integrin-mediated adhesions (2010)

During normal development and in disease, cohesive tissues undergo rearrangements that require integration of signals from cell adhesions to neighboring cells and to the extracellular matrix (ECM). How a range of cell behaviors is coordinated by these different adhesion complexes is unknown. To analyze epithelial cell motile behavior in response to combinations of cell-ECM and cell-cell adhesion cues, we took a reductionist approach at the single-cell scale by using unique, functionalized micropatterned surfaces comprising alternating stripes of ECM (collagenIV) and adjustable amounts of E-cadherin-Fc (EcadFc). On these surfaces, individual cells spatially segregated integrin- and cadherin-based complexes between collagenIV and EcadFc surfaces, respectively. Cell migration required collagenIV and did not occur on surfaces functionalized with only EcadFc. However, E-cadherin adhesion dampened lamellipodia activity on both collagenIV and EcadFc surfaces and biased the direction of cell migration without affecting the migration rate, all in an EcadFc concentration-dependent manner. Traction force microscopy showed that spatial confinement of integrin-based adhesions to collagenIV stripes induced anisotropic cell traction on collagenIV and migration directional bias. Selective depletion of different pools of alphaE-catenin, an E-cadherin and actin binding protein, identified a membrane-associated pool required for E-cadherin-mediated adhesion and down-regulation of lamellipodia activity and a cytosolic pool that down-regulated the migration rate in an E-cadherin adhesion-independent manner. These results demonstrate that there is crosstalk between E-cadherin- and integrin-based adhesion complexes and that E-cadherin regulates lamellipodia activity and cell migration directionality, but not cell migration rate.
Virus-mediated delivery of antigenic epitopes into dendritic cells as a means to induce CTL. (1997)

Dendritic cells (DC) are potent inducers of CD8+ T cells and can stimulate protective antitumor immunity when pulsed with an antigenic peptide or protein. We used a replication-deficient adenovirus containing a Kb-restricted antigenic peptide of chicken OVA to study CTL induction in vitro and in vivo after adenovirus-mediated gene transfer into DC. The efficiency of adenovirus-infected DC in eliciting a specific CTL response was compared with immunizations with a recombinant vaccinia virus and DC pulsed with peptide or protein. An immortalized DC line derived from a C57BL/6 mouse and freshly isolated splenic DC from C57BL/6 mice were used in CTL induction. Virus-infected DC elicited the strongest Ag-specific CTL response in vitro and in vivo and induced protective antitumor immunity to a challenge with EG.7 tumors (EL-4 cell line expressing OVA). Direct immunization of mice with recombinant adenovirus resulted in the induction of high titers of neutralizing Abs, which precluded a boost of a CTL response after repeated inoculations. However, repeated injections of virus-infected DC induced only low titers of neutralizing Abs. Furthermore, the presence of neutralizing Abs specific for the virus did not affect the usefulness of infected DC as repeated applications of virus-infected DC boosted the CTL response even in mice previously infected with the recombinant vector. The use of DC infected with a recombinant virus has advantages over other forms of immunization and could provide an alternative approach for designing vaccination therapies.
Autism spectrum disorder severity reflects the average contribution of de novo and familial influences (2014)

Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions--phenotypically and genetically--although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.
NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy (2015)

Natural killer (NK) cells play a major role in cancer immunotherapies that involve tumor-antigen targeting by monoclonal antibodies (mAbs). NK cells express a variety of activating and inhibitory receptors that serve to regulate the function and activity of the cells. In the context of targeting cells, NK cells can be "specifically activated" through certain Fc receptors that are expressed on their cell surface. NK cells can express FcγRIIIA and/or FcγRIIC, which can bind to the Fc portion of immunoglobulins, transmitting activating signals within NK cells. Once activated through Fc receptors by antibodies bound to target cells, NK cells are able to lyse target cells without priming, and secrete cytokines like interferon gamma to recruit adaptive immune cells. This antibody-dependent cell-mediated cytotoxicity (ADCC) of tumor cells is utilized in the treatment of various cancers overexpressing unique antigens, such as neuroblastoma, breast cancer, B cell lymphoma, and others. NK cells also express a family of receptors called killer immunoglobulin-like receptors (KIRs), which regulate the function and response of NK cells toward target cells through their interaction with their cognate ligands that are expressed on tumor cells. Genetic polymorphisms in KIR and KIR-ligands, as well as FcγRs may influence NK cell responsiveness in conjunction with mAb immunotherapies. This review focuses on current therapeutic mAbs, different strategies to augment the anti-tumor efficacy of ADCC, and genotypic factors that may influence patient responses to antibody-dependent immunotherapies.
Oncolytic viruses: a step into cancer immunotherapy (2011)

Abstract: Oncolytic virotherapy is currently under investigation in phase I–III clinical trials for approval as a new cancer treatment. Oncolytic viruses (OVs) selectively infect, replicate in, and kill tumor cells. For a long time, the therapeutic efficacy was thought to depend on the direct viral oncolysis (virocentric view). The host immune system was considered as a brake that impaired virus delivery and spread. Attention was paid primarily to approaches enhancing virus tumor selectivity and cytotoxicity and/or that limited antiviral responses. Thinking has changed over the past few years with the discovery that OV therapy was also inducing indirect oncolysis mechanisms. Among them, induction of an antitumor immunity following OV injection appeared to be a key factor for an efficient therapeutic activity (immunocentric view). Indeed, tumor-specific immune cells persist post-therapy and can search and destroy any tumor cells that escape the OVs, and thus immune memory may prevent relapse of the disease. Various strategies, which are summarized in this manuscript, have been developed to enhance the efficacy of OV therapy with a focus on its immunotherapeutic aspects. These include genetic engineering and combination with existing cancer treatments. Several are currently being evaluated in human patients and already display promising efficacy. Keywords: oncolytic virus, cancer immunotherapy, tumor antigen, cancer vaccine, combination strategies
Hannah Montana’s Bare, Unprotected Back: Miley Cyrus’s <i>Vanity Fair</i> Outing (2010)

ere we go again: another kid we have made into a centerfold and tell ourselves is merely “cute” (as if there were a “merely” there). She follows our undercover instructions, tarts herself up for public consumption, and now takes the heat for doing as she’s told. This time it’s Miley Cyrus, subject of some photos, the most recent by the canny (and smarmy) Annie Leibovitz in June 2008’s Vanity Fair. The photo in question shows a heavily madeup Cyrus, then fifteen, hair messy, eyes droopy, clutching a sheet to her chest as she faces us from the side, flashing (gasp) bare shoulders and full back. The possibility exists— you care, right?—that she is topless, maybe bottomless, maybe even shoeless—who can know for sure? Some feel (and many have said) that she looks as if she had just had sex or something equally unthinkable for a fifteen year old (which explains why we think it). Others say, c’mon, get over it, she’s only doing what kids enjoy doing, get a life, leave her alone. I side with the second group, I guess, though I can’t but wonder why so much attention is being paid. Hey, I went on one site inviting comments—I am a responsible scholar and figured I should inform myself—and blithely set the printer to running. I found myself, 347 pages later, with a couple of thousand gems like this:
A molluskivorous Conus toxin: conserved frameworks in conotoxins (1989)

We purified and characterized a 27 amino acid toxin from a snail-hunting Conus venom, Conus textile. This toxin causes convulsive-like activity in snails and causes subordinate lobsters to assume an exaggerated dominant posture. The sequence of this peptide is Trp-Cys-Lys-Gln-Ser-Gly-Glu-Met-Cys-Asn-Leu-Leu-Asp-Gln-Asn-Cys-Cys-Asp- Gly-Tyr-Cys-Ile-Val-Leu-Val-Cys-Thr. The sequence was confirmed by determining the nucleotide sequence of a cDNA clone coding for the peptide. The conservation of Cys residues compared to the omega-conotoxins from piscivorous Conus venom suggests that toxins from different cone venoms may use only a few "Cys-motifs" as conserved structural backbones for targeting to a variety of receptors in different animals.
Crystal Structure of the Biglycan Dimer and Evidence That Dimerization Is Essential for Folding and Stability of Class I Small Leucine-rich Repeat Proteoglycans (2006)

Biglycan and decorin are two closely related proteoglycans whose protein cores contain leucine-rich repeats flanked by disulfides. We have previously shown that decorin is dimeric both in solution and in crystal structures. In this study we determined whether biglycan dimerizes and investigated the role of dimerization in the folding and stability of these proteoglycans. We used light scattering to show that biglycan is dimeric in solution and solved the crystal structure of the glycoprotein core of biglycan at 3.40-angstroms resolution. This structure reveals that biglycan dimerizes in the same way as decorin, i.e. by apposition of the concave inner surfaces of the leucine-rich repeat domains. We demonstrate that low concentrations of guanidinium chloride denature biglycan and decorin but that the denaturation is completely reversible following removal of the guanidinium chloride, as assessed by circular dichroism spectroscopy. Furthermore, the rate of refolding is dependent on protein concentration, demonstrating that it is not a unimolecular process. Upon heating, decorin shows a single structural transition at a T(m) of 45-46 degrees C but refolds completely upon cooling to 25 degrees C. This property of decorin enabled us to show both by calorimetry and light scattering that dimer to monomer transition coincided with unfolding and monomer to dimer transition coincided with refolding; thus these processes are inextricably linked. We further conclude that folded monomeric biglycan or decorin cannot exist in solution. This implies novel interrelated functions for the parallel beta sheet faces of these leucine-rich repeat proteoglycans, including dimerization and stabilization of protein folding.
SOMETHING FROM ALMOST NOTHING: Carbon Dioxide Fixation in Chemoautotrophs (1998)

The last decade has seen significant advances in our understanding of the physiology, ecology, and molecular biology of chemoautotrophic bacteria. Many ecosystems are dependent on CO2 fixation by either free-living or symbiotic chemoautotrophs. CO2 fixation in the chemoautotroph occurs via the Calvin-Benson-Bassham cycle. The cycle is characterized by three unique enzymatic activities: ribulose bisphosphate carboxylase/oxygenase, phosphoribulokinase, and sedoheptulose bisphosphatase. Ribulose bisphosphate carboxylase/oxygenase is commonly found in the cytoplasm, but a number of bacteria package much of the enzyme into polyhedral organelles, the carboxysomes. The carboxysome genes are located adjacent to cbb genes, which are often, but not always, clustered in large operons. The availability of carbon and reduced substrates control the expression of cbb genes in concert with the LysR-type transcriptional regulator, CbbR. Additional regulatory proteins may also be involved. All of these, as well as related topics, are discussed in detail in this review.
Evaluation of a miniature blood glucose sensor. (1989)

A miniature version of the electrocatalytic glucose sensor has been designed and fabricated with thick-film metalization technology. The in vitro stability tests of the sensor were performed in buffered saline, human plasma ultrafiltrate, and bovine plasma. For bovine plasma studies the sensor was directly coated with a semipermeable ethylene vinyl alcohol (EVAL) membrane. To stabilize the activity of the sensing platinum electrode, a fast-pulsing reactivation method was applied. Good performance of the continuously operating sensor was achieved in buffer (10% stability of the baseline current within 12 days) and human ultrafiltrate (10% stability of the baseline current and 5% stability of the sensitivity within 7 days). However, for measurements in plasma a slow degradation of the sensor's sensitivity (approximately 10% per day) was observed. These results indicate that when a proper screening membrane is provided the continuous glucose monitoring of body fluids with the miniature sensor is possible for at least 7 days.