gebhart/patrepeval huggingface dataset:
Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review (2018)

Deregulation of the cyclin D-CDK4/6-INK4-RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle-specific mechanisms and cell cycle-nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.
Antigenicity of trophoblast and possible antigen-masking effects during pregnancy. (1975)

The interaction between cultured human trophoblast cells and materanl lymphocytes was used as an in vitro model to investigate trophoblast antigenicity. Cytotoxic effects in the trophoblast monolayer were apparent after 72 hr incubation and depended on the presence of non-lymphoid cell types in addition to lymphocytes. Lysis of trophoblast was preceded by blast cell formation and apparently involved close contact between the maternal cells and the trophoblast cells. The nature of the cytotoxic reaction suggested the presence of histocompatibility factors on trypsinized trophoblast cells. This manifestation could be due to removal of fibrinoid or enhancing antibody from the cultured cells. The ability of trypsinized trophoblast cells to synthesize mucoprotein was investigated by the Hale colloidal iron test and found to be unimpaired. The effect of maternal serum on the recognition of human trophoblast antigens by maternal lymphocytes was used as an in vitro model to investigate the occurrence of enhancing antibody in maternal serum. The cytotoxic effects of maternal lymphocytes on trophoblast were completely prevented by the presence of maternal serum, this protective effect being reduced significantly by removal of IgG from the maternal serum. A slight protective effect of allogeneic pregnancy serum was also observed. It is suggested that these findings support a role for immunological enhancement in maintaining the foetal allograft.
Extrinsic Innervation of the Canine Superior Vena Cava, Pulmonary, Portal and Renal Veins (1984)

The responses of the superior vena cava, portal, pulmonary, and renal veins to electrical stimulation of sympathetic nerves were investigated in dog. The vascular response was measured by the method with an intravascular cuff. The contractile responses to neural stimuli were mediated mainly by adrenergic mechanism in the four veins and that of the portal vein was, in addition, mediated in part by cholinergic one. The latter mechanism was also found in some cases of the pulmonary vein. As for the superior vena cava and the left renal vein the right-side dominancy in innervation was observed. These observations suggest a possible correlation between the embryogenesis of vein and its innervation.
A Chinese hamster ovary cell mutant with a heat-sensitive, conditional-lethal defect in vacuolar function. (1984)

We describe a mutant derived from Chinese hamster ovary cells that is offt-sensitive for viability and for resistance to certain protein toxins. This mutant, termed G.7.1, grows normally at 34 degrees C but does not grow in Dulbecco's modified Eagle's medium at 39.5 degrees C. However, when this medium is supplemented with FeSO4, the mutant cells will grow at the elevated temperature. At 39.5 degrees C, G.7.1 cells acquire resistance to diphtheria toxin, modeccin, and Pseudomonas aeruginosa exotoxin A, all of which are protein toxins that require endocytosis and exposure to a low pH within vesicles before they can invade the cytosol and kill cells. The properties of mutant G.7.1 could result from a heat-sensitive lesion that impairs vacuolar acidification. We assayed the ATP-stimulated generation of pH gradients across the membrane of vesicles in cell-free preparations from mutant and parental cells by the partitioning of acridine orange into acidic compartments and found that the acidification response of the mutant cells was heat-labile. Altogether the evidence suggests that G.7.1 cells contain a heat-sensitive lesion that impairs vacuolar acidification and that they fail to grow in normal medium at 39.5 degrees C because they cannot extract Fe+3 from transferrin, a process that normally requires exposing transferrin to a low pH within endosomal vesicles.
Combined immune checkpoint blockade as a therapeutic strategy for BRCA1 -mutated breast cancer (2017)

Immune checkpoint inhibitors have emerged as a potent new class of anticancer therapy. They have changed the treatment landscape for a range of tumors, particularly those with a high mutational load. To date, however, modest results have been observed in breast cancer, where tumors are rarely hypermutated. Because <i>BRCA1</i>-associated tumors frequently exhibit a triple-negative phenotype with extensive lymphocyte infiltration, we explored their mutational load, immune profile, and response to checkpoint inhibition in a <i>Brca1</i>-deficient tumor model. <i>BRCA1</i>-mutated triple-negative breast cancers (TNBCs) exhibited an increased somatic mutational load and greater numbers of tumor-infiltrating lymphocytes, with increased expression of immunomodulatory genes including <i>PDCD1</i> (<i>PD-1</i>) and <i>CTLA4</i>, when compared to TNBCs from <i>BRCA1</i>-wild-type patients. Cisplatin treatment combined with dual anti-programmed death-1 and anti-cytotoxic T lymphocyte-associated antigen 4 therapy substantially augmented antitumor immunity in <i>Brca1</i>-deficient mice, resulting in an avid systemic and intratumoral immune response. This response involved enhanced dendritic cell activation, reduced suppressive FOXP3<sup>+</sup> regulatory T cells, and concomitant increase in the activation of tumor-infiltrating cytotoxic CD8<sup>+</sup> and CD4<sup>+</sup> T cells, characterized by the induction of polyfunctional cytokine-producing T cells. Dual (but not single) checkpoint blockade together with cisplatin profoundly attenuated the growth of <i>Brca1</i>-deficient tumors in vivo and improved survival. These findings provide a rationale for clinical studies of combined immune checkpoint blockade in <i>BRCA1</i>-associated TNBC.
Dynamics of Electron Transport by Elastic Bending of Short DNA Duplexes. Experimental Study and Quantitative Modeling of the Cyclic Voltammetric Behavior of 3‘-Ferrocenyl DNA End-Grafted on Gold (2005)

The dynamics of electron transport within a molecular monolayer of 3'-ferrocenylated-(dT)(20) strands, 5'-thiol end-grafted onto gold electrode surfaces via a short C2-alkyl linker, is analyzed using cyclic voltammetry as the excitation/measurement technique. It is shown that the single-stranded DNA layer behaves as a diffusionless system, due to the high flexibility of the ss-DNA chain. Upon hybridization by the fully complementary (dA)(20) target, the DNA-modified gold electrode displays a highly unusual voltammetric behavior, the faradaic signal even ultimately switching off at a high enough potential scan rate. This remarkable extinction phenomenon is qualitatively and quantitatively justified by the model of elastic bending diffusion developed in the present work which describes the motion of the DNA-borne ferrocene moiety as resulting from the elastic bending of the duplex DNA toward and away from the electrode surface. Its use allows us to demonstrate that the dynamics of electron transport within the hybridized DNA layer is solely controlled by the intrinsic bending elasticity of ds-DNA. Fast scan rate cyclic voltammetry of end-grafted, redox-labeled DNA layers is shown to be an extremely efficient method to probe the bending dynamics of short-DNA fragments in the submillisecond time range. The persistence length of the end-anchored ds-DNA, a parameter quantifying the flexibility of the nanometer-long duplex, can then be straightforwardly and accurately determined from the voltammetry data.
Location of phosphatidylethanolamine and phosphatidylserine in the human platelet plasma membrane. (1976)

The location of phospholipids in the human platelet plasma membrane was probed with 2, 4, 6-trinitrobenzenesulfonate (TNBS). TNBS does not penetrate inintact cells and can label phosphatidylethanolamine (PE) and phosphatidylserine (PS). In tact platelets, PE is not accessible to TNBS during the initial 15 min. However, 6.9% PE reacts with TNBS after 30 min and 17.9% PE is labeled after 90 min. In intact platelets, PS is not labeled even after 2 h. In contrast, in phospholipids extracted from platelets 71% PE and 26.5% PS react with TNBS within 5 min. This indicates that PS is inaccessible and PE is relatively inaccessible to TNBS in intact platelets. After incubation of platelets with thrombin, there is increased labeling of PE but no labeling of PS. The incubation of platelets with thrombin (0.05 U/ml) for 5 min results in 16.2% increase of PE labeling during subsequent 30-min incubation with TNBS. PS does not appear to be a component of the functional surface of platelets. However, exposure of PE may have a critical role in platelet hemostatic function. The implication of the study is that there is asymmetry of phopholipids in the platelet plasma membrane which has considerable physiological significance.
Stroke induced brain changes: Implications for stem cell transplantation (2011)

Ischemic stroke remains a major health problem associated with high mortality and severe morbidity. In spite of the extensive research in the field of stroke biology, there is little effective treatment for a completed disease onset. Numerous neuroprotective strategies have failed in clinical trials because of lack of efficacy or unacceptable side-effects. The challenge of clinical trial design is now to understand the process leading to ischemic brain injury and thus identify the targets for intervention in stroke. Therefore, uncovering cellular and molecular processes involved in ischemic brain injury is of critical importance. The review discusses the current understanding of these processes engaged in pathogenesis of stroke including excitotoxicity and inflammation. In addition recruitment of endogenous progenitors engaged in neurogenesis and vascular regeneration has been implicated. All of the aforementioned changes opted for therapeutic intervention to protect neurons in the region adjacent to the ischemic cerebral tissue and enhance cell recovery. Stem cell transplantation seems to offer a major promise of this therapy in stroke disorders.
An Electromechanical Spinal Injury Technique with Dynamic Sensitivity (1992)

Over the past decade, our laboratory has attempted to create a simple, accurate device that could be used to produce reliable and quantifiable spinal cord injuries in the rodent. We report here on our latest of several modifications of a spinal cord impactor that has allowed us to meet these design criteria. The impactor uses the dynamic capacity of an electromagnetic driver (Ling shaker) and a unique pattern generator to briefly compress the dorsal surface of the spinal cord at velocities that may mimic compression injuries seen in the human. Calibrated, independent transducer systems provide open-loop output of the precise movement (displacement) of the impactor probe and the force necessary to achieve a given displacement. Touch sensitivity is accomplished by vibrating the probe slightly as it approaches the dural surface. This also allows a known biomechanical starting point. This combination of improvements in sensitivity and ability to measure all componenets of the dynamic compression has allowed us to determine detailed biomechanical descriptors of these impact injuries with low coefficients of variation. Furthermore, such descriptors correlate highly with histopathologic and behavioral outcome measures in animal populations with a variety of injury severities.
<title>DCT quantization matrices visually optimized for individual images</title> (1993)

Several image compression standards (JPEG, MPEG, H.261) are based on the Discrete Cosine Transform (DCT). These standards do not specify the actual DCT quantization matrix. Ahumada &amp; Peterson and Peterson, Ahumada &amp; Watson provide mathematical formulae to compute a perceptually lossless quantization matrix. Here I show how to compute a matrix that is optimized for a particular image. The method treats each DCT coefficient as an approximation to the local response of a visual `channel.' For a given quantization matrix, the DCT quantization errors are adjusted by contrast sensitivity, light adaptation, and contrast masking, and are pooled non-linearly over the blocks of the image. This yields an 8 X 8 `perceptual error matrix.' A second non-linear pooling over the perceptual error matrix yields total perceptual error. With this model we may estimate the quantization matrix for a particular image that yields minimum bit rate for a given total perceptual error, or minimum perceptual error for a given bit rate. Custom matrices for a number of images show clear improvement over image-independent matrices. Custom matrices are compatible with the JPEG standard, which requires transmission of the quantization matrix.
Suggestive Evidence That the “Blocking Antibodies” of Tumor-Bearing Individuals May Be Antigen-Antibody Complexes (1971)

Sera from mice carrying progressively growing sarcomas induced by Moloney virus or methylcholanthrene can block the cytotoxic effect of lymphocytes immune to the tumor-specific antigens of the respective neoplasms. The blocking effect can be specifically removed by absorbing sera with the respective types of tumor cells, and it can be recovered from these cells by elution at low pH. If the low pH is maintained, it is possible to separate out a low and a high molecular weight fraction from the eluates. If the fractions are added to the target cells for 45 minutes and then removed, neither of these fractions can block lymphocyte-mediated cytotoxicity, while a 1:1 mixture of them has a specific blocking effect. If they are admixed with the lymphocytes, incubated for 1 hr, and then allowed to incubate with the target cells and lymphocytes during the entire 2 days of the test, the low molecular weight fraction, as well as the mixture, but not the high molecular weight fraction, has a blocking activity. It is suggested that the blocking factor in sera from tumor-bearing animals, as regularly tested, is an antigen-antibody complex, capable of binding to the target cells and/or reacting with lymphocytes immune to their antigens, thus blocking the lymphocytes' reactivity; the latter reaction is postulated to be of a temporary nature.
Time Reversal and Its Application to Tomography with Diffracting Sources (2004)

An exact time-domain method is proposed to time reverse a transient scalar wave using only the field measured on an arbitrary closed surface enclosing the initial source. Under certain conditions, a time-reversed field can be approximated by retransmitting the measured signals in a reversed temporal order. Exact reconstruction for three-dimensional broadband diffraction tomography (a linearized inverse scattering problem) is proposed by time-reversing the measured field back to the time when each secondary source is excited. The algorithm is verified by a numerical simulation. Extension to the case using Green's function in a heterogeneous medium is discussed.
A RAPID METHOD FOR VIABLE CELL TITRATION AND CLONE PRODUCTION WITH HELA CELLS IN TISSUE CULTURE: THE USE OF X-IRRADIATED CELLS TO SUPPLY CONDITIONING FACTORS (1955)

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.
Quantitation of Human Immunodeficiency Virus Type 1 RNA in Plasma by Using Blood Dried on Filter Paper (1998)

We compared whole blood dried on filter paper to the standard assay with frozen cell-free plasma for use in the quantitation of the human immunodeficiency virus RNA load in blood. RNA values from filter paper, corrected for the hematocrit, gave results comparable to those of the standard assay in terms of sensitivity and reproducibility.
Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome (2003)

In this study, we defined the role of peroxisome proliferator-activated receptor beta/delta (PPARdelta) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARdelta subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARdelta controls fatty acid oxidation by regulating genes involved in fatty acid transport, beta-oxidation, and mitochondrial respiration. Similar PPARdelta-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid beta-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid beta-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPARdelta is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.
Endotoxic lipid A interaction with human platelets. Structure-function analysis of lipid A homologs obtained from Salmonella minnesota Re595 lipopolysaccharide. (1990)

We previously reported that human blood platelets are directly stimulated by endotoxic Lipid A via the protein kinase C pathway (Grabarek, J., Timmons, S., and Hawiger, J. (1988) J. Clin. Invest. 82, 964-971). To study the relationship between the molecular structure of Lipid A and its ability to activate human platelets, we used Lipid A homologs derived from Salmonella minnesota Re595 lipopolysaccharide. Preparations of Lipid A are heterogeneous in regard to the degree of substitution of fatty acids which result in multiple homologs. These were separated by thin-layer chromatography and characterized by fast atom bombardment spectroscopy and related techniques (Johnson R. S., Her, G.-R., Grabarek, J., Hawiger, J., and Reinhold, V. N. (1990) J. Biol. Chem. 265, 8108-8116). The homologs of monophosphoryl Lipid A (MLA) present in fractions TLC-8 (heptaacyl MLA ion, m/z 1953), TLC-7 (three hexaacyl species with predominant MLA ion m/z 1715), and TLC-6 (four pentaacyl homologs with predominant MLA ion, m/z 1505) induced secretion of [14C]serotonin and aggregation of platelets. Lipid A homologs in fractions TLC-5 (three tetraacyl MLA ions, m/z 1323, 1307, and 1279), TLC-4 (one major triacyl MLA ion, m/z 1097), TLC-3 (tetraacyl MLA ion, m/z 1278), TLC-2 (a diphosphoryl hexaacyl Lipid A ion, m/z 1795, and several ions of low abundance), and TLC-1 (two ions, m/z 1097 and 666) were not active in regard to human platelet aggregation and [14C]serotonin secretion. The most active homolog was heptaacyl MLA ion, m/z 1953, present in TLC-8, while homologs present in TLC-7 and TLC-6 were 5 and 10 times less active, respectively. Rapid phosphorylation of a human platelet protein of Mr 40,000-47,000 (P47), a substrate for protein kinase C activation, preceded secretion of serotonin when platelets were triggered by the most active heptaacyl MLA ion, m/z 1953. These events were time-dependent, with half-maximal response of phosphorylation of P47 at 30 s and [14C]serotonin secretion at 45 s. A marked difference in the degree of phosphorylation of P47 was observed with heptaacyl MLA homolog present in TLC-8 inducing complete phosphorylation (97%), whereas less acylated Lipid A homologs present in TLC-1 caused marginal phosphorylation (20%). These results indicate that the degree of acylation of monophosphoryl Lipid A determines its functional properties toward human platelets in regard to secretion of [14C]serotonin, aggregation, and activation of protein kinase C.(ABSTRACT TRUNCATED AT 400 WORDS)
Endogenous Inhibitors of Angiogenesis (2005)

Angiogenesis, the formation of new blood vessels, is required for many pathologic processes, including invasive tumor growth as well as physiologic organ/tissue maintenance. Angiogenesis during development and adulthood is likely regulated by a balance between endogenous proangiogenic and antiangiogenic factors. It is speculated that tumor growth requires disruption of such balance; thus, the angiogenic switch must be turned "on" for cancer progression. If the angiogenic switch needs to be turned on to facilitate the tumor growth, the question remains as to what the physiologic status of this switch is in the adult human body; is it "off," with inhibitors outweighing the stimulators, or maintained at a fine "balance," keeping the proangiogenic properties of many factors at a delicate "activity" balance with endogenous inhibitors of angiogenesis. The physiologic status of this balance is important to understand as it might determine an individual's predisposition to turn the switch on during pathologic events dependent on angiogenesis. Conceivably, if the physiologic angiogenesis balance in human population exists somewhere between off and even balance, an individual's capacity and rate to turn the switch on might reflect their normal physiologic angiogenic status. In this regard, although extensive knowledge has been gained in our understanding of endogenous growth factors that stimulate angiogenesis, the activities associated with endogenous inhibitors are poorly understood. In this review, we will present an overview of the knowledge gained in studies related to the identification and characterization of 27 different endogenous inhibitors of angiogenesis.
Poly(hydroxyalkanoates)‐Based Polymeric Nanoparticles for Drug Delivery (2009)

Poly (hydroxyalkanoates) (PHAs) have recently attracted a great deal of academic and industrial interest for their biodegradability and biocompatibility making them suitable for environmental and biomedical applications. Poly(3-hydroxybutyrate-) (PHB-) and Poly(DL-lactide-co-glycolide) (PLGA-) based nanoparticles were prepared using the dialysis method as yet unreported for the preparation of nanoparticles based on PHB. Processing conditions were varied in order to evaluate their influence on morphology, drug encapsulation, and size of nanoparticles. The relevant results obtained give a theoretical understanding of the phenomenon occurring during colloidal formation. The adopted procedure allows for a relatively small diameter and homogeneity in size distribution of the PHB nanoparticles to be obtained compared to other methods like the one based on solvent evaporation which leads to particles on microscale. The biocompatibility of PHB and relative nanoparticles was investigated and both exhibited very good cytocompatibility.
Phase I Trial of 131I-huA33 in Patients with Advanced Colorectal Carcinoma (2005)

Radioimmunotherapy using 131I-huA33 shows promise in targeting colorectal tumors, and is deliverable at a maximum tolerated dose of 40 mCi/m2. Further studies of 131I-huA33 in combination with chemotherapy are planned.