gebhart/patrepeval huggingface dataset:
Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40 (2017)

<b>Purpose:</b> Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to affect patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T-cell costimulatory receptors, such as OX40, remains a critical question.<b>Experimental Design:</b> We utilized an anti-PD-1-refractory, orthotopically transplanted MMTV-PyMT mammary cancer model to investigate the antitumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. As PD-1 naturally aids in immune contraction after T-cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 followed by anti-PD-1.<b>Results:</b> The concurrent addition of anti-PD-1 significantly attenuated the therapeutic effect of anti-OX40 alone. Combination-treated mice had considerable increases in type I and type II serum cytokines and significantly augmented expression of inhibitory receptors or exhaustion markers CTLA-4 and TIM-3 on T cells. Combination treatment increased intratumoral CD4<sup>+</sup> T-cell proliferation at day 13, but at day 19, both CD4<sup>+</sup> and CD8<sup>+</sup> T-cell proliferation was significantly reduced compared with untreated mice. In two tumor models, sequential combination of anti-OX40 followed by anti-PD-1 (but not the reverse order) resulted in significant increases in therapeutic efficacy. Against MMTV-PyMT tumors, sequential combination was dependent on both CD4<sup>+</sup> and CD8<sup>+</sup> T cells and completely regressed tumors in approximately 30% of treated animals.<b>Conclusions:</b> These results highlight the importance of timing for optimized therapeutic effect with combination immunotherapies and suggest the testing of sequencing in combination immunotherapy clinical trials. <i>Clin Cancer Res; 23(20); 6165-77. ©2017 AACR</i><i>See related commentary by Colombo, p. 5999</i>.
Consistent Immunostaining for Cyclin D1 Can Be Achieved on a Routine Basis Using a Newly Available Rabbit Monoclonal Antibody (2004)

Rabbit monoclonal antibody (MAb), which has become available only recently, theoretically combines the advantage of the high affinity attributable to its rabbit origin and the high specificity due to its monoclonal nature. Since immunohistochemical demonstration of cyclin D1 is notoriously difficult, this study aims to assess whether a newly available rabbit MAb against cyclin D1 (SP4) can improve the consistency of immunostaining, especially for the diagnosis of mantle cell lymphoma (MCL). A total of 150 cases of lymphoproliferative lesions, including 30 cases of MCL, histologic mimickers of MCL, and various types of lymphomas and leukemias, were studied. Immunostaining was performed on formalin-fixed, paraffin-embedded tissue sections using a labeled streptavidin-biotin peroxidase system in an automated immunostainer. All cases of MCL expressed cyclin D1, with a higher median staining score (8 out of a maximum of 12) compared with mouse MAb DCS-6 (score 4). In addition, 2 of 15 cases of B-cell chronic lymphocytic leukemia (B-CLL), 3 of 12 cases of multiple myeloma, and 2 of 5 cases of hairy cell leukemia were also positive. Comparable staining results could also be achieved by an optimized manual staining protocol. This study thus confirms the superior performance of the rabbit MAb SP4, which should permit consistent immunostaining for cyclin D1 to be readily achieved. The value of cyclin D1 immunohistochemistry in the differential diagnosis of MCL from other low-grade B-cell lymphomas is also affirmed, but with the caveat that rare cases of B-CLL can also be cyclin D1 positive.
Effects of Xanomeline, a Selective Muscarinic Receptor Agonist, on Cognitive Function and Behavioral Symptoms in Alzheimer Disease (1997)

The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.
Protection of C3H/HeN mice from challenge with Borrelia burgdorferi through active immunization with OspA, OspB, or OspC, but not with OspD or the 83-kilodalton antigen (1994)

Recent advances in the development of animal models for Lyme borreliosis have provided means of identifying potential targets for the design of a subunit vaccine to prevent this disease. The C3H/HeN mouse model was used to study several Borrelia burgdorferi antigens from a single isolate for their ability to elicit borreliacidal and protective antibodies. The ospA, ospB, ospC, ospD, and 83-kDa genes from a California isolate, SON 188, were cloned and expressed in Escherichia coli as proteins fused to the C-terminal end of maltose-binding protein. Active immunization of mice with these fusion proteins elicited high titers of antibodies that recognized the homologous SON 188 antigens upon immunoblotting. Antibodies generated to the OspA and OspB fusion proteins, but not to the OspC, OspD, and the 83-kDa fusion proteins, demonstrated in vitro borreliacidal activity. Challenge of all actively immunized mice with 10(7) SON 188 spirochetes resulted in infection in all mice receiving the OspD or 83-kDa immunogens but not in any mice receiving the OspA, OspB, or OspC fusion proteins. These results demonstrate the potential of OspA, OspB, and OspC as components of a subunit vaccine for the prevention of Lyme borreliosis.
Txrf Semiconductor Applications (1993)

This is a review of Total reflection X-Ray Fluorescence (TXRF) applications for semiconductors. This review is limited to surface analysis of contamination for semiconductors and does not include chemical analysis in semiconductor processing. TXRF for surface analysis is a relatively new technology. One of the first publications occurred in 1986 using synchrotron radiation. Publications using commercially available TXRF instruments for semiconductor applications began in 1988. Today there are on the order of 100 TXRF instruments worldwide in the semiconductor industry. Since 1988 there have been about 100 publications in this field, but this number does not include numerous abstracts and publications in Japan where the majority of the commercial instruments are found today. The commercial instruments were developed for the primary application of characterizing the cleaning of planar silicon wafers, however, numerous unforeseen applications were developed by users and many of those applications are reported here. In essence TXRF has much broader application today in the semiconductor industry than supporting the cleaning of silicon wafers.
A method for measuring barrier heights, metal work functions and fixed charge densities in metal/SiO2/Si capacitors (2002)

A method for measuring metal barrier heights, work function and fixed charge densities in metal/SiO2/Si capacitors is developed and verified. This technique is based on theoretical studies of tunneling phenomenon through a potential barrier and requires measurement of current versus voltage sweeps at two different temperatures. Unlike the commonly used capacitance method, this method does not require a set of capacitors with different gate oxide thickness for determining work functions and fixed charge densities in metal/SiO2/Si capacitors. Hence, this method provides a fast means for investigating metal work function and fixed charge densities in metal-gated SiO2 capacitors.
Intracellular Proteases (1987)

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size ...Read More
Colorectal Cancer Epidemiology: Incidence, Mortality, Survival, and Risk Factors (2009)

In this article, the incidence, mortality, and survival rates for colorectal cancer are reviewed, with attention paid to regional variations and changes over time. A concise overview of known risk factors associated with colorectal cancer is provided, including familial and hereditary factors, as well as environmental lifestyle-related risk factors such as physical inactivity, obesity, smoking, and alcohol consumption.
Role of insulin‐like growth factor binding protein‐3 in breast cancer cell growth (2002)

The mitogenic effects of insulin-like growth factors (IGFs) are regulated by a family of insulin-like growth factor binding proteins (IGFBPs). One member of this family, IGFBP-3, mediates the growth-inhibitory and apoptosis-inducing effects of a number of growth factors and hormones such as transforming growth factor-beta, retinoic acid, and 1,25-dihydroxyvitamin D3. IGFBP-3 may act in an IGF-dependent manner by attenuating the interaction of pericellular IGFs with the type-I IGF receptor. It may also act in an IGF-independent manner by initiating intracellular signaling from a cell surface receptor, or by direct nuclear action, or both. The possibility of a membrane-bound receptor is strengthened by recent studies which have identified members of the transforming growth factor-beta receptor family as having a role, either directly or indirectly, in signaling from the cell surface by IGFBP-3. A number of growth factors and hormones stimulate the expression and secretion of cellular IGFBP-3, which then signals from the cell surface to bring about some of the effects attributed to the primary agents. Within the cell, the apoptosis-inducing tumor suppressor, p53, can also induce IGFBP-3 expression and secretion. Since IGFBP-3 upregulates the cell cycle inhibitor, p21(Waf1), and increases the ratio of proapoptotic to antiapoptotic members of the Bcl family, it appears to exert the same effects on major downstream targets of cell signaling as p53 does. The nuclear localization of IGFBP-3 has been described in a number of cell types. IGFBP-3 may act to import IGFs or other nuclear localization signal-deficient signaling molecules into the nucleus. It may also act directly in the nucleus by enhancing the activity of retinoid X receptor-alpha and thereby promote apoptosis. All of the above phenomena will be discussed with particular emphasis on the growth of breast cancer cells.
Pathogenic mechanisms of IgE-mediated inflammation in self-destructive autoimmune responses (2017)

Autoantibodies of the IgG subclass are pathogenic in a number of autoimmune disorders such as systemic lupus erythomatosus. The presence of circulating IgE autoantibodies in autoimmune patients has also been known for almost 40 years. Despite their role in allergies, IgE autoantibodies are not associated with a higher rate of atopy in these patients. However, recently they have been recognized as active drivers of autoimmunity through mechanisms involving the secretion of Type I interferons by plasmacytoid dendritic cells (pDC), the recruitment of basophils to lymph nodes, and the activation of adaptive immune responses through B and T cells. Here, we will review the formation, prevalence, affinity, and roles of the IgE autoantibodies that have been described in autoimmunity. We also present novel evidence supporting that triggering of IgE receptors in pDC induces LC3-associated phagocytosis, a cellular process also known as LAP that is associated with interferon responses. The activation of pDC with immune complexes formed by DNA-specific IgE antibodies also induce potent B-cell differentiation and plasma cell formation, which further define IgE's role in autoimmune humoral responses.
Reconstituted Killer Cell Inhibitory Receptors for Major Histocompatibility Complex Class I Molecules Control Mast Cell Activation Induced via Immunoreceptor Tyrosine-based Activation Motifs (1997)

Natural killer and T cells express at their surface, members of a multigenic family of killer cell inhibitory receptors (KIR) for major histocompatibility complex Class I molecules. KIR engagement leads to the inhibition of natural killer and T cell activation programs. We investigated here the functional reconstitution of KIR in a non-lymphoid cell type. Using stable transfection in the RBL-2H3 mast cell line, we demonstrated that (i) KIR can inhibit signals induced by FcepsilonRIgamma or CD3zeta polypeptides that bear immunoreceptor tyrosine-based activation motifs; (ii) two distinct immunoreceptor tyrosine-based inhibition motifs-bearing receptors, i.e. KIR and FcgammaRIIB, use distinct inhibitory pathways since KIR engagement inhibits the intracellular Ca2+ release from endoplasmic reticulum stores, in contrast to FcgammaRIIB, which only inhibits extracellular Ca2+ entry; (iii) KIR require co-ligation with an immunoreceptor tyrosine-based activation motif-dependent receptor to mediate their inhibitory function. This latter finding is central to the mechanism by which KIR selectively inhibit only the activatory receptors in close vicinity. Taken together our observations also contribute to define and extend the family of immunoreceptor tyrosine-based inhibition motif-bearing receptors involved in the negative control of cell activation.
Neurotrophic factors and neuromuscular disease: I. General comments, the neurotrophin family, and neuropoietic cytokines (1999)

Neurotrophic factors are growth factors or cytokines that are inducible polypeptides and permit intercellular communication. An explosion of information about neurotrophic factors is setting the stage for significant advances in neural disease therapy in the next century. The effects of these trophic factors are overlapping and pleiotropic, acting on many cell types and tissues to control proliferation and differentiation of developing neurons and to exert a variety of functions on mature neurons. Studies of receptors unique to several neurotrophic factor families have revealed exquisite mechanisms of signal transduction. Preclinical trials in neuromuscular disease were promising, but results from initial clinical trials have been disappointing; new and better designed clinical trials are under way. Laboratory investigators also are exploring techniques to deliver factors directly to the central nervous system by means of viral vectors or to exert neurotrophic signals on the nervous system using novel small molecules that stimulate neurotrophic factor or neuroimmunophilin receptors. Combination therapies, refined delivery techniques, and treatment timing may be the key for successful treatment with neurotrophic factors. In this two-part review, we discuss the neurobiology of neurotrophic factors, the characteristics of the major neurotrophic factors, and their therapeutic potential in neuromuscular disease.
Central Adrenergic Suppression Augments the Insulin and Glucagon Secretory, and the Glycogenolytic Responses in Streptozotocin-Diabetic Rats (1991)

It has been suggested that the increased activity of the sympathetic nervous system and the resultant increase in the tissue catecholamine levels contribute to the pathogenesis of diabetes. In this study we evaluated the effect of clonidine, a central adrenergic agonist that decreases sympathetic tone, on the serum levels of glucose, insulin, glucagon and norepinephrine and on the hepatic glycogen content in normal and streptozotocin-diabetic rats. The animals were treated with clonidine 25 micrograms/kg/day interperitoneally for 3 weeks to suppress the central adrenergic impulses. Clonidine treatment significantly increased the weight gain, but did not affect plasma glucose, insulin, glucagon and norepinephrine in the diabetic animals. Pancreatic insulin and liver glycogen contents were significantly higher in the clonidine-treated than in the untreated diabetic rats. However, clonidine did not affect pancreatic insulin and liver glycogen content of nondiabetic animals. The intravenous administration of glucagon increased plasma glucose in the clonidine-treated, but not in the saline-treated diabetic rats. Insulin-induced hypoglycemia significantly enhanced glucagon release in clonidine-treated but not in saline-treated diabetic rats. We conclude that the suppression of central adrenergic activity may ameliorate the effects of insulin insufficiency on pancreatic hormone secretion and hepatic glycogen content.
The LR33020 GraphX processor: a single chip X-terminal controller (2003)

A description is given of the LR33020 GraphX processor, an application-specific version of the MIPS R3000 architecture designed specifically for X-terminal systems. Beginning with the R3000 CPU core, the LR33020 integrates caches, write buffers, and memory controllers with dedicated hardware graphics support. Features incorporated into the graphics portion of the device include a BitBLT coprocessor, DMA channels, 64-b data path, programmable video timing, video FIFO, PS/2 style port, and direct support for Ethernet and other off-chip peripheral devices. The LR33020 can be configured as a monochrome, 2- or 4-b grayscale, or 8-, 16- or 32-b color controller. By coupling a high-performance RISC (reduced instruction set computer) CPU with dedicated graphics functions, the LR33020 offers a high-performance yet cost-effective controller for third-generation X-terminal systems.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Physiological methods to measure motor function in humans and animals with spinal cord injury (2003)

This article compares some physiological methods commonly used to measure the functional capability of the motor system in humans and animals after spinal cord injury. Some of the differences between animal and human experimentation are considered first. Then we discuss how to measure the effectiveness of conduction through the motor system. We describe ways to assess the integration of different inputs at the spinal cord and to measure the responsiveness of the neuromuscular system. We conclude that comparisons across species are invaluable to understand the control of movement, both before and after injury.
Studies of effects of recombinant human tumor necrosis factor on autochthonous tumor and transplanted normal tissue in mice. (1990)

The acute hemorrhagic necrosis of tumor nodules caused by the systemic administration of recombinant human tumor necrosis factor alpha (rhTNF-alpha) has been partially attributed to changes in tumor neovascularity. In this study, the effects of rhTNF-alpha were tested on primary autochthonous sarcomas induced in C57BL/6 mice by 3-methylcholanthrene, on spontaneous mammary tumors in C3H/HEN mammary tumor virus positive mice, and on the rejection of normal tissue transplants at different stages of maturity in C57BL/6 mice. Primary i.m. tumors induced by injection of 3-methylcholanthrene grew slowly over a 3-month period and became acutely necrotic after i.v. injection of rhTNF-alpha (2-6 micrograms). In addition, rhTNF-alpha caused a reduction in tumor area of 24% over 10 days compared to a 43% increase in tumor area in control mice receiving excipient (P2 less than 0.01). Histopathologically, tumors underwent central necrosis with a neutrophilic infiltration as was observed previously for serially transplanted tumors following rhTNF-alpha administration. Spontaneous, virally induced mammary tumors underwent a 11% regression on administration of rhTNF-alpha (4-6 micrograms) compared to a 24% growth in mice receiving excipient (P2 less than 0.05). Normal mice were grafted with syngeneic (C57BL/6) or partially allogeneic (C57BL/10 to C57BL/6) skin and were treated with a single dose of rhTNF-alpha (5-20 micrograms) i.v. at either 5, 10, or 15 days posttransplantation. rhTNF-alpha administration had no effect on the integrity of the skin grafts at any maturation point tested (syngeneic graft survival at 60 days: excipient, 35 of 36 versus 20 micrograms rhTNF-alpha, 35 of 36; allogeneic graft survival: excipient, 46 +/- 8 days versus 20 micrograms rhTNF-alpha, 48 +/- 10 days). In addition, rhTNF-alpha had no effect on the integrity of a syngeneic neonatal s.c. heart graft (graft survival at 60 days, excipient, 35 of 36 versus rhTNF-alpha, 30 of 33). Thus, although rhTNF-alpha administration led to marked necrosis and growth inhibition of vascularized tumor, no effect was observed on vascularized normal tissue transplants. To evaluate possible systemic effects of the tumor bearing state on the maturing neovascularity of normal tissue grafts, the three transplant models were studied in mice bearing a 9-day established MCA-106 s.c. sarcoma. After treatment with rhTNF-alpha (2-6 micrograms), acute necrosis and tumor size reduction was apparent in the s.c. tumors; however, no effect was seen in any of the normal tissue transplants.(ABSTRACT TRUNCATED AT 400 WORDS)
The importance of diagnostic accuracy in colonic inflammatory bowel disease (2000)

There is significant interobserver variation in the histological diagnosis of colonic IBD. This may have a profound effect on clinical patient care and, especially, on the choice of operation. More accurate diagnostic criteria are needed to facilitate patient care and to optimize treatment outcome.
Tumor suppression by small molecule inhibitors of translation initiation (2012)

Translation initiation factors are over-expressed and/or activated in many human cancers and may contribute to their genesis and/or progression. Removal of physiologic restraints on translation initiation causes malignant transformation. Conversely, restoration of physiological restrains on translation initiation reverts malignant phenotypes. Here, we extensively characterize the anti-cancer activity of two small molecule inhibitors of translation initiation: #1181, which targets the eIF2∙GTP∙Met-tRNAi ternary complex, and 4EGI-1, which targets the eIF4F complex. In vitro, both molecules inhibit translation initiation, abrogate preferentially translation of mRNAs coding for oncogenic proteins, and inhibit proliferation of human cancer cells. In vivo, both #1181 and 4EGI-1 strongly inhibit growth of human breast and melanoma cancer xenografts without any apparent macroscopic- or microscopic-toxicity. Mechanistically, #1181 phosphorylates eIF2α while 4EGI-1 disrupts eIF4G/eIF4E interaction in the tumors excised from mice treated with these agents. These data indicate that inhibition of translation initiation is a new paradigm in cancer therapy.
CoMP in heterogeneous networks: A low-complexity linear transceiver design (2012)

Coordinated multipoint transmission (CoMP) is considered for a heterogeneous network where different kinds of base stations (BS) are located. We focus on linear transceiver design with the goal of maximizing the weighted sum rate in the downlink of a multiple-input multiple-output orthogonal frequency division multiple access (MIMO-OFDMA) system. The problem is shown to be non-convex, thus, the problem of finding the global optimum is an intrinsically intractable, NP hard problem. We propose an algorithm which divides the main problem into several convex subproblems, and, is shown to provide efficient suboptimal solutions.
The Princeton University behavioral synthesis system (1992)

The Princeton University behavioral synthesis system (PUBSS) is a high-level synthesis system targeted to control-dominated machines. PUBSS compiles a very high-speed integrated circuit description language (VHDL) behavior model, in which the design can be described as multiple communicating processes plus registers, and generates a register-transfer implementation. The authors describe the compiler with emphasis on the automaton-based algorithms which allow efficient specification and manipulation of control-dominated systems. >