gebhart/patrepeval huggingface dataset:
Bovine antibody against Cryptosporidium parvum elicits a circumsporozoite precipitate-like reaction and has immunotherapeutic effect against persistent cryptosporidiosis in SCID mice (1994)

Control of cryptosporidiosis is currently hampered by the absence of drugs or vaccines proven consistently effective against Cryptosporidium parvum. On the basis of observations that anti-C. parvum antibody has therapeutic effect against cryptosporidiosis, cows were immunized with C. parvum to produce hyperimmune colostral antibody. An antibody-rich fraction was prepared and differentiated from control (nonhyperimmune) antibody by enzyme-linked immunosorbent assay, immunofluorescence assay, immunoelectron microscopy, and in vitro neutralizing titer against DEAE-cellulose-isolated C. parvum sporozoites. Oocyst, purified sporozoite, and merozoite antigens recognized by hyperimmune antibody were defined by Western blot (immunoblot). Hyperimmune antibody recognized antigens common to oocysts, sporozoites, and merozoites, as well as stage-specific antigens. Upon incubation with hyperimmune antibody, sporozoites underwent distinct morphologic changes characterized by progressive formation and eventual release of membranous sporozoite surface antigen-antibody complexes, similar to the malaria circumsporozoite precipitate reaction. The infectivity of sporozoites having undergone this reaction was neutralized. The reaction was minimal or absent on sporozoites incubated with control antibody. To determine therapeutic effect in vivo, persistent C. parvum infection was established in adult severe combined immune-deficient (SCID) mice by oral inoculation with 10(7) oocysts. At 5 weeks postinfection, infected mice were treated for 10 days with hyperimmune or control antibody by inclusion in drinking water and daily gavage. Fecal oocyst shedding and infection scores in the gastrointestinal tract and gall bladder/common bile duct in hyperimmune antibody-treated mice were significantly lower than those in the control antibody-treated mice. Hyperimmune bovine antibody prepared against C. parvum may provide a first-generation therapy for control of cryptosporidiosis. Additionally, the defined antigens can be evaluated as subunit immunogens to produce better-characterized polyclonal antibody for control of cryptosporidiosis or as targets for monoclonal antibody-based immunotherapy.
Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease (2001)

Chronic granulomatous disease (CGD) is an inherited immunodeficiency in which the absence of the phagocyte superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase results in recurrent bacterial and fungal infections. A murine model of X-linked CGD (X-CGD) was used to explore variables influencing reconstitution of host defense following bone marrow transplantation and retroviral-mediated gene transfer. The outcomes of experimental infection with Aspergillus fumigatus, Staphylococcus aureus, or Burkholderia cepacia were compared in wild-type, X-CGD mice, and transplanted X-CGD mice that were chimeric for either wild-type neutrophils or neutrophils with partial correction of NADPH oxidase activity after retroviral-mediated gene transfer. Host defense to these pathogens was improved in X-CGD mice even with correction of a limited number of neutrophils. However, intact protection against bacterial pathogens required relatively greater numbers of oxidant-generating phagocytes compared to protection against A fumigatus. The host response also appeared to be influenced by the relative level of cellular NADPH oxidase activity, particularly for A fumigatus. These results may have implications for developing effective approaches for gene therapy of CGD. (Blood. 2001;97:3738-3745)
Electrical Detection of Femtomolar DNA via Gold‐Nanoparticle Enhancement in Carbon‐Nanotube‐Network Field‐Effect Transistors (2008)

A dramatic sensitivity enhancement in electrical detection of DNA hybridization using single-walled carbon nanotube networked field effect transistors (SNFETs) via introducing reporter DNA-Au nanoparticle (AuNP) conjugates in the hybridization step is reported. The amplified change in drain current allows to reliably determine the DNA concentration down to ∼100 fM.
A Limited Group of Class I Histone Deacetylases Acts To Repress Human Immunodeficiency Virus Type 1 Expression (2009)

Silencing of the integrated human immunodeficiency virus type 1 (HIV-1) genome in resting CD4(+) T cells is a significant contributor to the persistence of infection, allowing the virus to evade both immune detection and pharmaceutical attack. Nonselective histone deacetylase (HDAC) inhibitors are capable of inducing expression of quiescent HIV-1 in latently infected cells. However, potent global HDAC inhibition can induce host toxicity. To determine the specific HDACs that regulate HIV-1 transcription, we evaluated HDAC1 to HDAC11 RNA expression and protein expression and compartmentalization in the resting CD4(+) T cells of HIV-1-positive, aviremic patients. HDAC1, -3, and -7 had the highest mRNA expression levels in these cells. Although all HDACs were detected in resting CD4(+) T cells by Western blot analysis, HDAC5, -8, and -11 were primarily sequestered in the cytoplasm. Using chromatin immunoprecipitation assays, we detected HDAC1, -2, and -3 at the HIV-1 promoter in Jurkat J89GFP cells. Targeted inhibition of HDACs by small interfering RNA demonstrated that HDAC2 and HDAC3 contribute to repression of HIV-1 long terminal repeat expression in the HeLa P4/R5 cell line model of latency. Together, these results suggest that HDAC inhibitors specific for a limited number of class I HDACs may offer a targeted approach to the disruption of persistent HIV-1 infection.
Phase I study of a neutralizing monoclonal anti-CTLA4 antibody (MDX-010) in patients with relapse of malignancy after allogeneic hematopoietic stem cell transplantation (2005)

Relapse of malignancy remains a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HCT). Tumors may utilize a variety of mechanisms to evade the adoptive immunotherapy provided by allo-HCT. These may include lack of costimulation and direct or indirect inhibition of T-cell activation. CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4) is a homologue of CD28 that functions as a negative regulator of T-cell activation. Blockade of CTLA-4 using neutralizing antibodies has demonstrated potent anticancer effects in animal models of antitumor immunity. Tumor regression as well as autoimmune phenomena have been seen in phase I/II clinical trials of CTLA-4 blockade in advanced solid tumors. Although CTLA-4 blockade may augment graft-versus-malignancy after allo-HCT, GVHD and other immune complications may also be increased. We have conducted a phase I dose-escalation trial of a neutralizing human monoclonal anti-CTLA-4 antibody (MDX-010) in patients with relapse of malignancy after allo-HCT. Eligibility criteria included allo-HCT≥ 90 days previously, > 50% donor T-cell chimerism, no prior grade 3/4 GVHD, and no prophylaxis/therapy for GVHD for≥ 6 weeks. Eligible patients received a single dose of MDX-010 over 90 minutes. Patients were allowed DLI at a dose of 5× 106 CD3 cells/kg 8 weeks after MDX-010 if no GVHD occurred and progression of malignancy (PD) was present. Six patients (3 males and 3 females; median age 44 years; 2 cases of CML, 1 case of AML, 1 case of myeloma, 1 case of renal carcinoma, 1 case of breast cancer) have been treated (4 at a dose level of 0.1 mg/kg, 3 at a dose level of 0.33 mg/kg). MDX-010 was well tolerated in this setting; no infusional toxicity was seen. No patient has developed clinically significant exacerbation of GVHD or new-onset GVHD after infusion. One patient (dose, 0.1 mg/kg) developed a grade 3 polyarthropathy with rheumatoid nodules 14 weeks after MDX-010 and 6 weeks post-DLI, which resolved with corticosteroid therapy. No other autoimmune complications were seen. MTD has not been reached. Two patients have demonstrated possible anticancer responses (ie, partial remission of AML refractory to prior therapies, molecular remission of CML maintained off imatinib). With a median follow-up of 164 days, 1 patient has died (PD), 5 patients are alive, and 1 patient is in CR. Pharmacokinetic and correlative science data will be presented. This study shows safety with possible antitumor effects at the dose levels tested.
Synergistic Effects of Combination Therapy With Anti-EGFR and Anti- Src Therapy in Colorectal Cancer (2006)

Background: Cetuximab, a monoclonal antibody to the ligand-binding domain of the epidermal growth factor receptor (EGFR), has demonstrated benefit for patients with metastatic colorectal cancer regardless of their EGFR expression levels. This suggests that other factors may determine sensitivity to this agent. Activation of Src, a nonreceptor tyrosine kinase, is a potential mediator of chemoresistance. Increased levels of Src have been correlated with more aggressive phenotypes and poorer prognosis in patients. Combined Src and EGFR inhibition may provide additional benefit. Methods: We investigated the combination of cetuximab and dasatinib (BMS-354825), a Src inhibitor recently approved by the US Food and Drug Administration (FDA) for chronic myelogenous leukemia. Two cell lines with low and moderate levels of unmutated EGFR were utilized: HT29 and LS174T, respectively. MTT assays were performed after 48 hours of drug exposure. Clonogenic assays were analyzed after 14 days of continuous drug exposure. Formal synergy was determined by CalcuSyn software (Biosoft, Great Shelford, Cambridge, United Kingdom). Results: Neither LS174T nor HT29 cells are responsive to cetuximab in the MTT assay at clinically relevant doses. The IC50’s for dasatinib in LS174T and HT29 are outside the range that has been achievable in patients. However, the combination of cetuximab and dasatinib showed synergistic growth inhibition at clinically achievable doses in the LS174T cell line, with supra-additivity in the HT29 cell line. This effect was confirmed
Contractile C2C12myotube model for studying exercise-inducible responses in skeletal muscle (2008)

Adequate exercise leads to a vast variety of physiological changes in skeletal muscle as well as other tissues/organs and is also responsible for maintaining healthy muscle displaying enhanced insulin-responsive glucose uptake via GLUT4 translocation. We generated highly developed contractile C(2)C(12) myotubes by manipulating intracellular Ca(2+) transients with electric pulse stimulation (EPS) that is endowed with properties similar to those of in vivo skeletal muscle in terms of 1) excitation-induced contractile activity as a result of de novo sarcomere formation, 2) activation of both the AMP kinase and stress-activated MAP kinase cascades, and 3) improved insulin responsiveness as assessed by GLUT4 recycling. Tbc1d1, a Rab-GAP implicated in exercise-induced GLUT4 translocation in skeletal muscle, also appeared to be phosphorylated on Ser(231) after EPS-induced contraction. In addition, a switch in myosin heavy-chain (MHC) expression from "fast type" to "slow type" was observed in the C(2)C(12) myotubes endowed with EPS-induced repetitive contractility. Taking advantage of these highly developed contractile C(2)C(12) myotubes, we identified myotube-derived factors responsive to EPS-evoked contraction, including the CXC chemokines CXCL1/KC and CXCL5/LIX, as well as IL-6, previously reported to be upregulated in contracting muscles in vivo. Importantly, animal treadmill experiments revealed that exercise significantly increased systemic levels of CXCL1/KC, perhaps derived from contracting muscle. Taken together, these results confirm that we have established a specialized muscle cell culture model allowing contraction-inducible cellular responses to be explored. Utilizing this model, we identified contraction-inducible myokines potentially linked to the metabolic alterations, immune responses, and angiogenesis induced by exercise.
Control of the SOST Bone Enhancer by PTH Using MEF2 Transcription Factors (2007)

These data strongly suggest that SOST expression in osteocytes of adult bone and its inhibition by PTH is mediated by MEF2A, C, and D transcription factors controlling the SOST bone enhancer. Hence, MEF2s are implicated in the regulation of adult bone mass.
Specific receptors of platelet-activating factor, receptor heterogeneity, and signal transduction mechanisms. (1992)

Platelet-activating factor (PAF) exerts its actions through the activation of specific PAF receptors found in a variety of cells and tissues. The signal transduction process induced by PAF appears to be modulated by guanine nucleotide-regulatory proteins (G-proteins) in both rabbit and human platelets and also in human polymorphonuclear leukocytes (PMNs). The PAF receptor, the G-protein coupled to the receptor, and the signal transduction mechanisms in human platelets are different from those in human PMNs. The PAF receptor in human PMNs may also be different from that in human eosinophils. The existence of receptor heterogeneity in guinea pig eosinophils is also proposed. Thus PAF receptor subtypes do exist. Further investigations are required to understand the role of each individual PAF receptor subtype.
Hepatic stem cells in liver regeneration (1996)

The concept that the liver contains epithelial cells that share some of the major properties of stem cells of the well-characterized, stem cell-fed lineages found in bone marrow, intestinal epithelium, and epidermis is now well supported. Nevertheless, the population dynamics of the major types of liver epithelial cells, hepatocytes, and bile epithelia display a striking difference from the population dynamics of the classic stem cell systems. The focus of this review is on recent studies of the activation and expansion of liver stem cells in vivo and the role these cells may play in regeneration of the liver. The requirement for a selective and sustained expression of growth factors during the early stages of stem cell activation is highlighted. In addition, results are presented supporting the hypothesis that after loss of liver mass, both the quiescent stem cells as well as the residual differentiated hepatocytes and bile duct epithelial cells are activated to proliferate. However, significant contribution of the stem cells to the regeneration process only occurs under circumstances in which the residual differentiated cells are functionally compromised and/or cannot proliferate.
Peto's paradox and the evolution of cancer suppression (2014)

In order to successfully build and maintain a multicellular body, somatic cells must be constrained from proliferating uncontrollably and destroying the organism. If all mammalian cells were equally susceptible to oncogenic mutations and had identical tumor suppressor mechanisms, one would expect that the risk of cancer would be proportional to the body size and lifespan of a species. This is because a greater number of cells and cell divisions over a lifetime would increase the chance of accumulating mutations that result in malignant transformation. Peto’s paradox is the clash between the theory that cancer incidence should increase with body size and lifespan, and the observation that it does not. In this thesis, I present the first comprehensive survey of empirical evidence across mammals in support of Peto’s paradox in addition to computational models that explore the numerous hypotheses that may help resolve the paradox. I provide a detailed examination of tumor suppression in African elephants (Loxodonta africana) and show that the genome contains redundant copies of the tumor suppressor gene TP53. I give evidence that these redundant copies are actively transcribed and also observe an increased apoptotic response after exposure to ionizing radiation, which may be linked to the expression of these genes. Few genomes of large, long-lived organisms are currently available, which motivated my work to provide the sequence and de novo assembly of the humpback whale (Megaptera novaeangliae) genome. In this genome, I discovered a set of tumor suppressor genes that have evolved at an accelerated rate along the whale lineage, which is suggestive of adaptation. Additionally, I find one gene that has undergone convergent evolution between the African elephant and the humpback whale. The overarching goal of my research is to gain a better understanding of how evolution has suppressed cancer in large, long-lived organisms in the hopes of ultimately developing improved cancer prevention in humans.
Tumor-Associated Macrophage Infiltration in Pulmonary Adenocarcinoma: Association with Angiogenesis and Poor Prognosis (1999)

The relation between tumor-associated macrophage (TAM) density and the density of microvessels was investigated in specimens from 113 patients with pulmonary adenocarcinoma, as was the influence of TAM density on prognosis. The rank correlation test revealed a significant relation between TAM density and microvessel density (y = 14.418 + 0.863x, r = 0.454, p > 0.0001). A significant difference in patient survival rate was detected between tumors with a TAM density defined as high and those with a TAM density defined as low (p < 0.01). Multivariate analysis also showed that TAM density was significantly related to survival (p < 0.05). These data indicate that TAM infiltration may contribute to tumor angiogenesis, and that TAM density is a useful prognostic marker in pulmonary adenocarcinoma.
Predicting real-time service-level metrics from device statistics (2015)

While real-time service assurance is critical for emerging telecom cloud services, understanding and predicting performance metrics for such services is hard. In this paper, we pursue an approach based upon statistical learning whereby the behavior of the target system is learned from observations. We use methods that learn from device statistics and predict metrics for services running on these devices. Specifically, we collect statistics from a Linux kernel of a server machine and predict client-side metrics for a video-streaming service (VLC). The fact that we collect thousands of kernel variables, while omitting service instrumentation, makes our approach service-independent and unique. While our current lab configuration is simple, our results, gained through extensive experimentation, prove the feasibility of accurately predicting client-side metrics, such as video frame rates and RTP packet rates, often within 10-15% error (NMAE), also under high computational load and across traces from different scenarios.
Standardised versus Individualised Parenteral Nutrition. Further Food for Thought. (2016)

Parenteral Nutrition may be prescribed as a standard PN (SPN) formulation or as an individualised PN (IPN) formulation. SPN may have advantages in terms of rapid availability, less prescription errors, decreased risk of infection and cost savings but IPN, specifically tailored to an infants needs, may achieve better outcomes in terms of nutrient intake and weight gain. The aim of our study was to determine if VLBW infants in our NICU benefited from receiving IPN over currently available SPN solutions. Our findings were that VLBW infants prescribed IPN received significantly more amino acid (28%), glucose (6%), energy (11%) and calcium (8%) from the aqueous phase of PN than had they received a similar volume of SPN. The benefits were seen over all the days for which PN was administered. In conclusion, IPN was found to offer significant benefits to our VLBW infants. Modifications to currently available SPN would result in better SPN formulations. Our study also supported the recent recommendation to reduce the calcium:phosphate ratio in PN solutions to avoid early hypophosphataemia.
Generation of induced pluripotent stem cells from human blood (2009)

Human dermal fibroblasts obtained by skin biopsy can be reprogrammed directly to pluripotency by the ectopic expression of defined transcription factors. Here, we describe the derivation of induced pluripotent stem cells from CD34+ mobilized human peripheral blood cells using retroviral transduction of OCT4/SOX2/KLF4/MYC. Blood-derived human induced pluripotent stem cells are indistinguishable from human embryonic stem cells with respect to morphology, expression of surface antigens, and pluripotency-associated transcription factors, DNA methylation status at pluripotent cell-specific genes, and the capacity to differentiate in vitro and in teratomas. The ability to reprogram cells from human blood will allow the generation of patient-specific stem cells for diseases in which the disease-causing somatic mutations are restricted to cells of the hematopoietic lineage.
Improved Elicitation of Neutralizing Antibodies against Primary Human Immunodeficiency Viruses by Soluble Stabilized Envelope Glycoprotein Trimers (2001)

Human immunodeficiency virus (HIV-1) envelope glycoprotein subunits, such as the gp120 exterior glycoprotein, typically elicit antibodies that neutralize T-cell-line-adapted (TCLA), but not primary, clinical isolates of HIV-1. Here we compare the immunogenicity of gp120 and soluble stabilized trimers, which were designed to resemble the functional envelope glycoprotein oligomers of primary and TCLA HIV-1 strains. For both primary and TCLA virus proteins, soluble stabilized trimers generated neutralizing antibody responses more efficiently than gp120 did. Trimers derived from a primary isolate elicited antibodies that neutralized primary and TCLA HIV-1 strains. By contrast, trimers derived from a TCLA isolate generated antibodies that neutralized only the homologous TCLA virus. Thus, soluble stabilized envelope glycoprotein trimers derived from primary HIV-1 isolates represent defined immunogens capable of eliciting neutralizing antibodies that are active against clinically relevant HIV-1 strains.
Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism (2016)

Venous thromboembolism occurs frequently in cancer patients. Two variants in the factor 5 gene (F5), rs6025 encoding for the factor V Leiden mutation R506Q, and rs4524 encoding K858R, have been found to be associated with venous thromboembolism. We assessed the joint effect of active cancer and these two F5 variants on venous thromboembolism risk in a case-cohort study. Cases with a first venous thromboembolism (n=609) and a randomly selected age-weighted cohort (n=1,691) were sampled from the general population in Tromsø, Norway. Venous thromboembolism was classified as cancer-related if it occurred in the period 6 months before to 2 years after a diagnosis of cancer. Active cancer was associated with an 8.9-fold higher risk of venous thromboembolism (95% CI 7.2-10.9). The risk of cancer-related venous thromboembolism was 16.7-fold (95% CI 9.9-28.0) higher in subjects heterozygous for rs6025 compared with non-carriers of this variant without active cancer. In subjects with active cancer the risk of venous thromboembolism was 15.9-fold higher (95% CI 9.1-27.9) in those with one risk allele at rs4524, and 21.1-fold (95% CI 12.4-35.8) higher in those with two risk alleles compared with non-carriers without active cancer. A synergistic interaction was observed between active cancer and factor V Leiden (relative excess risk due to interaction 7.0; 95% CI 0.5-14.4) and rs4524 (relative excess risk due to interaction 15.0; 95% CI 7.5-29.2). The incidence of venous thromboembolism during the initial 6 months following a diagnosis of cancer was particularly high in subjects with risk alleles at these loci. This implies that the combination of cancer and F5 variants synergistically increases venous thromboembolism risk.