gebhart/patrepeval huggingface dataset:
Viral Vectors for Cancer Gene Therapy: Viral Dissemination and Tumor Targeting (2005)

Cancer gene therapy is the most promising and active field in gene therapy treatment. Although previous experimental and clinical trials have brought forward some exciting cases, in general, the clinical benefits have been limited. A major difference between virus-mediated gene therapy and other therapies is the poor physical diffusibility of viral vectors, which is also one of the major obstacles in cancer gene therapy. As safety is a prerequisite to enhanced viral dissemination, tumor-specific targeting becomes crucial. The present review focuses on questions related to efficient viral dissemination in tumor masses and how to sustain a high level of oncolytic virus targeting of tumor cells only. We will first consider two common reasons for limited virus spread in tumor masses and then discuss strategies for improving the tumor-specific oncolysis of currently used viral vectors and to comment on their advantages and potential problems.
Size dependence of magnetic parameters and surface disorder in magnetite nanoparticles (2009)

Magnetic properties of oleic acid/oleylamine coated magnetite nanoparticles of average diameter D=4, 6, 8, 10, and 12nm are reported. The samples were characterized by transmission electron microscopy and x-ray diffraction (XRD) with XRD showing increasing disorder with decreasing D. Magnetization M vs temperature T data show the blocking temperature TB decreasing with decreasing D from TB=38K for 12nm to TB=6.5K for D=4nm. The saturation magnetization Ms at 2K also decreases from Ms=62emu∕g for 12nm to Ms=17emu∕g for 4nm but the coercivity at 2K increases with a decrease in D. It is shown that Ms fits Ms=92(1−2d∕D)3 with d=0.68nm for D&amp;gt;4nm and d=0.86 for D=4nm. This equation is derived assuming a core-shell model with shell of thickness d consisting of disordered spins not contributing to Ms.
Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel. (1992)

The principal voltage-sensitive sodium channel from human heart has been cloned, sequenced, and functionally expressed. The cDNA, designated hH1, encodes a 2016-amino acid protein that is homologous to other members of the sodium channel multigene family and bears greater than 90% identity to the tetrodotoxin-insensitive sodium channel characteristic of rat heart and of immature and denervated rat skeletal muscle. Northern blot analysis demonstrates an approximately 9.0-kilobase transcript expressed in human atrial and ventricular cardiac muscle but not in adult skeletal muscle, brain, myometrium, liver, or spleen. When expressed in Xenopus oocytes, hH1 exhibits rapid activation and inactivation kinetics similar to native cardiac sodium channels. The single channel conductance of hH1 to sodium ions is about twice that of the homologous rat channel and hH1 is more resistant to block by tetrodotoxin (IC50 = 5.7 microM). hH1 is also resistant to mu-conotoxin but sensitive to block by therapeutic concentrations of lidocaine in a use-dependent manner.
Space-Based High Resolution Gamma Ray Telescope (1988)

We are developing and testing a high resolution, large area gamma ray telescope to be employed in a space based environment. The new concept in the telescope design is the combination of liquid and gas drift chambers with scintillation detectors for imaging and tracking the secondary particles generated by the gammas with a very high angular and energy resolution. The telescope consists of a Liquid Argon Converter, an Argon-Methane Gas Drift Chamber, and a Liquid Argon Calorimeter, and has an event by event processing and decision making feature.
Fish models for environmental carcinogenesis: the rainbow trout. (1996)

Progress over the past 30 years has revealed many strengths of the rainbow trout as an alternative model for environmental carcinogenesis research. These include low rearing costs, an early life-stage ultrasensitive bioassay, sensitivity to many classes of carcinogen, a well-described tumor pathology, responsiveness to tumor promoters and inhibitors, and a mechanistically informative nonmammalian comparative status. Low-cost husbandry, for example, has permitted statistically challenging tumor study designs with up to 10,000 trout to investigate the quantitative interrelationships among carcinogen dose, anticarcinogen dose, DNA adduct formation, and final tumor outcome. The basic elements of the trout carcinogen bioassay include multiple exposure routes, carcinogen response, husbandry requirements, and pathology. The principal known neoplasms occur in liver (mixed hepatocellular/cholangiocellular adenoma and carcinoma, hepatocellular carcinoma), kidney (nephroblastoma), swim bladder (adenopapilloma), and stomach (adenopapilloma). Trout possess a complex but incompletely characterized array of cytochromes P450, transferases, and other enzymic systems for phase I and phase II procarcinogen metabolism. In general, trout exhibit only limited capacity for DNA repair, especially for removal of bulky DNA adducts. This factor, together with a high capacity for P450 bioactivation and negligible glutathione transferase-mediated detoxication of the epoxide, accounts for the exceptional sensitivity of trout to aflatoxin B1 carcinogenesis. At the gene level, all trout tumors except nephroblastoma exhibit variable and often high incidences of oncogenic Ki-ras gene mutations. Mutations in the trout p53 tumor suppressor gene have yet to be described. There are many aspects of the trout model, especially the lack of complete organ homology, that limit its application as a surrogate for human cancer research. Within these limitations, however, it is apparent that trout and other fish models can serve as highly useful adjuncts to conventional rodent models in the study of environmental carcinogenesis and its modulation. For some problems, fish models can provide wholly unique approaches.
A neural system dynamics modeling platform and its applications in randomized controlled trial data analysis (2021)

Conventional statistical methods used in clinical trials lack the ability to predict patient specific risk and very often do not consider the effects of time varying interventions. The aim of this study is to test a novel artificial neural network based model for clinical trial analysis to represent the continuous time evolution of risk. The novel methodology tested utilizes system dynamics and artificial neural networks. This methodology was applied to analyze data from 2,221 patients with acute myocardial infarction enrolled in a well characterized randomized study, the HORIZONS-AMI trial. Outcomes analyzed included: (1) target lesion revascularization (TLR) and (2) stent thrombosis. The proposed neural system dynamics (NSD) model was compared against traditional Cox Proportional Hazards (Cox PH) and Cox neural network (NN) models. Model performance was evaluated using C-statistic at 1, 2 -and 3- years follow-up and model-based simulation studies were performed to examine the effect of different variables on the predicted risk of TLR and stent thrombosis. The NSD model achieved comparable performance to Cox models for TLR. For stent thrombosis, the NSD model outperformed Cox models (1-year C-statistic: Stent thrombosis – Cox PH: 0.60, Cox NN: 0.66, neural SD model: 0.69). The neural SD model identified clinically relevant variables such as stent count, stent type and multiple lesions treated as significant predictors for TLR; and stent count and peak platelet count for stent thrombosis. Simulations illustrated change in predicted TLR risk maximal for the neural SD model, compared to other models. For stent thrombosis, simulation scenario illustrated predicted event rate doubling when clopidogrel is discontinued at 6 months compared to extended use. We have demonstrated an alternative analytical methodology that combines system dynamics and artificial neural networks to analyze results from a randomized trial. This novel approach can incorporate patient-specific longitudinal data and provide personalized risk prediction.
Papillomavirus L1 capsids agglutinate mouse erythrocytes through a proteinaceous receptor (1995)

Virus-like particles (VLPs) composed of L1 derived from bovine papillomavirus type 1 (BPV-1), several human papillomavirus types, or cottontail rabbit papillomavirus (CRPV) agglutinated mouse but not human or rat erythrocytes. Treatment of mouse erythrocytes with trypsin prevented hemagglutination (HA) by BPV-1. Sera from rabbits immunized with native CRPV VLPs, which protect against experimental CRPV infection, exhibited high titers of antibodies that inhibited CRPV VLP HA activity, while sera from rabbits immunized with denatured CRPV VLPs or native BPV VLPs, which do not protect against CRPV infection, were not inhibitory. Testing for HA inhibition is a rapid and simple method for examining the serological relatedness of papillomaviruses and measuring protective antibody titers after VLP vaccination.
The Ability of an Oligomeric Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Antigen To Elicit Neutralizing Antibodies against Primary HIV-1 Isolates Is Improved following Partial Deletion of the Second Hypervariable Region (2001)

Partial deletion of the second hypervariable region from the envelope of the primary-like SF162 virus increases the exposure of certain neutralization epitopes and renders the virus, SF162DeltaV2, highly susceptible to neutralization by clade B and non-clade B human immunodeficiency virus (HIV-positive) sera (L. Stamatatos and C. Cheng-Mayer, J. Virol. 78:7840-7845, 1998). This observation led us to propose that the modified, SF162DeltaV2-derived envelope may elicit higher titers of cross-reactive neutralizing antibodies than the unmodified SF162-derived envelope. To test this hypothesis, we immunized rabbits and rhesus macaques with the gp140 form of these two envelopes. In rabbits, both immunogens elicited similar titers of binding antibodies but the modified immunogen was more effective in eliciting neutralizing antibodies, not only against the SF162DeltaV2 and SF162 viruses but also against several heterologous primary HIV type 1 (HIV-1) isolates. In rhesus macaques both immunogens elicited potent binding antibodies, but again the modified immunogen was more effective in eliciting the generation of neutralizing antibodies against the SF162DeltaV2 and SF162 viruses. Antibodies capable of neutralizing several, but not all, heterologous primary HIV-1 isolates tested were elicited only in macaques immunized with the modified immunogen. The efficiency of neutralization of these heterologous isolates was lower than that recorded against the SF162 isolate. Our results strongly suggest that although soluble oligomeric envelope subunit vaccines may elicit neutralizing antibody responses against heterologous primary HIV-1 isolates, these responses will not be broad and potent unless specific modifications are introduced to increase the exposure of conserved neutralization epitopes.
Development of New Carboxylic Acid-Based MMP Inhibitors Derived from Functionalized Propargylglycines (2001)

A series of carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A (MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a compound with reasonable potency. Introduction of polar groups was required in order to generate inhibitors with acceptable water solubility, and this often resulted in a loss of potency as in compound 63. High serum protein binding proved to be a difficult hurdle with many compounds such as 48 showing >99% binding. Some compounds such as 64 displayed approximately 90% binding, but no reliable method was discovered for designing molecules with low protein binding. Finally, selected data regarding the pharmacokinetic behavior of these compounds is presented.
Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). (2003)

This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant standard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA. The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to standard antirheumatic therapy, including one or more traditional DMARD, corticosteroids, NSAID, and analgesics.
InAs/AlSb heterostructure field-effect transistors using a Si-doped InAs/AlSb short-period superlattice modulation doping barrier (1998)

Modulation doping of InAs/AlSb quantum wells generally requires the use of chalcogenide donor impurities because silicon, the usual donor of choice in molecular beam epitaxy, displays an amphoteric behavior in antimonide compounds. In the present article, we demonstrate the use of a Si-doped InAs/AlSb short-period superlattice (with Si co-deposited with the InAs) to modulation dope the current-carrying InAs channel of an InAs/AlSb heterostructure field-effect transistor (HFET). Using this new approach, we have fabricated 1.5 μm gate InAs/AlSb HFETs with a measured extrinsic transconductance of 550 mS/mm at 300 K. The present band gap engineering approach eliminates the requirement for captive chalcogenide donor sources to modulation dope InAs/AlSb quantum wells. Design alternatives to the use of the short-period superlattice are also considered and demonstrated.
Sézary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors (2010)

Cutaneous T-cell lymphoma (CTCL) encompasses leukemic variants (L-CTCL) such as Sézary syndrome (SS) and primarily cutaneous variants such as mycosis fungoides (MF). To clarify the relationship between these clinically disparate presentations, we studied the phenotype of T cells from L-CTCL and MF. Clonal malignant T cells from the blood of L-CTCL patients universally coexpressed the lymph node homing molecules CCR7 and L-selectin as well as the differentiation marker CD27, a phenotype consistent with central memory T cells. CCR4 was also universally expressed at high levels, and there was variable expression of other skin addressins (CCR6, CCR10, and CLA). In contrast, T cells isolated from MF skin lesions lacked CCR7/L-selectin and CD27 but strongly expressed CCR4 and CLA, a phenotype suggestive of skin resident effector memory T cells. Our results suggest that SS is a malignancy of central memory T cells and MF is a malignancy of skin resident effector memory T cells.
Expression of a protective intestinal immune response can be inhibited at three distinct sites by treatment with anti-alpha 4 integrin. (1993)

The alpha 4 integrins mediate lymphocyte adhesion to Peyer's patch high endothelial vessels and homing to Peyer's patch, as well as to mesenteric lymph nodes. In rats, immunity to infection with the nematode Trichinella spiralis is known to be mediated by CD4+ OX22- (CD45RC-) cells that home to the intestine in large numbers. These experiments were conducted to determine whether the alpha 4 integrins or LFA-1 were involved in the expression of intestinal immunity to T. spiralis. Injection of the anti-alpha 4 integrin, mAb TA-2, but not anti-LFA-1, mAb TA-3, impaired the expression of immunity. An effect of TA-2 was measured at three distinct sites along the activation pathway leading to the migration of protective CD4+ OX22- cells to the intestine. Injection of TA-2 on the same day as infection prevented normal rejection of the parasite and abrogated the characteristic appearance of blast cells in draining lymph 3 days after infection. A similar effect on the migration of blast cells at day 3 was seen when TA-2 was injected 1 day after infection, and injection 2 days after infection still reduced the number of protective cells entering TD lymph on day 3. The effect of TA-2 and TA-3 on homing of dividing cells to the gut was examined by injecting dividing cells i.v. at the same time as antibody. Under these conditions migration of dividing cells to the gut was reduced by 90 to 95% and their capacity to adoptively transfer worm rejection blocked. Furthermore, TA-2 treatment also inhibited protection when it was injected 12, 18, or 24 h after the transfer of protective cells, when these cells had already entered the gut, but not when TA-2 injection was delayed for 36 h. These results indicate the involvement of alpha 4 integrins at the following points in the generation, dissemination, and function of CD4+ OX22- effectors: 1) initial activation during the first 48 h of infection; 2) migration of protective cells to and extravasation in the gut; 3) a function after entry into gut tissues. The results suggest that entry of dividing cells into the gut is critical for the adoptive transfer of protection and that alpha 4 integrin has multiple roles in the manifestation of intestinal immunity.
The Global Regulator CodY Regulates Toxin Gene Expression inBacillus anthracisand Is Required for Full Virulence (2009)

ABSTRACT In gram-positive bacteria, CodY is an important regulator of genes whose expression changes upon nutrient limitation and acts as a repressor of virulence gene expression in some pathogenic species. Here, we report the role of CodY in Bacillus anthracis , the etiologic agent of anthrax. Disruption of codY completely abolished virulence in a toxinogenic, noncapsulated strain, indicating that the activity of CodY is required for full virulence of B. anthracis . Global transcriptome analysis of a codY mutant and the parental strain revealed extensive differences. These differences could reflect direct control for some genes, as suggested by the presence of CodY binding sequences in their promoter regions, or indirect effects via the CodY-dependent control of other regulatory proteins or metabolic rearrangements in the codY mutant strain. The differences included reduced expression of the anthrax toxin genes in the mutant strain, which was confirmed by lacZ reporter fusions and immunoblotting. The accumulation of the global virulence regulator AtxA protein was strongly reduced in the mutant strain. However, in agreement with the microarray data, expression of atxA , as measured using an atxA-lacZ transcriptional fusion and by assaying atxA mRNA, was not significantly affected in the codY mutant. An atxA-lacZ translational fusion was also unaffected. Overexpression of atxA restored toxin component synthesis in the codY mutant strain. These results suggest that CodY controls toxin gene expression by regulating AtxA accumulation posttranslationally.
Long‐Term Therapy with Oral Treprostinil in Pulmonary Arterial Hypertension Failed to Lead to Improvement in Important Physiologic Measures: Results from a Single Center (2015)

Sustained-release oral treprostinil, an oral prostacyclin, led to significant improvement in 6-minute walk distance (6MWD) versus placebo in treatment-naive patients with pulmonary arterial hypertension (PAH) but failed to lead to significant improvement in two 16-week trials in patients receiving background PAH therapies (FREEDOM studies). Long-term studies are lacking. Our objective was to evaluate 6MWD, functional class, hemodynamics, and other long-term outcomes during oral treprostinil administration in PAH. Patients receiving oral treprostinil through the FREEDOM studies at our institution were included and were followed for up to 7 years. The primary end point was change in pulmonary vascular resistance (PVR) at first follow-up catheterization. Other end points included 6MWD, functional class, and other hemodynamic results. Thirty-seven patients received oral treprostinil for a median of 948 days, with 81%, 61%, and 47% continuing therapy at 1, 2, and 3 years, respectively. Mean treprostinil dose at 3, 12, and 24 months was 4.3 ± 2.3, 8.6 ± 3.2, and 11.7 ± 5.8 mg/24 h, respectively. Compared with pretreatment values, there was no significant change in 6MWD at 3 or 12 months, no improvement in functional class at 12 months, and no significant change in hemodynamics at the first follow-up catheterization (N = 34). Oral treprostinil dose was inversely associated with change in PVR (r = -0.42, P < 0.05), and change in PVR was numerically better among patients in the highest dosing quartile. No significant improvement in 6MWD, functional class, or hemodynamics versus pretreatment values was seen with long-term oral treprostinil therapy, potentially because of inability to achieve a clinically effective dose.
IL-4 Enhances Keratinocyte Expression of CXCR3 Agonistic Chemokines (2000)

IFN-induced protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-chemoattractant (I-TAC) belong to the non-glutamate-leucine-arginine motif CXC chemokine family and act solely through the CXCR3 receptor for potent attraction of T lymphocytes. In this study, we evaluated the capacity of the T cell-derived cytokines IL-4, IL-10, and IL-17 to modulate IP-10, Mig, and I-TAC in cultured human keratinocytes and CXCR3 expression in T cells from allergic contact dermatitis (ACD). IL-4, but not IL-10 or IL-17, significantly up-regulated IFN-gamma- or TNF-alpha-induced IP-10, Mig, and I-TAC mRNA accumulation in keratinocytes and increased the levels of IP-10 and Mig in keratinocyte supernatants. Immunohistochemistry of skin affected by ACD revealed that >70% of infiltrating cells were reactive for CXCR3 and that CXCR3 staining colocalized in CD4+ and CD8+ T cells. Nickel-specific CD4+ and CD8+ T cell lines established from ACD skin produced IFN-gamma and IL-4 and expressed moderate to high levels of CXCR3. Finally, CXCR3 agonistic chemokines released by stimulated keratinocytes triggered calcium mobilization in skin-derived nickel-specific CD4+ T cells and promoted their migration, with supernatant from keratinocyte cultures stimulated with IFN-gamma and IL-4 attracting more efficaciously than supernatant from keratinocytes activated with IFN-gamma alone. In conclusion, IL-4 exerts a proinflammatory function on keratinocytes by potentiating IFN-gamma and TNF-alpha induction of IP-10, Mig, and I-TAC, which in turn may determine a prominent recruitment of CXCR3+ T lymphocytes at inflammatory reaction sites.
A Phase I Study of Quisinostat (JNJ-26481585), an Oral Hydroxamate Histone Deacetylase Inhibitor with Evidence of Target Modulation and Antitumor Activity, in Patients with Advanced Solid Tumors (2013)

The adverse event profile of quisinostat was comparable with that of other HDACi. Intermittent schedules were better tolerated than continuous schedules. On the basis of tolerability, pharmacokinetic predictions, and pharmacodynamic effects, the recommended dose for phase II studies is 12 mg on the MWF schedule.
Heterodyne detection of ultrasound from rough surfaces using a double phase conjugate mirror (1995)

We present an improved version of the classical heterodyne interferometer for ultrasound detection, which includes a double phase conjugate mirror (DPCM) in the detection arm. The DPCM performs wave front adaptation to plane wave of the speckled beam scattered by the rough surface of the sample. The performances of the system are analyzed regarding the transmission (≊30%) and fidelity (≊70%) of the phase conjugation and the response time and étendue of the device. An example of application to the detection of laser generated ultrasound is also presented.