gebhart/patrepeval huggingface dataset:
Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials (2010)

Intervention with interferon-β (IFNβ) therapy counters early inflammatory damage to myelin and protects axons; such therapy might demonstrate greater efficacy earlier in the disease course compared with later when permanent damage has already occurred. Clinical trials conducted in patients with clinically isolated syndrome (CIS) show clinical benefits of early treatment of multiple sclerosis (MS), as evidenced by delayed conversion to clinically definite multiple sclerosis and reduced disability 3 years later; however, statistical significance is lost at 5 years. Moreover, in the CIS trials, patients who began treatment later in the course of MS did not benefit as much as those who began treatment earlier. In the treatment of relapsing-remitting multiple sclerosis (RRMS), immunomodulatory drug (IMD) therapy markedly reduced relapse rates and the burden of disease, as assessed by MRI. IFNβ therapy has demonstrated greater benefits in RRMS than in secondary progressive multiple sclerosis (SPMS). The SPMS trials consistently show reduction in relapse rates and accumulation of new MRI lesions, but have conflicting results for time to disability progression, which is the primary outcome measure in SPMS trials. Current evidence suggests that IFNβ therapy may be more effective in the early stages of SPMS, characterized by relapsing episodes and MRI evidence of greater brain lesion disease activity. Thus, intervention with IFNβ therapy is appropriate for all stages of MS except PPMS or non-relapsing SPMS. Intervention with glatiramer acetate is appropriate for RRMS. The balance of evidence indicates that early therapy is essential to delay the accumulation of irreversible neurologic damage and consequent disability.
Humanized mouse models of HIV infection. (2011)

Because of the limited tropism of HIV, in vivo modeling of this virus has been almost exclusively limited to other lentiviruses, such as simian immunodeficiency virus, that reproduce many important characteristics of HIV infection. However, there are significant genetic and biological differences among lentiviruses and some HIV-specific interventions are not effective against other lentiviruses in nonhuman hosts. For these reasons, much emphasis has recently been placed on developing alternative animal models that support HIV replication and recapitulate key aspects of HIV infection and pathogenesis in humans. Humanized mice, CD34+ hematopoietic progenitor cell transplanted immunodeficient mice, and in particular mice also implanted with human thymus/liver tissue (bone marrow liver thymus mice) that develop a functional human immune system, have been the focus of a great deal of attention as possible models to study virtually all aspects of HIV biology and pathogenesis. Humanized mice are systemically reconstituted with human lymphoid cells, offering rapid, reliable, and reproducible experimental systems for HIV research. Peripheral blood of humanized mice can be readily sampled longitudinally to assess reconstitution with human cells and to monitor HIV replication, permitting the evaluation of multiple parameters of HIV infection such as viral load levels, CD4+ T-cell depletion, immune activation, as well as the effects of therapeutic interventions. Of high relevance to HIV transmission is the extensive characterization and validation of the reconstitution with human lymphoid cells of the female reproductive tract and of the gastrointestinal tract of humanized bone marrow liver thymus mice that renders them susceptible to both vaginal and rectal HIV infection. Other important attributes of all types of humanized mice include: (i) their small size and cost that make them widely accessible; (ii) multiple cohorts of humanized mice can be made from multiple human donors and each cohort has identical human cells, permitting control of intragenetic variables; (iii) continuous de novo production of human immune cells from the transplanted CD34+ cells within each humanized mouse facilitates long-term experiments; (iv) both primary and laboratory HIV isolates can be used for experiments; and (v) in addition to therapeutic interventions, rectal and vaginal HIV prevention approaches can be studied. In summary, humanized mice can have an important role in virtually all aspects of HIV research, including the analysis of HIV replication, the evaluation of HIV restriction factors, the characterization of successful biomedical HIV prevention strategies, the evaluation of new treatment regimens, and the evaluation of novel HIV eradication strategies.
Designer Aminoglycosides That Selectively Inhibit Cytoplasmic Rather than Mitochondrial Ribosomes Show Decreased Ototoxicity (2013)

There is compelling evidence that aminoglycoside (AG) antibiotics can induce the mammalian ribosome to suppress disease-causing nonsense mutations and partially restore the expression of functional proteins. However, prolonged AG treatment can cause detrimental side effects in patients, including most prominently, ototoxicity. Recent mechanistic discussions have considered the relative contributions of mitochondrial and cytoplasmic protein synthesis inhibition to AG-induced ototoxicity. We show that AGs inhibit mitochondrial protein synthesis in mammalian cells and perturb cell respiration, leading to a time- and dose-dependent increase in superoxide overproduction and accumulation of free ferrous iron in mitochondria caused by oxidative damage of mitochondrial aconitase, ultimately leading to cell apoptosis via the Fenton reaction. These deleterious effects increase with the increased potency of AG to inhibit the mitochondrial rather than cytoplasmic protein synthesis, which in turn correlates with their ototoxic potential in both murine cochlear explants and the guinea pig in vivo. The deleterious effects of AGs were alleviated in synthetic derivatives specially designed for the treatment of genetic diseases caused by nonsense mutations and possessing low affinity toward mitochondrial ribosomes. This work highlights the benefit of a mechanism-based drug redesign strategy that can maximize the translational value of "readthrough therapy" while mitigating drug-induced side effects. This approach holds promise for patients suffering from genetic diseases caused by nonsense mutations.
Peptide immunotherapy for allergic disease (2003)

The only disease-modifying treatment available for IgE-mediated disease is specific immunotherapy, but the retention of B cell epitopes in whole allergen preparations confers a risk of IgE-mediated systemic reactions to their administration. Compelling evidence for the central role of T cells in allergic disease suggests that IgE-binding epitopes could be removed from such therapy, improving safety without affecting efficacy. Short, allergen-derived peptides lack the conformational determinants required for IgE crosslinking and are, therefore, an attractive therapeutic possibility. However, human leukocyte antigen (HLA) polymorphism means that T cell peptide epitopes present a huge diversity, which makes the design of peptide-based vaccines problematic. Over the past 10 years, advances in our understanding of epitope selection and major histocompatibility complex (MHC)-peptide-T cell receptor interactions have taken this therapy forward to early clinical trials with human volunteers.
Bad bugs and beleaguered bladders: Interplay between uropathogenicEscherichia coliand innate host defenses (2000)

Strains of uropathogenic Escherichia coli (UPEC) are the causative agents in the vast majority of all urinary tract infections. Upon entering the urinary tract, UPEC strains face a formidable array of host defenses, including the flow of urine and a panoply of antimicrobial factors. To gain an initial foothold within the bladder, most UPEC strains encode filamentous surface adhesive organelles called type 1 pili that can mediate bacterial attachment to, and invasion of, bladder epithelial cells. Invasion provides UPEC with a protective environment in which bacteria can either replicate or persist in a quiescent state. Infection with type 1-piliated E. coli can trigger a number of host responses, including cytokine production, inflammation, and the exfoliation of infected bladder epithelial cells. Despite numerous host defenses and even antibiotic treatments that can effectively sterilize the urine, recent studies demonstrate that uropathogens can persist within the bladder tissue. These bacteria may serve as a reservoir for recurrent infections, a common problem affecting millions each year.
Pharmacologic Unmasking of Epigenetically Silenced Genes in Breast Cancer (2009)

This study identified new cancer-specific methylated genes to help elucidate the biology of breast cancer and as candidate diagnostic markers for the disease.
Rationale for adjuvant chemotherapy (1977)

Surgery or radiation therapy fails to cure clinically evident human cancer, in the main, if the disease is systemic (has metastasized) when first recognized, because neither modality can effectively remove or kill distant and/or unrecognized metastases. Starting drug treatment of a tumor when it is first clinically recognized, or when it re-presents following noncurative surgical or radiological treatment, fails to cure over 90% of cancer in man because the body burden of tumor cells exceeds the tumor cell kill potential of nearly all of the most effective drugs or drug combinations against most tumors. The indicated approach to improving cure rates under these circumstances is to use chemotherapy as an adjuvant to effective (life-prolonging) but noncurative surgical and/or radiological treatment. Surgical adjuvant chemotherapy of carcinoma of the breast and osteogenic sarcoma has already been shown to increase the disease-free interval over that obtained with surgery alone, and the probability of having achieved significant increases in long-term cure rates is high. Laboratory studies with transplantable metastatic lung, breast, and colon carcinomas and melanotic melanoma, and with a spontaneous breast carcinoma of mice, all of which are uniformly fatal if untreated, have shown that: 1) the incidence of metastatic disease is directly related to tumor mass, 2) surgical cure rates drop as tumor mass at surgery increases, 3) grossly evident primary tumors are generally not curable by drug treatment, and 4) surgical adjuvant chemotherapy increases the long-term cure rates with all of these tumors and significantly increases the life span of treatment failures. Effective surgical adjuvant chemotherapy is both dose-responsive and related to the body burden of metastatic tumor at time of drug treatment. The effectiveness of surgical adjuvant chemotherapy decreases 1) as the tumor staging is advanced prior to surgery, 2) as the interval from surgery to start of effective chemotherapy is increased, and 3) as the drug doses are reduced. Additionally, and of critical importance to treatment planning, some drugs that are marginally effective or ineffective against the presurgical total body burden of tumor cells are curative in some to all mice with metastatic disease if given shortly after surgical removal of the primary tumor.
Function and Solution Structure of Huwentoxin-IV, a Potent Neuronal Tetrodotoxin (TTX)-sensitive Sodium Channel Antagonist from Chinese Bird Spider Selenocosmia huwena (2002)

We have isolated a highly potent neurotoxin from the venom of the Chinese bird spider, Selenocosmia huwena. This 4.1-kDa toxin, which has been named huwentoxin-IV, contains 35 residues with three disulfide bridges: Cys-2-Cys-17, Cys-9-Cys-24, and Cys-16-Cys-31, assigned by a chemical strategy including partial reduction of the toxin and sequence analysis of the modified intermediates. It specifically inhibits the neuronal tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel with the IC(50) value of 30 nm in adult rat dorsal root ganglion neurons, while having no significant effect on the tetrodotoxin-resistant (TTX-R) voltage-gated sodium channel. This toxin seems to be a site I toxin affecting the sodium channel through a mechanism quite similar to that of TTX: it suppresses the peak sodium current without altering the activation or inactivation kinetics. The three-dimensional structure of huwentoxin-IV has been determined by two-dimensional (1)H NMR combined with distant geometry and simulated annealing calculation by using 527 nuclear Overhauser effect constraints and 14 dihedral constraints. The resulting structure is composed of a double-stranded antiparallel beta-sheet (Leu-22-Ser-25 and Trp-30-Tyr-33) and four turns (Glu-4-Lys-7, Pro-11-Asp-14, Lys-18-Lys-21 and Arg-26-Arg-29) and belongs to the inhibitor cystine knot structural family. After comparison with other toxins purified from the same species, we are convinced that the positively charged residues of loop IV (residues 25-29), especially residue Arg-26, must be crucial to its binding to the neuronal tetrodotoxin-sensitive voltage-gated sodium channel.
Dispersion variable fibre Bragg grating using apiezoelectric stack (1996)

The authors describe novel dispersion variable fibre Bragg grating device using a segmented piezoelectric stack to combat chromatic dispersion. By applying appropriate voltages to the independently controlled constituent segments, it is shown that the dispersion can be varied from ~8770 to ~940 ps/nm with an increase in bandwidth from ~0.03 to ~0.32 nm.
Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (Review) (2010)

Prostate cancer is one of the most commonly diagnosed cancers in men. The number of affected men is expected to rapidly increase as the population of males over the age of 50 grows worldwide. For patients who are not cured by local treatment and experience metastatic disease, neither androgen ablation nor chemotherapy can abrogate progression and death from androgen-independent/hormone-refractory disease. Therefore, finding strategies for the prevention of prostate cancer initiation and disease progression is a medical challenge. Consumption of cruciferous vegetables has been reported to be associated with reduced incidence of prostate cancer cases. The isothiocyanates, including phenethyl isothiocyanate (PEITC), from cruciferous vegetables have been demonstrated as active components responsible for chemoprevention. In this review, we summarize the recent findings of PEITC on prostate cancer prevention with an emphasis on epigenetic mechanisms. Studies have indicated that PEITC mediates gene regulation, such as downregulation of androgen receptor expression and induction of endogenous cyclin-dependent kinase inhibitors, p21 and p27. The gene for detoxifying enzyme pi-class glutathione S-transferase (GSTP1), silenced in the vast majority of prostate tumor cells, could be reactivated and the enzymatic function recovered. This may be through epigenetic mechanisms as PEITC is a dual inhibitor of histone deacetylases and aberrant CpG island methylation of various genes. The epigenetic regulation may play a critical role, along with interactive mechanisms including the disruption of microtubule polymerization, in prostate cancer prevention by PEITC. These mechanisms target and correct the aberrations fundamental to the initiation and progression of carcinogenesis in cells, and restoring the cells to a more normal state. Inhibiting and eliminating cancer cells forms the basis of cancer prevention.
Capillary and slab gel electrophoresis profiling of oligosaccharides (1995)

Capillary electrophoresis with laser-induced fluorescent detection, a one-dimensional version of the well-established planar analytical method of polyacrylamide gel electrophoresis, has been proven to be a powerful new microanalytical method for profiling complex carbohydrates. In this paper a comparison is presented between the planar high concentration polyacrylamide gel electrophoresis method and capillary electrophoresis of different carbohydrates with respect to performance and efficiency. N-Linked oligosaccharides were released from several glycoproteins, including fetuin, human immunodeficiency virus (HIV) envelope recombinant glycoprotein (GP-120), alpha 1-acid glycoprotein and ribonuclease B, using recombinant peptide-N-glycosidase F (PNGase F). Both separation methods involve labeling of the released carbohydrates at the reducing end with the fluorescent dye, disodium 8-amino-1,3,6-naphthalene trisulfonate (ANTS). Fluorophore labeling was followed by separation of the labeled oligosaccharides either by high concentration polyacrylamide gel electrophoresis or capillary electrophoresis.
Immunotherapy with Chinese medicinal herbs. II. Reversal of cyclophosphamide-induced immune suppression by administration of fractionated Astragalus membranaceus in vivo. (1988)

A partially purified fraction (F3) with an estimated molecular weight of 20,000 to 25,000 derived from the traditional Chinese medicinal herb Astragalus membranaceus, was found to possess a potent immunorestorative activity in vitro. Its capacity to aborogate the local xenogeneic graft versus host reaction (XGVHR) following injection in vivo was further studied in a newly developed animal model designed for preclinical evaluation of various biological response modifiers. F3 was injected intravenously into cyclophosphamide-primed rats at varied concentrations and schedules prior to grafting of mononuclear cells from healthy normal donors. Maximal abrogation of the local XGVHR mounted by the mononuclear cells, was observed following injection of 5.55 mg of F3 daily for eight days. This abrogation of XGVHR indicates a reversal of the immunosuppressive effect of cyclophosphamide as manifested by a significant decline in the local XGVHR volume from 99.42 +/- 9.2 mm3 (positive control) to 39.78 +/- 8.3 mm3 (p less than 0.001). This reversal of cyclophosphamide-induced immunosuppression by the administration of F3 was complete, since the volume of the abrogated local XGVHR (39.78 +/- 8.3 mm3) was comparable to 34.79 +/- 5.69 mm3 (p greater than 0.1) in the negative control group (no cyclophosphamide-priming; saline injection only). These data indicate that F3 administration markedly enhances the rats' ability to reject the xenogeneic graft and therefore possesses a strong immune potentiating activity in vivo. These preclinical data also provide the rational basis for the use of extracts of Astragalus membranaceus in phase I clinical trials among patients suffering from iatrogenic or inherent immune deficiency states.
MRI guided and monitored focused ultrasound thermal ablation methods: a review of progress (2004)

This paper reviews the current status in using magnetic resonance imaging (MRI) to guide and monitor thermal coagulation of tumours using focused ultrasound. The patient treatment procedure with a second generation phased array system will be described. Several clinical trials have found that patient treatments are feasible and that MRI thermometry allows noninvasive monitoring of clinical treatments. Overall, this emerging modality holds significant potential for non-invasive tumour treatment of both benign and malignant tumours.
The Role of Tumor Necrosis Factor α in Modulating the Quantity of Peripheral Blood-Derived, Cytokine-Driven Human Dendritic Cells and Its Role in Enhancing the Quality of Dendritic Cell Function in Presenting Soluble Antigens to CD4+ T Cells In Vitro (1998)

Because dendritic cells (DC) are critically involved in both initiating primary and boosting secondary host immune responses, attention has focused on the use of DC in vaccine strategies to enhance reactivity to tumor-associated antigens. We have reported previously the induction of major histocompatibility complex class II-specific T-cell responses after stimulation with tumor antigen-pulsed DC in vitro. The identification of in vitro conditions that would generate large numbers of DC with more potent antigen-presenting cell (APC) capacity would be an important step in the further development of clinical cancer vaccine approaches in humans. We have focused attention on identifying certain exogenous cytokines added to DC cultures that would lead to augmented human DC number and function. DC progenitors from peripheral blood mononuclear cells (PBMC) were enriched by adherence to plastic, and the adherent cells were then cultured in serum-free XVIVO-15 medium (SFM) for 7 days with added granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). At day 7, cultures contained cells that displayed the typical phenotypic and morphologic characteristics of DC. Importantly, we have found that the further addition of tumor necrosis factor α (TNFα) at day 7 resulted in a twofold higher yield of DC compared with non–TNFα-containing DC cultures at day 14. Moreover, 14-day cultured DC generated in the presence of TNFα (when added at day 7) demonstrated marked enhancement in their capacity to stimulate a primary allogeneic mixed leukocyte reaction (8-fold increase in stimulation index [SI]) as well as to present soluble tetanus toxoid and candida albicans (10- to 100-fold increases in SI) to purified CD4+ T cells. These defined conditions allowed for significantly fewer DC and lower concentrations of soluble antigen to be used for the pulsing of DC to efficiently trigger specific T-cell proliferative responses in vitro. When compared with non–TNFα-supplemented cultures, these DC also displayed an increased surface expression of CD83 as well as the costimulatory molecules, CD80 and CD86. Removal of TNFα from the DC cultures after 2 or 4 days reduced its enhancing effect on DC yield, phenotype, and function. Thus, the continuous presence of TNFα over a 7-day period was necessary to achieve the maximum enhancing effect observed. Collectively, our findings point out the importance of exogenous TNFα added to cultures of cytokine-driven human DC under serum-free conditions, which resulted in an enhanced number and function of these APC. On the basis of these results, we plan to initiate clinical vaccine trials in patients that use tumor-pulsed DC generated under these defined conditions.
Somatic Mitochondrial DNA Mutations in Mammalian Aging (2010)

Mitochondrial dysfunction is heavily implicated in the multifactorial aging process. Aging humans have increased levels of somatic mtDNA mutations that tend to undergo clonal expansion to cause mosaic respiratory chain deficiency in various tissues, such as heart, brain, skeletal muscle, and gut. Genetic mouse models have shown that somatic mtDNA mutations and cell type-specific respiratory chain dysfunction can cause a variety of phenotypes associated with aging and age-related disease. There is thus strong observational and experimental evidence to implicate somatic mtDNA mutations and mosaic respiratory chain dysfunction in the mammalian aging process. The hypothesis that somatic mtDNA mutations are generated by oxidative damage has not been conclusively proven. Emerging data instead suggest that the inherent error rate of mitochondrial DNA (mtDNA) polymerase gamma (Pol gamma) may be responsible for the majority of somatic mtDNA mutations. The roles for mtDNA damage and replication errors in aging need to be further experimentally addressed.