gebhart/patrepeval huggingface dataset:
Prevention of urinary and fecal incontinence in adults. (2007)

Epidemiologic surveys are cost-effective ways to estimate the prevalence of UI in large nationally representative population groups. Routine clinical evaluation should include an assessment of the risk factors, symptoms, and signs of incontinence. Pregnant or menopausal women, women with vaginal prolapse, males treated for prostate disease, patients with rectal prolapse, and frail elderly and nursing home residents are high risk groups. Individualized management programs can improve continence in LTC facilities but are hard to sustain. Regular monitoring and documentation of the continence status in relation to implemented continence services should be quality of care indicators for nursing homes. Pelvic floor muscle trainings with biofeedback can resolve incontinence and improve quality of life. Surgery is effective in curing stress UI in females. Clinical interventions for UI in males and for FI in adults need future investigation. A list of research recommendations is offered.
Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. (1991)

Using a polyclonal antibody that is monospecific for the erbB-2 oncogene product, an immunohistochemical study of the expression of erbB-2 protein was performed in formalin-fixed paraffin-embedded tissue sections from 260 primary gastric cancers. erbB-2 protein expression in which the reaction was localized to the cell membranes was observed in 31 (11.9%) cancers. All nontumor cells and normal gastric epithelium were negative for membrane staining. There was not a significant association between erbB-2 staining and histological type or venous invasion. erbB-2 protein expression was associated with serosal invasion, lymph node metastasis, and lymphatic invasion. In addition, erbB-2 protein expression correlated with a high number of lymph node metastases. Furthermore, the risk of recurrence in lymph node was over 3 times higher in patients with erbB-2 protein-positive tumors than in those with erbB-2 protein-negative ones. When erbB-2 protein expression and the clinical parameters were entered simultaneously into the Cox regression model, erbB-2 protein expression emerged as an independent prognostic indicator. Patients with erbB-2 protein-positive tumors had 5-fold greater relative risk of death, as compared with those with erbB-2 protein-negative tumors. These results indicate that erbB-2 protein expression is an important independent prognostic indicator in gastric cancer. The high malignant potential of erbB-2 protein-positive tumors may be associated with the very high potential for lymph node metastasis.
Intravenous Safety and Pharmacokinetics of a Novel Dimerizer Drug, AP1903, in Healthy Volunteers (2001)

AP1903 is a novel gene-targeted drug that is being developed for use in drug-regulated cell therapies. An intravenous, single-blind, placebo- and saline-controlled, ascending-dose study was performed to evaluate the safety, tolerability, and pharmacokinetics of AP1903. Twenty-eight normal healthy male volunteers were randomized into five dosage groups of AP1903 (0.01, 0.05, 0.1, 0.5, and 1 mg/kg). Within each group, 4 volunteers received a single dose of AP1903, 1 volunteer received an equal volume of placebo, and 1 received an equal volume of normal saline. The only exception was in the 0.5 mg/kg group, in which 4 volunteers were dosed: 3 received AP1903 and 1 received normal saline. All dosages were administered as intravenous infusions over 2 hours. Clinical safety parameters were monitored, and serial blood and urine samples were collected for analysis of AP1903. No drug-related adverse events were observed at any of the dose levels with the possible exception of facial flushing in 1 volunteer at the 1.0 mg/kg dose level. AP1903 plasma levels were directly proportional to the administered dose, with mean Cmax values ranging from approximately 10 to 1,275 ng/mL over the 0.01 to 1.0 mg/kg dose range. Following the infusion period, blood concentrations revealed a rapid distribution phase, with plasma levels being reduced to approximately 18%, 7%, and 1% of the maximal concentration at 0.5, 2, and 10 hours postdose, respectively. AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable pharmacokinetic profile at doses well above the anticipated therapeutic dose.
Combinations of retinoic acid with either sodium butyrate, dimethyl sulfoxide, or hexamethylene bisacetamide synergistically induce differentiation of the human myeloid leukemia cell line HL60. (1990)

All-trans-retinoic acid (RA), sodium n-butyrate (NaB), hexamethylene bisacetamide (HMBA), and dimethyl sulfoxide (DMSO) induce differentiation of the human acute myeloid leukemia cell line HL60. In the clinic, RA, NaB, or HMBA induce complete or partial remissions. However, the achievement and maintenance of effective plasma concentrations and toxicity have been problems. These difficulties led us to study the interaction of RA with these inducers. We found that combinations of RA with either NaB, HMBA, or DMSO synergistically induced terminal differentiation of HL60. A measure of the effectiveness of these combinations was that the doses of NaB, HMBA, and DMSO required alone to induce half-maximal differentiation were decreased about 4-fold in combination with normal plasma concentrations of about 30 nM RA. RA or NaB alone did not enhance the growth of HL60 cells. In contrast, HMBA or DMSO alone increased growth of HL60 cells even at concentrations that did not induce differentiation. The addition of RA reduced the promotion of growth and increased the extent of terminal differentiation seen with HMBA and DMSO alone. These data suggest that treatment of some malignancies with combinations of RA with HMBA or NaB may maintain differentiation-inducing effects and decrease the problems associated with the achievement and maintenance of effective plasma concentrations as single agents.
The Catalytic Domain of Insulin-degrading Enzyme Forms a Denaturant-resistant Complex with Amyloid β Peptide (2008)

Insulin-degrading enzyme (IDE) is central to the turnover of insulin and degrades amyloid beta (Abeta) in the mammalian brain. Biochemical and genetic data support the notion that IDE may play a role in late onset Alzheimer disease (AD), and recent studies suggest an association between AD and diabetes mellitus type 2. Here we show that a natively folded recombinant IDE was capable of forming a stable complex with Abeta that resisted dissociation after treatment with strong denaturants. This interaction was also observed with rat brain IDE and detected in an SDS-soluble fraction from AD cortical tissue. Abeta sequence 17-27, known to be crucial in amyloid assembly, was sufficient to form a stable complex with IDE. Monomeric as opposed to aggregated Abeta was competent to associate irreversibly with IDE following a very slow kinetics (t(1/2) approximately 45 min). Partial denaturation of IDE as well as preincubation with a 10-fold molar excess of insulin prevented complex formation, suggesting that the irreversible interaction of Abeta takes place with at least part of the substrate binding site of the protease. Limited proteolysis showed that Abeta remained bound to a approximately 25-kDa N-terminal fragment of IDE in an SDS-resistant manner. Mass spectrometry after in gel digestion of the IDE .Abeta complex showed that peptides derived from the region that includes the catalytic site of IDE were recovered with Abeta. Taken together, these results are suggestive of an unprecedented mechanism of conformation-dependent substrate binding that may perturb Abeta clearance, insulin turnover, and promote AD pathogenesis.
A novel human nonviral retroposon derived from an endogenous retrovirus (1987)

In a human genome, we found dispersed repetitive sequences homologous to part of a human endogenous retrovirus termed HERV-K which resembled mouse mammary tumor virus. For elucidation of their structure and organization, we cloned some of these sequences from a human gene library. The sequence common to the cloned DNA was ca. 630 base-pairs (bp) in length with an A-rich tail at the 3' end and was found to be a SINE (short interspersed repeated sequence) type nonviral retroposon. In this retroposon, the 5' end had multiple copies of a 40 bp direct repeat very rich in GC content and about the next 510 nucleotides were homologous to the 3' long terminal repeat and its upstream flanking region of the HERV-K genome. This retroposon was thus given the name, SINE-R element since most of it derived from a retrovirus. SINE-R elements were present at 4,000 to 5,000 copies per haploid human genome. The nucleotide sequence was ca. 90% homologous among the cloned elements.
Steel Factor Sustains SCL Expression and the Survival of Purified CD34 + Bone Marrow Cells in the Absence of Detectable Cell Differentiation (2001)

CD34+ cells express the basic helix-loop-helix transcription factor SCL, which is essential for blood cell formation in vivo. In addition, their survival is critically dependent on hemopoietic growth factors. We therefore compared the effects of Steel factor (SF) and GM-CSF on the survival, proliferation, and differentiation of primary human CD34+ cells, as well as the role of SCL during these processes. GM-CSF suppresses apoptosis in CD34+ cells, which proliferate and differentiate into mature granulocytic and monocytic cells (CD34-CD13+) and loose SCL expression. In contrast, SF suppresses apoptosis without a significant increase in cell numbers, and the cells remain CD34+ and SCL+ with a blast-like morphology. Examination of apoptosis by the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) reaction and of the cell cycle status indicated that SF is both a survival factor and a mitogenic factor for CD34+ cells. There was, however, constant cell death in a fraction of the population, which could be rescued by GM-CSF. Co-addition of SF and GM-CSF prevents the downregulation of SCL observed in the presence of GM-CSF by itself, allows for prolonged survival and expansion of CD34+ cells in culture, inhibits monocytic differentiation and impairs granulocytic differentiation. Finally, exposure to an antisense SCL but not a control oligonucleotide decreases SCL protein levels and prevents the suppression of apoptosis by SF without affecting GM-CSF-dependent cell survival. These observations suggest that the hemopoietic transcription factor SCL regulates the survival of CD34+ cells in response to SF.
Seeing Beyond the End of the World in Strange Days and Until the End of the World (2003)

Herein we offer a critique of contemporary filmic visions of apocalypse. The problem with many Hollywood-style apocalyptic films is that they expect the end of the world to be a spectacular end of the whole world. Against this, by reviewing two contemporary films (Strange Days and Until the End of the World) we suggest that apocalypse may take on a greater significance if we understand that there are many worlds, and that rather than expecting the end of the world, we should be more vigilant in our examinations of the endings of a world. With this in mind, apocalyptic predictions given by Jesus in the gospels are reread and we note how these prophecies have already been fulfilled.
Does Alzheimer's disease begin in the brainstem? (2009)

Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimer's disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high-order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake-sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging - Reagan Institute (NIA-RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, beta-amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD-related neuropathological changes.
Targeting the untargetable KRAS in cancer therapy (2019)

<i>RAS</i> is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated <i>RAS</i> isoform, KRAS is intensively studied in the past years. Despite its well-recognized importance in cancer malignancy, continuous efforts in the past three decades failed to develop approved therapies for <i>KRAS</i> mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.
Disruption of Golgi structure and function in mammalian cells expressing a mutant dynamin (2000)

The large GTPase dynamin is a mechanoenzyme that participates in the scission of nascent vesicles from the plasma membrane. Recently, dynamin has been demonstrated to associate with the Golgi apparatus in mammalian cells by morphological and biochemical methods. Additional studies using a well characterized, cell-free assay have supported these findings by demonstrating a requirement for dynamin function in the formation of clathrin-coated, and non-clathrin-coated vesicles from the trans-Golgi network (TGN). In this study, we tested if dynamin participates in Golgi function in living cells through the expression of a dominant negative dynamin construct (K44A). Cells co-transfected to express this mutant dynamin and a GFP-tagged Golgi resident protein (TGN38) exhibit Golgi structures that are either compacted, vesiculated, or tubulated. Electron microscopy of these mutant cells revealed large numbers of Golgi stacks comprised of highly tubulated cisternae and an extraordinary number of coated vesicle buds. Cells expressing mutant dynamin and GFP-tagged VSVG demonstrated a marked retention (8- to 11-fold) of the nascent viral G-protein in the Golgi compared to control cells. These observations in living cells are consistent with previous morphological and in vitro studies demonstrating a role for dynamin in the formation of secretory vesicles from the TGN.
Flexible and Formal Modeling of Microprocessors with Application to Retargetable Simulation (2003)

Given the growth in application-specific processors, there is a strong need for a retargetable modeling framework that is capable of accurately capturing complex processor behaviors and generating efficient simulators. We propose the operation state machine (OSM) computation model to serve as the foundation of such a modeling framework. The OSM model separates the processor into two interacting layers: the operation layer where operation semantics and timing are modeled, and the hardware layer where disciplined hardware units interact. This declarative model allows for direct synthesis of micro-architecture simulators as it encapsulates precise concurrency semantics of microprocessors. We illustrate the practical benefits of this model through two case studies - the StrongARM core and the PowerPC-750 superscalar processor. The experimental results demonstrate that the OSM model has excellent modeling productivity and model efficiency. Additional applications of this modeling framework include derivation of information required by compilers and formal analysis for processor validation.
Evaluation of Insoluble Bone Gelatin as a Carrier for Enhancement of Osteogenic Protein-1-Induced Intertransverse Process Lumbar Fusion in a Rabbit Model (2008)

In this study, ISBG + OP-1 resulted in more effective lumbar intertransverse process fusion than autograft, OP-1 putty or ISBG alone. ISBG is capable of enhancing OP-1-induced bone formation.
Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. (1993)

Regions giving rise to reentry after myocardial infarction are complex and can include bystander areas, slow conduction zones, and isthmuses for impulse propagation at which radiofrequency current lesions can interrupt reentry.
Use of polyethyleneimine polymer in cell culture as attachment factor and lipofection enhancer (2004)

Polyethyleneimine is an effective attachment factor for weakly anchoring cell lines and primary cells. Its use in lipofection protocols makes the procedures more reliable and increases the yield of expressed products with commonly used cell lines such as PC-12 and HEK-293 cells.
Oncolytic Viruses—Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer (2017)

Oncolytic viruses (OVs) are an emerging treatment option for many cancer types and have recently been the focus of extensive research aiming to develop their therapeutic potential. The ultimate aim is to design a virus which can effectively replicate within the host, specifically target and lyse tumor cells and induce robust, long lasting tumor-specific immunity. There are a number of viruses which are either naturally tumor-selective or can be modified to specifically target and eliminate tumor cells. This means they are able to infect only tumor cells and healthy tissue remains unharmed. This specificity is imperative in order to reduce the side effects of oncolytic virotherapy. These viruses can also be modified by various methods including insertion and deletion of specific genes with the aim of improving their efficacy and safety profiles. In this review, we have provided an overview of the various virus species currently being investigated for their oncolytic potential and the positive and negative effects of a multitude of modifications used to increase their infectivity, anti-tumor immunity, and treatment safety, in particular focusing on the interaction of tumor cells and OVs.
The carbonate-silicate geochemical cycle and its effect on atmospheric carbon dioxide over the past 100 million years (1983)

A computer model has been constructed that considers the effects on the CO/sub 2/ level of the atmosphere, and the Ca, Mg, and HCO/sub 3/ levels of the ocean, of the following processes: weathering on the continents of calcite, dolomite, and calcium-and-magnesium-containing silicates; biogenic precipitation and removal of CaCO/sub 3/ from the ocean; removal of Mg from the ocean via volcanic-seawater reaction; and the metamorphic-magmatic decarbonation of calcite and dolomite (and resulting CO/sub 2/ degassing) as a consequence of plate subduction. Assuming steady state, values for fluxes to and from the atmosphere and oceans are first derived for the modern ocean-atmosphere system. Then the consequences of perturbing steady state are examined by deriving rate expressions for all transfer reactions. These rate expressions are constructed so as to reflect changes over the past 100 my. Results indicate that the CO/sub 2/ content of the atmosphere is highly sensitive to changes in seafloor spreading rate and continental land area, and, to a much lesser extent, to changes in the relative masses of calcite and dolomite. Consideration of a number of alternative seafloor spreading rate formulations shows that in all cases a several-fold higher CO/sub 2/ level for the Cretaceous atmosphere (65-100 mymore » BP) is obtained via the model. Assuming that CO/sub 2/ level and surface air temperature are positively correlated via an atmospheric greenhouse model, they authors predict Cretaceous paleotemperatures which are in rough general agreement with independent published data. Consequently, their results point to plate tectonics, as it affects both metamorphic-magmatic decarbonation and changes in continental land area, as a major control of world climate.« less
Multiple cytokines stimulate the binding of a common 145-kilodalton protein to Shc at the Grb2 recognition site of Shc. (1994)

We recently reported that interleukin-3, Steel factor, and erythropoietin all induce the tyrosine phosphorylation of Shc and its association with Grb2 in hemopoietic cell lines. We have now further characterized the proteins that become associated with Shc following stimulation with these cytokines and found that, in response to all three, the tyrosine-phosphorylated form of Shc binds to common 145- and 52-kDa proteins which also become tyrosine phosphorylated in response to these growth factors. The 145-kDa protein, which appears, from antiphosphotyrosine blots of two-dimensional O'Farrell gels, to exist in four different phosphorylation states following cytokine stimulation (with isoelectric points ranging from 7.2 to 7.8), does not appear to be immunologically related to the beta subunit of the interleukin-3 receptor, c-Kit, BCR, ABL, JAK1, JAK2, Sos1, eps15, or insulin receptor substrate 1 protein. Silver-stained sodium dodecyl sulfate gels indicate that the association of the 145-kDa protein with Shc occurs only after cytokine stimulation and that it can bind to the tyrosine-phosphorylated form of Shc in its non-tyrosine-phosphorylated state. The latter finding, in conjunction with the observations that p145 does not bind, in vitro, to the Src homology 2 (SH2) domain of Shc, that it is not present in anti-Grb2 immunoprecipitates, and that a phosphopeptide which blocks the binding of Shc to the SH2 domain of Grb2 also blocks the binding of Shc to p145, suggests that p145 contains an SH2 domain and competes with Grb2 for the same tyrosine-phosphorylated site on Shc. This implicates p145 as a potential regulator of Ras activity and, perhaps, of other as yet unidentified functions of Shc.