gebhart/patrepeval huggingface dataset:
Endoscopic Suspension of the Vesical Neck for Urinary Incontinence in Females (1980)

The key to restoring urinary continence in the female is to raise the internal vesical neck of the bladder to a position behind the symphysis pubis. The operation which accomplishes this with the least morbidity, the most accuracy and the greatest permanency is endoscopic suspension; it is particularly applicable in patients with obesity, multiple operative failures, radiation incontinence, and severe pelvic fractures. Between December 1973 and May 1979, 203 patients underwent 211 operations with a minimum of six months of follow-up study at final review (November 1979). Twenty per cent of the patients were totally incontinent on referral, and 60 per cent lost urine with minimal activity; only 20 per cent of the patients had typical stress urinary incontinence, requiring coughing or sneezing to lose urine. Among the 203 patients, there were 188 previous operations for urinary incontinence, including 74 Marshall-Marchetti retropubic repairs. Forty-seven patients have been followed for over four years, and 156 patients have been followed for six months to four years. While 138 patients had a previous hysterectomy, 65 patients had not; the presence of the uterus did not affect the results. Urinary incontinence is not an indication for hysterectomy. Ninety-one per cent of the 203 patients were cured of their urinary incontinence by endoscopic suspension of the vesical neck. Technical advantages over the retropubic vesical neck suspensions include the use of monofilament heavy nylon (No. 2), a vaginally placed Dacron((R)) buttress to prevent tearing of the pubocervical fascia, less postoperative morbidity, minimal blood loss, functional measurements and anatomic visualization of a restored vesical neck during the operative procedure, easy access to a surgically difficult pelvis, and simultaneous repair of significant rectoceles or substantial cystoceles through the same operative field.
Targeted Expression of Cyclin D2 Results in Cardiomyocyte DNA Synthesis and Infarct Regression in Transgenic Mice (2004)

Restriction point transit and commitment to a new round of cell division is regulated by the activity of cyclin-dependent kinase 4 and its obligate activating partners, the D-type cyclins. In this study, we examined the ability of D-type cyclins to promote cardiomyocyte cell cycle activity. Adult transgenic mice expressing cyclin D1, D2, or D3 under the regulation of the alpha cardiac myosin heavy chain promoter exhibited high rates of cardiomyocyte DNA synthesis under baseline conditions. Cardiac injury in mice expressing cyclin D1 or D3 resulted in cytoplasmic cyclin D accumulation, with a concomitant reduction in the level of cardiomyocyte DNA synthesis. In contrast, cardiac injury in mice expressing cyclin D2 did not alter subcellular cyclin localization. Consequently, cardiomyocyte cell cycle activity persisted in injured hearts expressing cyclin D2, ultimately resulting in infarct regression. These data suggested that modulation of D-type cyclins could be exploited to promote regenerative growth in injured hearts.
Therapeutic efficacy of a novel FAK inhibitor TAE226 in ovarian carcinoma (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

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Objective: Focal adhesion kinase (FAK) overexpression is frequently found in ovarian and other cancers and is predictive of poor clinical outcome. In the current study, we characterized the biological and therapeutic effects of a novel FAK inhibitor,TAE226.

Methods: Taxane-sensitive (SKOV3ip1 and HeyA8) and taxane-resistant (HeyA8-MDR) cell lines were used for in vitro and in vivo therapy experiments using TAE226 alone and in combination with docetaxel. Assessment of cell proliferation (PCNA), angiogenesis (CD31 staining) and apoptosis (TUNEL) was performed by immunohistochemical and immunofluorescence techniques.

Results: In vitro , TAE226 inhibited phosphorylation of FAK at both Y397 and Y861, inhibited cell growth in a time- and dose- dependent manner, and enhanced docetaxel-mediated growth inhibition by 10 and 20 fold in the taxane-sensitive and resistant cell lines, respectively. In vivo , FAK inhibition by TAE226, significantly reduced tumor burden in the HeyA8, SKOV3ip1, and HeyA8-MDR models compared to the vehicle treated controls. Treatment with both TAE226 and docetaxel had greater efficacy than either agent alone in all three models (HeyA8: 75% reduction; p<0.002; SKOV3ip1: 97% reduction; p<0.001; HeyA8-MDR: 70% reduction; p<0.04). In addition, TAE226 alone and in combination with chemotherapy prolonged survival in tumor-bearing mice. Even in larger tumors, combination therapy with TAE226 and docetaxel resulted in tumor regression, as determined by bioluminescent imaging. Combination therapy induced apoptosis of tumor-associated endothelial cells and reduced microvessel density and tumor cell proliferation compared to control and single-agent therapy.

Conclusions: TAE226 in combination with docetaxel is highly effective for the treatment of ovarian carcinoma. Therefore, FAK inactivation may be an attractive therapeutic approach against ovarian cancer.
Thermal Stabilization of Enzymes Immobilized within Carbon Paste Electrodes (1997)

In this note we report on the remarkable thermal stabilization of enzymes immobilized in carbon paste electrodes. Amperometric biosensors are shown for the first time to withstand a prolonged high-temperature (>50 °C) stress. Nearly full activity of glucose oxidase is retained over periods of up to 4 months of thermal stress at 60-80 °C. Dramatic improvements in the thermostability are observed for polyphenol oxidase, lactate oxidase, alcohol oxidase, horseradish peroxidase, and amino acid oxidase. Such resistance to heat-induced denaturation is attributed to the conformational rigidity of these biocatalysts within the highly hydrophobic (mineral oil or silicone grease) pasting liquid. While no chemical stabilizer is needed for attaining such protective action, it appears that low humidity (i.e., low water content) is essential for minimizing the protein mobility. Besides their implications for electrochemical biosensors, such observations should lead to a new generation of thermoresistant enzyme reactors based on nonpolar semisolid supports.
Stimulation of endosteal bone formation by systemic injections of recombinant basic fibroblast growth factor in rats. (1995)

In vivo effects of basic fibroblast growth factor (bFGF) on bone formation was examined in rats. Daily systemic injections of 100 micrograms/kg bFGF for 7 days caused a marked stimulation of endosteal bone formation in both cortical and secondary cancellous bone areas. Histological examinations revealed that the sequence of responses to the injections of bFGF consisted of three phases: an early increase in the number of preosteoblastic cells over the osteoblastic cell layer (days 1-3), recruitment of osteoblasts from preosteoblastic cells (days 3-5), and an increase in new bone formation (days 5-7). These histological changes in the endosteum correlated closely with histomorphometrical parameters of bone formation, and the endosteal mineral apposition rate was almost unaffected during the initial 4 days but was markedly enhanced after this period. Immunohistochemical examinations using antitransforming growth factor (TGF)-beta 1 antibody demonstrated that immunostaining of preosteoblastic cells for TGF-beta already increased 1 day after bFGF treatment. Distribution of TGF-beta in osteoblasts and bone matrices began to increase on day 3, and all the osteoblasts and new bone matrices were intensively immuno-stained on day 7. These results demonstrate that systemic injections of bFGF in rats stimulate endosteal bone formation, and that the stimulation of bone formation is preceded by an initial increase in preosteoblastic cells with later recruitment of osteoblasts from these cells. Because the distribution of TGF-beta in the endosteal cells is increased by bFGF, the effect of bFGF may at least in part be mediated by TGF-beta. However, the precise mechanism of action of bFGF on bone formation remains to be clarified.
High‐performance liquid chromatographic profiling of fluorescent labelled N‐glycans on glycoproteins (2002)

Abstract Monitoring protein glycosylation is becoming increasingly important as novel recombinant glycoprotein therapeutics, such as glycoprotein hormones, cytokines and clotting factors, are introduced into clinical use. In this report, we describe an HPLC strategy and an improved and simplified pre‐column derivatization procedure to profile N‐linked glycans obtained from a variety of commercially available glycoproteins as examples. N‐Glycans were first released by peptide:N‐glycosidase F and labelled with the fluorescent label, 4‐aminobenzoic acid by reductive amination. The labelled N‐Glycans were then resolved by normal‐phase HPLC and the N‐glycan profile could be further improved by separating the N‐glycans first according to charge by anion‐exchange HPLC prior to the normal‐phase HPLC. If required, identification of the fractionated derivatized oligosaccharides can be determined by mass spectrometry. The whole profiling process is simple and can be implemented in most laboratories. Because of the high sensitivity, batch glycan‐analysis of low‐yield recombinant glycoproteins such as samples in ampoules or obtained in the early stage of production development is possible. Copyright © 2002 John Wiley &amp; Sons, Ltd.
Netrin UNC-6 and the Regulation of Branching and Extension of Motoneuron Axons from the Ventral Nerve Cord of Caenorhabditis elegans (1999)

In the Caenorhabditis elegans embryo, some ventral midline motoneurons extend a process circumferentially to the dorsal midline and a process longitudinally along ventral nerve cord interneurons. Circumferential migrations are guided by netrin UNC-6, which repels motoneuron axons dorsally. Although the motoneuron cell bodies and the longitudinal axons are positioned along UNC-6-expressing interneurons in the ventral nerve cord, the circumferential processes extend only from the motoneuron cell bodies and from defined locations along some longitudinal axons. This implies a mechanism regulates motoneuron branching of UNC-6-responsive processes. We show that expression of unc-6DeltaC, which encodes UNC-6 without domain C, partially rescues circumferential migration defects in unc-6 null animals. This activity depends on the netrin receptors UNC-5 and UNC-40. These results indicate that UNC-6DeltaC can provide the circumferential guidance functions of UNC-6. Furthermore, we show that expression of unc-6DeltaC causes motoneuron branching and the extension of processes from abnormal positions along the ventral nerve cord. This activity is also UNC-5- and UNC-40-dependent. We propose that local interactions mediated by domain C regulate motoneuron branching and responsiveness to the UNC-6 cue.
Purification and physicochemical properties of limited proteolysis products of T4 helix destabilizing protein (gene 32 protein). (1978)

Limited proteolysis of T4 helix destabilizing protein (gene 32 protein = gp32) produced three stable products, gp32*I, gp32*II, and gp32*III. Gp32*I and gp32*II produced by chymotrypsin digestion were purified by duplex DNA-cellulose column chromatography and their amino acid compositions, NH/sub 2/-terminal sequences, and isoelectric points were compared with those of the undigested gp32. Results indicated that removal of an acidic region (A) from the COOH-terminal of gp32 produced gp32*I. Removal of a basic region (B) from the NH-terminal of gp32*I produced gp32*III. In previous experiments with poly(d(A-T)) we have shown that gp32*I was a stronger helix destabilizer than gp32. With the removal of A-region, the kinetic block in melting of naturally occurring double-stranded DNA observed with gp32 seems to be eliminated. In the presence of gp32*I the temperature at the midpoint of the helix-coil transition of T4 DNA was lowered over 70/sup 0/C at 12 mM (Na/sup +/ + K/sup +/) and 56/sup 0/C at 102 mM (Na/sup +/ + K/sup +/). No extensive melting of T4 DNA was observed in the presence of gp32 before thermal denaturation of the protein occurred. With 10 mM Mg/sup 2 +/ ion the helix-coil transition of T4 DNA in the presence of gp32*Imore » was reversible. Proteolytic digestion of mMg32 bound to single-stranded DNA indicated that the NH/sub 2/-terminal is inside of the complex because it is protected from proteolytic enzymes while the COOH-terminal is outside because it is as or more vulnerable to proteases than when in unbound gp32.« less
Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34+ hematopoietic progenitor cells (2000)

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that can be used for vaccination purposes, to induce a specific T-cell response in vivo against melanoma-associated antigens. We have shown that the sequential use of early-acting hematopoietic growth factors, stem cell factor, IL-3 and IL-6, followed by differentiation with IL-4 and granulocyte-macrophage colony-stimulating factor allows the in vitro generation of large numbers of immature DCs from CD34+ peripheral blood progenitor cells. Maturation to interdigitating DCs could specifically be induced within 24 hr by addition of TNF-α. Here, we report on a phase I clinical vaccination trial in melanoma patients using peptide-pulsed DCs. Fourteen HLA-A1+ or HLA-A2+ patients received at least 4 i.v. infusions of 5 × 106 to 5 × 107 DCs pulsed with a pool of peptides including either MAGE-1, MAGE-3 (HLA-A1) or Melan-A, gp100, tyrosinase (HLA-A2), depending on the HLA haplotype. A total of 83 vaccinations were performed. Clinical side effects were mild and consisted of low-grade fever (WHO grade I–II). Clinical and immunological responses consisted of anti-tumor responses in 2 patients, increased melanoma peptide-specific delayed-type hypersensitivity reactions in 4 patients, significant expansion of Melan-A- and gp100-specific cytotoxic T lymphocytes in the peripheral blood lymphocytes of 1 patient after vaccination and development of vitiligo in another HLA-A2+ patient. Our data indicate that the vaccination of peptide-pulsed DCs is capable of inducing clinical and systemic tumor-specific immune responses without provoking major side effects. Int. J. Cancer 86:385–392, 2000. © 2000 Wiley-Liss, Inc.
Surgery of the ear and temporal bone (2005)

I EXAMINATION OF THE EAR * Office Examination of the Ear Joseph B. Nadol, Jr. and Harold F. Schuknecht * Photography and Documentation of Pathological Findings Steven D. Rauch and Jeffrey Spiegel * Audiologic Tests for Otologic Surgery Dianne H. Meyer and Edward L. Applebaum * Imaging of the Temporal Bone Hugh D. Curtin and Osamu Sakai * Evaluation of the Vestibular System Conrad Wall, III, Richard F. Lewis, and Steven D. Rauch * Evaluation of Facial Paralysis Arvind Kumar, Arlene Barr and Aftab Patni * Intraoperative Monitoring of the Facial Nerve and Hearing Robert A. Levine, Steven F. Ronner and Aaron R. Thornton * Outcome Measurements for Ear Surgery Pa-Chun Wang, Richard E. Gliklich and Joseph B. Nadol, Jr. II SOFT TISSUE APPROACHES AND MANAGEMENT * Incisions and Approaches Joseph B. Nadol, Jr * Skin Grafting in Otologic Surgery Joseph B. Nadol, Jr. and Harold F. Schuknecht III OSSEOUS APPROACHES TO THE TEMPORAL BONE * Osseous Approaches to the Temporal Bone Joseph B. Nadol, Jr. * Transtemporal and Transpetrous Approaches to the Cranial Base Michael J. McKenna * Management of Soft Tissue and Osseous Stenosis of the Ear Canal and Canalplasty Steven D. Rauch * Perforations of the Tympanic Membrane Dennis S. Poe * Granular Myringitis Richard M. Levinson IV SURGERY FOR DISORDERS OF THE EAR CANAL AND TYMPANIC MEMBRANE * Acute Mastoiditis Michael J. McKenna and Roland D. Eavey * Chronic Otitis Media Joseph B. Nadol, Jr. * Complications of Chronic Otitis Media Jeffrey P. Harris, David W. Kim and David H. Darrow * Osteoradionecrosis of the Temporal Bone Joseph B. Nadol, Jr. * Malignant External Otitis Marlene L. Durand V SURGERY FOR CONDUCTIVE HEARING LOSS * Otitis Media with Effusion Michael J. Cunningham and Roland D. Eavey * Surgery for Otosclerosis Joseph B. Nadol, Jr. and Harold F. Schuknecht (deceased) * Ossiculoplasty and Tympanoplasty in Chronic Otitis Media Saumil N. Merchant * Congenital Aural Atresia Antonio De la Cruz and Jose N. Fayad * Congenital Cholesteatoma Trevor J. McGill and Reza Rahbar VI SURGERY FOR SENSORINEURAL HEARING LOSS * Surgery for Sensorineural Hearing Loss: Perilymph Fistula Steven D. Rauch * Cochlear Implantation and Implantable Hearing Aids Joseph B. Nadol, Jr. VII SURGERY FOR VERTIGO * Labyrinthectomy Joseph B. Nadol, Jr. and Michael J. McKenna * Shunt Procedures Harold F. Schuknecht (posthumous) and Michael J. McKenna
A Drosophila Model of Multiple Endocrine Neoplasia Type 2 (2005)

Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that RetMEN2 mutations significantly alter Ret-signaling properties, but the precise mechanisms by which RetMEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for RetMEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRetMEN2 isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRetMEN2 acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRetMEN2 phenotypes identified new genes that are required for the phenotypic outcomes of dRetMEN2 activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis.
Overexpression of fibroblast growth factor receptor 3 in a human thyroid carcinoma cell line results in overgrowth of the confluent cultures (1999)

Recent reports indicate that a gain-of-function mutation in fibroblast growth factor receptor 3 (FGFR-3) inhibits cell growth in the cartilaginous growth plates. These results suggest that FGFR-3 may be the receptor transducing growth inhibitory signals. Using reverse transcription-PCR we examined seven papillary thyroid carcinomas to determine FGFR-3 expression. Six out of the seven papillary carcinomas expressed FGFR-3. To clarify the role of FGFR-3 in thyroid carcinoma, FGFR-3 was overexpressed in an established human papillary thyroid carcinoma cell line. High levels of FGFR-3 protein were identified in cells stably transfected with the vector containing FGFR-3 cDNA. The specific binding of 125I-FGF-2 of these cells was threefold higher than that of control cells. Growth rates of cells overexpressing FGFR-3 were similar to those of control cells. However, cells overexpressing FGFR-3 continued to grow beyond the density at which control cells stopped proliferating. These results suggest that FGFR-3 in thyroid carcinoma is not involved strongly in the cell proliferation mechanism but may contribute to the malignant extension of some of the carcinomas by modifying cell contact signaling.
Optimal routing control: repeated game approach (2002)

Communication networks shared by selfish users are considered and modeled as noncooperative repeated games. Each user is interested only in optimizing its own performance by controlling the routing of its load. We investigate the existence of a Nash equilibrium point (NEP) that achieves the system-wide optimum cost. The existence of a subgame-perfect NEP that not only achieves the system-wide optimum cost but also yields a cost for each user no greater than its stage game NEP cost is shown for two-node multiple link networks. It is shown that more general networks where all users have the same source-destination pair have a subgame-perfect NEP that achieves the minimum total system cost, under a mild technical condition. It is shown that general networks with users having multiple source-destination pairs do not necessarily have such an NEP.
Trocar-less Instrumentation for Laparoscopy (2007)

Trocar-less laparoscopy using magnetically anchored instruments is feasible and may expand intracorporeal instrument manipulation substantially beyond current-day capability. The ability to reduce the number of trocars necessary for laparoscopic surgery has the potential to revolutionize surgical practice.
Combination therapies in the context of anti-CD3 antibodies for the treatment of autoimmune diseases (2012)

Non-Fc receptor binding anti-CD3 antibodies are in clinical development for the treatment of autoimmune diseases. Results from phase 1/2 clinical trials suggest that teplizumab and otelixizumab preserve residual beta-cell function in patients with recent onset type 1 diabetes. Similarly, encouraging results from phase 1/2 clinical trials have been reported for visilizumab and foralumab in patients with inflammatory bowel disease. However, these CD3-directed therapies have recently suffered setbacks due to the reported inefficacy results observed during phase 2/3 clinical trials due to low dosages or inappropriate clinical endpoints. Due to adverse events observed in the phase 1/2 pilot trials, the dose of anti-CD3 antibodies was reduced in the phase 2/3 confirmatory trials. Thus, these studies reveal a narrow therapeutic window of anti-CD3-based therapies in which low doses are ineffective and higher pharmacologically active doses cause intolerable levels of adverse effects. Combining anti-CD3 antibodies with other drugs may be the most effective way to reduce toxicity while allowing significant therapeutic benefit. Indeed, monotherapy also has its limits from the perspective of targeting only a single arm of the immune process. Notably, several recent experimental studies show potent synergy between anti-CD3 antibodies and various therapeutic modalities for the treatment of autoimmune diseases. In this review we present a review of preclinical studies evaluating combination therapies using anti-CD3 antibodies for the treatment of autoimmune diseases.
The β 2 -adrenergic receptor/βarrestin complex recruits the clathrin adaptor AP-2 during endocytosis (1999)

betaarrestins mediate the desensitization of the beta2-adrenergic receptor (beta2AR) and many other G protein-coupled receptors (GPCRs). Additionally, betaarrestins initiate the endocytosis of these receptors via clathrin coated-pits and interact directly with clathrin. Consequently, it has been proposed that betaarrestins serve as clathrin adaptors for the GPCR family by linking these receptors to clathrin lattices. AP-2, the heterotetrameric clathrin adaptor protein, has been demonstrated to mediate the internalization of many types of plasma membrane proteins other than GPCRs. AP-2 interacts with the clathrin heavy chain and cytoplasmic domains of receptors such as those for epidermal growth factor and transferrin. In the present study we demonstrate the formation of an agonist-induced multimeric complex containing a GPCR, betaarrestin 2, and the beta2-adaptin subunit of AP-2. beta2-Adaptin binds betaarrestin 2 in a yeast two-hybrid assay and coimmunoprecipitates with betaarrestins and beta2AR in an agonist-dependent manner in HEK-293 cells. Moreover, beta2-adaptin translocates from the cytosol to the plasma membrane in response to the beta2AR agonist isoproterenol and colocalizes with beta2AR in clathrin-coated pits. Finally, expression of betaarrestin 2 minigene constructs containing the beta2-adaptin interacting region inhibits beta2AR endocytosis. These findings point to a role for AP-2 in GPCR endocytosis, and they suggest that AP-2 functions as a clathrin adaptor for the endocytosis of diverse classes of membrane receptors.