tbuckley/cabot-search huggingface dataset:
Plk1 Inhibition Enhances the Efficacy of Androgen Signaling Blockade in Castration-Resistant Prostate Cancer
Authors: Zhe Zhang, Xianzeng Hou, Chen Shao, Junjie Li, Ji-Xin Cheng, Shihuan Kuang, Nihal Ahmad, Timothy Ratliff, Xiaoqi Liu
Journal: Cancer Research (2014)

Prostate cancer is thought to be driven by oxidative stress, lipid metabolism, androgen receptor (AR) signaling, and activation of the PI3K-AKT-mTOR pathway, but it is uncertain how they may become coordinated during progression to castration-resistant disease that remains incurable. The mitotic kinase polo-like kinase 1 (Plk1) is elevated in prostate cancer, where its expression is linked to tumor grade. Notably, Plk1 signaling and lipid metabolism were identified recently as two of the top five most upregulated pathways in a mouse xenograft model of human prostate cancer. Herein, we show that oxidative stress activates both the PI3K-AKT-mTOR pathway and AR signaling in a Plk1-dependent manner in prostate cells. Inhibition of the PI3K-AKT-mTOR pathway prevented oxidative stress-induced activation of AR signaling. Plk1 modulation also affected cholesteryl ester accumulation in prostate cancer via the SREBP pathway. Finally, Plk1 inhibition enhanced cellular responses to androgen signaling inhibitors (ASI) and overcame ASI resistance in both cultured prostate cancer cells and patient-derived tumor xenografts. Given that activation of AR signaling and the PI3K-AKT-mTOR pathway is sufficient to elevate SREBP-dependent expression of key lipid biosynthesis enzymes in castration-resistant prostate cancer (CRPC), our findings argued that Plk1 activation was responsible for coordinating and driving these processes to promote and sustain the development of this advanced stage of disease. Overall, our results offer a strong mechanistic rationale to evaluate Plk1 inhibitors in combination drug trials to enhance the efficacy of ASIs in CRPC.
Lymphoma with multi gene rearrangement on the level of immunoglobulin heavy chain, light chains, and T-cell receptor β chain
Authors: Ami Klein, Ruth Zemer, Yosef Manor, Hava Shapiro, Mario Cordoba, Isabella Spivak, Judith Radnay
Journal: American Journal of Hematology (1997)

A unique case with diffuse mixed malignant lymphoma was investigated for gene rearrangement on the level of T-cell receptor (TCR), heavy chain immunoglobulin (Ig), and both light chains. Cell phenotype was examined with immunofluorescence techniques using antibodies against surface immunoglobulins (SIg) and the kappa and lambda light chains. Monoclonal antibodies were used against CD3, CD4, CD5, CD8, CD10, CD19, CD22, HLA-DR, and TdT. Gene rearrangement analysis for monoclonality determination was carried out with restricted DNA (EcoR I and Hind III) hybridized with one of the following 32P-labelled probes: T-cell receptor (TCR beta), immunoglobulin heavy chain (JH), k light chain, and lambda light chain. Phenotyping of the cell population from the excised lymph node (LN) revealed the presence of 66% B-cells and 35% T-cells. Most of the B cells (94%) expressed mu heavy chain only. Expression of both light chains was negligible (k = 7% and lambda = 2%). Gene rearrangement, which indicates monoclonality, was positive on the level of TCR, Ig heavy chain, and both light chains. The data obtained suggests a neoplastic transforming event in lymphoid stem cells, which preceded the subsequent differentiation process into either B or T lymphoma.
Efficacy and safety of nurse-administered propofol sedation during emergency upper endoscopy for gastrointestinal bleeding: a prospective study
Authors: G. Tohda, S. Higashi, H. Sakumoto, K. Sumiyoshi, T. Kane
Journal: Endoscopy (2006)

Recent studies have documented the safety of propofol sedation for endoscopic procedures, but many endoscopists are reluctant to use propofol for high-risk patients because of adverse effects. The aim of this study was to demonstrate the safety and efficacy of nurse-administered propofol sedation during emergency upper endoscopy for patients with gastrointestinal bleeding.Over a period of 18 months, 120 patients suffering from acute upper gastrointestinal bleeding received propofol sedation administered by a registered nurse. Among these, 15 patients were classified into American Society of Anesthesiologists (ASA) class IV, 84 were ASA class III, and 21 were ASA class II. Patients without gastrointestinal bleeding, who also received propofol during the same period and were matched for age, gender, and ASA class, served as controls.Endoscopic hemostasis was achieved in 98.3 % of patients, and 97.5 % were satisfied with the procedure. In patients with gastrointestinal bleeding, the rates of hypotension (systolic blood pressure < 90 mmHg) and hypoxemia (peripheral oxygen saturation < 90 %) were 8.3 % and 6.7 % respectively, values higher than those in the control group. However, neither mask ventilation nor endotracheal intubation was necessary. Although two patients with gastrointestinal bleeding developed pneumonia, most likely due to aspiration during the procedure, they recovered within 5 days of treatment. There were no sedation-associated severe complications or mortalities.Using a strict protocol designed to protect the patient's airway and cardiovascular function, nurse-administered propofol sedation during emergency upper gastrointestinal endoscopy is safe and appropriate in cases of acute gastrointestinal bleeding.
The TL region gene 37 encodes a Qa-1 antigen.
Authors: P R Wolf, R G Cook
Journal: The Journal of Experimental Medicine (1990)

Of all the biochemically defined mouse MHC class I molecules, the Qa-1 antigens are the only ones for which a gene has not been identified. Recent evidence has suggested that Qa-1 antigens are functional class I molecules and can function as restriction elements for gamma/delta T cells. We have examined the relationship between Qa-1 and the product of gene 37, a presumed novel class I antigen encoded within the TL region. Immunoprecipitation and polyacrylamide gel electrophoresis analysis of the molecules reactive with anti-Qa-1 and anti-37 sera show that the Qa-1 molecule of Qa-1b (Qa-1.2) mouse strains is identical to the product of gene 37 on the basis of molecular weight, pI, and strain distribution. Immunodepletion, biosynthetic labeling, and tunicamycin treatment confirm that the protein encoded by gene 37 in Qa-1b mice is Qa-1.2. In contrast, the anti-37 serum was unable to recognize the Qa-1 molecule in Qa-1a strains. Given the fact that the only allele to gene 37 thus far identified in a Qa-1a strain (A/J) has a termination codon in the alpha 3 domain, our data lead us to conclude that the Qa-1 molecule expressed in Qa-1a mice is not a true allelic product of the gene 37 encoded antigen of Qa-1b mouse strains.
Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling
Authors: Christof Bernemann, Carolin Hülsewig, Christian Ruckert, Sarah Schäfer, Lena Blümel, Georg Hempel, Martin Götte, Burkhard Greve, Peter J Barth, Ludwig Kiesel, Cornelia Liedtke
Journal: Molecular Cancer (2014)

Triple negative breast cancer (TNBC) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of overexpression or amplification of HER2. Despite an increased probability of response to chemotherapy, many patients resistant to current chemotherapy regimens suffer from a worse prognosis compared to other breast cancer subtypes. However, molecular determinants of response to chemotherapy specific to TNBC remain largely unknown. Thus, there is a high demand for biomarkers potentially stratifying triple negative breast cancer patients for neoadjuvant chemotherapies or alternative therapies. In order to identify genes correlating with both the triple negative breast cancer subtype as well as response to neoadjuvant chemotherapy we employed publicly available gene expression profiles of patients, which had received neoadjuvant chemotherapy. Analysis of tissue microarrays as well as breast cancer cell lines revealed correlation to the triple negative breast cancer subtype. Subsequently, effects of siRNA-mediated knockdown on response to standard chemotherapeutic agents as well as radiation therapy were analyzed. Additionally, we evaluated the molecular mechanisms by which SFRP1 alters the carcinogenic properties of breast cancer cells. SFRP1 was identified as being significantly overexpressed in TNBC compared to other breast cancer subtypes. Additionally, SFRP1 expression is significantly correlated with an increased probability of positive response to neoadjuvant chemotherapy. Knockdown of SFRP1 in triple negative breast cancer cells renders the cells more resistant to standard chemotherapy. Moreover, tumorigenic properties of the cells are modified by knockdown, as shown by both migration or invasion capacity as well reduced apoptotic events. Surprisingly, we found that these effects do not rely on Wnt signaling. Furthermore, we show that pro-apoptotic as well as migratory pathways are differentially regulated after SFRP1 knockdown. We could firstly show that SFRP1 strongly correlates with the triple negative breast cancer subtype and secondly, that SFRP1 might be used as a marker stratifying patients to positively respond to neoadjuvant chemotherapy. The mechanisms by which tumor suppressor SFRP1 influences carcinogenic properties of cancer cells do not rely on Wnt signaling, thereby demonstrating the complexity of tumor associated signaling pathways.
THE TREATMENT OF TORTICOLLIS
Authors: B. W. Howell
Journal: BMJ (1929)

Avertin is provided in a concentrated solution with amylene, hydrate-1 gram i'n 1 c.cm.The dose works out at betweeni 6 an-d 8 graims.The appropriate amount of thie solution is measured out anid enoughl distilled water to makze a 21 or 3 per ceiit..solutioni is lheated to 380 C. The avertin iS thenadded and(I the inixturc is shaken till a clear solutioni results.The Imiost impoiotaht points are that the tempFerature must niever exceed 40°C.and that the final soluitioll mlust be free from hydrobromic acid and tlierefore free from dibromacetaldehyde; 5 c.cm. of the dilute solutioni are taken anid a drop of 1 ill 1,000 Congo -redl solutioii -is added.Tlhe colour -slliuld remain brioght orange red.The blue reaction of free acid is sometimes -delayed and it is cssenitial to make the test-immediately before adminiistration.The solution beinig nlow r-eady anid satisfactory, it is injected into the rectu-m fairly slowly thi;ough a catheter and funnel.The cathe-ter muist be P"assed -well into the rectumli proper.The paitient is best arranged lyinig on the left side with a pillow uinder the pelvis.The 250 or 350 c.cm. of solution are easily retaiined if the injection takes three or four minutes.Attempts have been made to giv-e fractioial doses, ruiiiiing in iioie solutioni if the anaesthesia produced-by the originial d(ose was inadequate.It has been showll that tlie av-ertini in solution is more readily absorbed tha'n the water.This makes all calcula- tions with regar-d to strenigth of solution useless, and it is impossible to gauge rate of absorptioni or to prophesy the depth of anaesthesia whliich wnill be obtained.If undue dlep)th should be observed at ani early stage, wvashinii out the rectuml for the purpose of reinovinig aniy of the avertiin that may remain there is a souniid proceedinig.In practice, it seems best to give thel rectal inijection tlhirty niinutes before the advertised time of the operationi.This means that the paticnt nieed not be disturbed for tweenty minutes, and then may be takeni straight to the theatte.During the 'inductioni period we have endeav- ouired to keep the patient quiet, to keep the room dark, and to keep out all sources of irritation.Flessa, lhowever says that somiie patients resent strongly the sel)llchlral atmosphere, anid that light and iioise lhav-e iio effect uponi the inductioii, so that it is better to allow the ordiniary
COX-2 chronology
Authors: C J Hawkey
Journal: Gut (2005)

The role of selective cyclooxygenase (COX)-2 inhibitors in medical practice has become controversial since evidence emerged that their use is associated with an increased risk of myocardial infarction. Selective COX-2 inhibitors were seen as successor to non-selective non-steroidal anti-inflammatory drugs, in turn successors to aspirin. The importance of pain relief means that such drugs have always attracted attention. The fact that they work through inhibition of cyclooxygenase, are widespread, and have multiple effects also means that adverse effects that were unanticipated (even though predictable) have always emerged. In this paper I therefore present an historical perspective so that the lessons of the past may be applied to the present.
Antihelminth Compound Niclosamide Downregulates Wnt Signaling and Elicits Antitumor Responses in Tumors with Activating APC Mutations
Authors: Takuya Osada, Minyong Chen, Xiao Yi Yang, Ivan Spasojevic, Jeffrey B. Vandeusen, David Hsu, Bryan M. Clary, Timothy M. Clay, Wei Chen, Michael A. Morse, H. Kim Lyerly
Journal: Cancer Research (2011)

Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.
Tetrahydrobiopterin and endothelial nitric oxide synthase activity
Authors: F Cosentino
Journal: Cardiovascular Research (1999)

Time for primary review 23 days. 

Nitric oxide (NO) plays a crucial role in the regulation of vascular tone and maintenance of vascular integrity [1–3]. Indeed, nitric oxide reduces vascular tone, inhibits leucocytes adhesion to the endothelium, platelet-vessel wall interaction, as well as vascular smooth muscle cell proliferation and migration. Accordingly, major risk factors for atherosclerotic vascular disease such as hypercholesterolemia, diabetes, hypertension and smoking, have been associated with impaired nitric oxide activity [4–11].

In vivo the activity of the l-arginine-NO pathway is a balance between the synthesis and breakdown of NO. Although, there are several reasons to believe that NO synthesis could be impaired [12–14], reduced NO activity could be caused by enhanced catabolism. Indeed, the in vivo half-life of NO is determined mainly by its reaction with oxyhemoglobin and superoxide anion [15]. Superoxide (O2−) may rapidly react with NO to produce peroxynitrite (OONO−; [16]). This reaction is even faster than the one of O2− with superoxide dismutase to form hydrogen peroxide (H2O2) and molecular oxygen. High concentrations of ONOO− are very toxic, ONNO− can form peroxynitrous acid whose cleavage products are among the most reactive and damaging species in biological systems [17]. Taken together, these data indicate that catabolism of NO by its reaction with superoxide could be an important mechanism underlying endothelial dysfunction and oxidative vascular injury described in a number of vascular diseases [18,19]. It can be postulated that harmful concentrations of ONOO− can be achieved in a dysfunctional endothelium in which O2− generation is increased by cyclooxygenase, xanthine oxidase, and NADH oxidoreductase [20–22]. However, recent evidence indicates that decreased availability of tetrahydrobiopterin may be responsible for a dysfunction of nitric oxide synthase leading … 

* Corresponding author. Tel.: +41-1-255-2121; fax: +41-1-255-4251 100771.1237{at}compuserve.com
Soft Robotic Concepts in Catheter Design: an On‐Demand Fouling‐Release Urinary Catheter
Authors: Vrad Levering, Qiming Wang, Phanindhar Shivapooja, Xuanhe Zhao, Gabriel P. López
Journal: Advanced Healthcare Materials (2014)

Infectious biofilms are problematic in many healthcare-related devices and are especially challenging and ubiquitous in urinary catheters. This report presents an on-demand fouling-release methodology to mechanically disrupt and remove biofilms, and proposes this method for the active removal of infectious biofilms from the previously inaccessible main drainage lumen of urinary catheters. Mature Proteus mirabilis crystalline biofilms detach from silicone elastomer substrates upon application of strain to the substrate, and increasing the strain rate increases biofilm detachment. The study presents a quantitative relationship between applied strain rate and biofilm debonding through an analysis of biofilm segment length and the driving force for debonding. Based on this mechanism, hydraulic and pneumatic elastomer actuation is used to achieve surface strain selectively within the lumen of prototypes of sections of a fouling-release urinary catheter. Proof-of-concept prototypes of sections of active, fouling-release catheters are constructed using techniques typical to soft robotics including 3D printing and replica molding, and those prototypes demonstrate release of mature P. mirabilis crystalline biofilms (e.g., ≈90%) from strained surfaces. These results provide a basis for the development of a new urinary catheter technology in which infectious biofilms are effectively managed through new methods that are entirely complementary to existing approaches.
p-ANCAs in autoimmune liver disorders recognise human -tubulin isotype 5 and cross-react with microbial protein FtsZ
Authors: B. Terjung, J. Sohne, B. Lechtenberg, J. Gottwein, M. Muennich, V. Herzog, M. Mahler, T. Sauerbruch, U. Spengler
Journal: Gut (2009)

<h3>Objective</h3> Autoimmune hepatitis and primary sclerosing cholangitis are chronic inflammatory disorders of unknown aetiology, frequently associated with the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) directed against an unknown antigen of myeloid cells. <h3>Methods and Results</h3> Here, it is reported that p-ANCAs in autoimmune liver disorders react with β-tubulin isotype 5 (TBB-5) as autoantigen as well as with its evolutionary bacterial precursor protein FtsZ. Both proteins were confirmed as antigens of p-ANCAs in autoimmune liver disorders by demonstrating reactivity of ANCA-positive sera with recombinant TBB-5 (72–88%) and FtsZ (64–82%) on immunoblots and antigen-specific abrogation of ANCA immunofluorescence when sera had been preabsorbed with tubulin and FtsZ. Using sera from interleukin 10-deficient mice (<i>Il10<sup>–</sup>/<sup>–</sup></i>), an animal model of inflammatory bowel disease, it was also demonstrated that antibodies against TBB-5 are generated in response to intestinal microorganisms. However, unlike autoimmune liver disorders, human antibodies to FtsZ in the absence of TBB-5 antibodies were also a frequent finding in non-autoimmune liver diseases (up to 95%). Reactivity to TBB-5 without the presence of FtsZ antibodies was found in very few cases (&lt;1%) in autoimmune liver disorders. <h3>Conclusions</h3> Thus, p-ANCAs in autoimmune liver diseases are directed against human TBB-5 cross-reacting with the bacterial protein FtsZ, probably reflecting an abnormal immune response to intestinal microorganisms in susceptible, possibly genetically predisposed individuals.
Gene Therapy for Cancer: What Have We Done and Where Are We Going?
Authors: J. A. Roth, R. J. Cristiano
Journal: JNCI Journal of the National Cancer Institute (1997)

Gene-based therapies for cancer in clinical trials include strategies that involve augmentation of immunotherapeutic and chemotherapeutic approaches. These strategies include ex vivo and in vivo cytokine gene transfer, drug sensitization with genes for prodrug delivery, and the use of drug-resistance genes for bone marrow protection from high-dose chemotherapy. Inactivation of oncogene expression and gene replacement for tumor suppressor genes are among the strategies for targeting the underlying genetic lesions in the cancer cell. A review of clinical trial results to date, primarily in patients with very advanced cancers refractory to conventional treatments, indicates that these treatments can mediate tumor regression with acceptably low toxicity. Vector development remains a critical area for future research. Important areas for future research include modifying viral vectors to reduce toxicity and immunogenicity, increasing the transduction efficiency of nonviral vectors, enhancing vector targeting and specificity, regulating gene expression, and identifying synergies between gene-based agents and other cancer therapeutics.
The A Wave of the Apexcardiogram and Left Ventricular Diastolic Stiffness
Authors: THOMAS C. GIBSON, ROBERT MADRY, WILLIAM GROSSMAN, LAMBERT P. MCLAURIN, ERNEST CRAIGE
Journal: Circulation (1974)

This study was made to determine whether the A wave of the apexcardiogram (ACG), a reflection of the late diastolic response of the left ventricle to atrial systole, corresponded in a quantifiable way to left ventricular late diastolic stiffness (LVDS). Using a combined ultrasonic and hemodynamic technique, the slope of the late diastolic left ventricular pressure/diameter relationship (ΔP/ΔD) was calculated in 25 patients and used as a measure of effective LVDS. Most patients had valvular heart disease, all were in sinus rhythm and none had regional abnormalities of contraction. An ACG was recorded in all and the ratio of the size of the A wave to the total amplitude of the ACG wave (A/H) was calculated. When A/H was more than 11%, left ventricular hypertrophy (LVH) and the presence of a fourth heart sound were the rule in the group of patients studied. Using A/H as an independent variable, correlation coefficients were obtained for ΔP, ΔD, ΔP/ΔD, left ventricular end diastolic pressure (LVEDP), and left ventricular end diastolic volume (LVEDV). Correlation coefficients ( r ) were: ΔP = 0.68; ΔD = –0.05; ΔP/ΔD = 0.87; LVEDP = 0.73; LVEDV = 0.21. It is concluded that A/H corresponds best to LVDS and is a useful noninvasive measurement of this property of the left ventricle.
Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens
Authors: Quincey LaPlant, Vincent Vialou, Herbert E Covington, Dani Dumitriu, Jian Feng, Brandon L Warren, Ian Maze, David M Dietz, Emily L Watts, Sergio D Iñiguez, Ja Wook Koo, Ezekiell Mouzon, William Renthal, Fiona Hollis, Hui Wang, Michele A Noonan, Yanhua Ren, Amelia J Eisch, Carlos A Bolaños, Mohamed Kabbaj, Guanghua Xiao, Rachael L Neve, Yasmin L Hurd, Ronald S Oosting, Gouping Fan, John H Morrison, Eric J Nestler
Journal: Nature Neuroscience (2010)