tbuckley/cabot-search huggingface dataset:
Docetaxel enhances S-phase cytotoxicity with dFdCyd resulting in synergy
Authors: Leo J. Ostruszka, Kirsten M. Leu, Laurence H. Baker, Donna S. Shewach
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2965 

The combination of dFdCyd (gemcitabine, 2’,2’-difluoro-2’-deoxycytidine) and docetaxel has been found to be clinically effective in varying types of cancer. Recently, startling clinical results (37-53% response rates) have been observed in several reported series of sarcoma patients in which dFdCyd preceded docetaxel during treatment. The reason for this apparent synergy is unclear since dFdCyd and docetaxel have differing mechanisms of cytotoxicity. dFdCyd requires phosphorylation for activity: the diphosphate derivative inhibits de novo deoxynucleotide production leading to inhibition of DNA synthesis, while the triphosphate can be incorporated into DNA leading to cell death. Docetaxel stabilizes microtubules preventing depolymerization, resulting in mitotic arrest or aberrant mitosis. Recent evidence suggested that docetaxel may also have a secondary mechanism of cytotoxicity that targets S-phase, but little is known about it. Previously, we determined that the sequence of drug addition is important in vitro with the sequence dFdCyd followed by docetaxel producing the greatest synergy in A549 non-small cell lung cancer, MCF-7 breast cancer, and SAOS-2 sarcoma cells. For example, the 24 hr IC50 of dFdCyd in A549 cells was decreased 2-fold (16 nM to 7.4 nM) with the subsequent addition of docetaxel (0.5 nM, <IC5). These studies focused on the effect of docetaxel on the metabolism of dFdCyd and cell cycle progression under conditions which produced synergistic cytotoxicity in A549 cells. The addition of docetaxel (0.5 nM) after treatment with dFdCyd (20 nM, IC50) did not alter the accumulation of dFdCTP, nor did it increase its incorporation into DNA. Additionally, these conditions did not appear to alter cell cycle progression as measured by dual parameter flow cytometry (PI/BrdU). However, the addition of 2 nM docetaxel (IC75) to cells previously treated with dFdCyd (5-10 nM, <IC50) did result in a 3.1-fold increase in the amount of sub-G1 cells and a 2.3-fold increase in the number of SNI (an indicator for S-phase specific cell death) cells after 24 hr. In order to elucidate whether docetaxel was interacting with the effects of dFdCyd on deoxynucleotide pools or DNA synthesis, docetaxel was combined with either hydroxyurea or aphidicolin. Hydroxyurea followed by docetaxel did not produce synergy, only additivity. However, aphidicolin followed by docetaxel did produce synergy, indicating a possible interaction with DNA polymerases. Upon subsequent cell cycle analysis, it was observed that the addition of docetaxel to cells previously treated with aphidicolin increased both the amount of sub-G1 and SNI cells after 24 hr. This indicated that docetaxel was able to directly affect S-phase cells. Taken together, these studies suggest that docetaxel synergistically enhances the cytotoxicity of dFdCyd through S-phase specific interactions.
Abstract 2833: Mutation analysis of cancer drivers and DNA repair genes in chemosensitive versus resistant ovarian cancers
Authors: Einar Birkeland, Rakel Blaalid, Merete Bjørnslett, Anne Dørum, Per Eystein Lønning, Stian Knappskog
Journal: Cancer Research (2014)

Abstract Background: The mechanisms underlying resistance to chemotherapy in ovarian cancer are incompletely understood. Identifying genetic alterations associated with treatment response is decisive in the determination of which patients may benefit from adjuvant chemotherapy. Methods: Biopsies were collected from twenty patients diagnosed with ovarian cancer who were subjected to post-operative taxane- and platinum-containing chemotherapy. Patients were selected for genetic analyses based on response to chemotherapy, determined as time to relapse (10 sensitive and 10 resistant patients). A panel of 620 genes, including known cancer driver genes, as well as genes involved in DNA repair were analysed by massively parallel sequencing. Alignment and mutation calling was performed using MiSeq Reporter, with further manual filtering of variants to exclude common SNPs. Validation of low quality mutation calls was done by Sanger sequencing. Results: A median of 6 genes (range: 3 - 45) per patient was found to harbour non-synonymous mutations. Among previously identified driver genes in ovarian cancer, we found mutations in TP53, BRCA1, CDK12, NF1 and CSMD3. These mutations were more common among patients with more advanced disease and higher grade. For example, TP53 mutations were found in 10 out of 12 patients with high grade, stage 3c or 4 disease, and in 2 out of 5 with lower stage and/or grade. One patient was found to have a tumor potentially of a hyper-mutator phenotype with 49 mutations in 45 genes identified within our gene panel. With respect to treatment efficacy, 73 and 40 genes were found to be mutated exclusively in patients with a good and poor response to treatment, respectively. Conclusion: We describe the profile of mutations in cancer driver genes and DNA repair genes among patients suffering from ovarian cancer according to treatment response. Citation Format: Einar Birkeland, Rakel Blaalid, Merete Bjørnslett, Anne Dørum, Per Eystein Lønning, Stian Knappskog. Mutation analysis of cancer drivers and DNA repair genes in chemosensitive versus resistant ovarian cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2833. doi:10.1158/1538-7445.AM2014-2833
The sensitivity of D-dimer testing versus multislice CT in the diagnosis of postpartum pulmonary embolism in symptomatic high risk women
Authors: Mohamed Badawy, Ibrahiem Hassnin, Ahmed Shahin, Khalid Karam
Journal: European Respiratory Journal (2011)

Background:  Early detection of postpartum pulmonary embolism is a corner stone in prevention of its associated maternal mortality   Patients and methods:  We applied d-dimer testing and Multislice CT scanning (MSCT) with contrast of the chest of patients diagnosed climnically in the first postcesarean week as suspicious of pulmonary embolism. MSCT imaging results were taken as standard.   Results:  Out of 2359 cases, 60 cases (2.54%) were considered clinically highly suggestive of pulmonary embolism. Clinical parameters highly suggestive of pulmonary embolism were dyspnea (85%), overweight (51%), tachypnoea (55%) and all cases showed high D- dimer test above 500 Although d-dimer showed 100% specificity, compared to multislice CT (MSCT) scanning, yet 93.3% (56/60) of the patients showing positive d-dimer testing were proved by MSCT to be free of PE. This translates into a 6.7% positive predictive value obtained by d-dimer. Number needed to screen (NNS), in sense of number of patients needed to diagnose cases of pulmonary embolism, among patients tested positive for D-dimer testing was 15 (60/4=15).   Conclusions:  Postpartum d-dimer testing in patients showing suspicious symptoms of pulmonary embolism is not suitable for exclusion test, yet a strong screening tool.
Avustralyalı adölesan ve erişkinlerin hafta sonu güneşten korunma ve güneş yanığı prevalansı ve belirleyicileri, 2 3-2 4 yazı
Authors: Suzanne Dobbinson, Melanie Wakefield, David Hill, Afaf Girgis, Joanne F. Aitken, Kerri Beckmann, Anthony I. Reeder, Natalie Herd, Andrew Fairthorne, Kelly-Ann Bowles
Journal: Journal of the American Academy of Dermatology (2009)
SOCS1 Attenuates the Ability of Dendritic Cells to Break Self-Tolerance and Induce Antitumor Immunity by Controlling Cytokine Production and Signaling
Authors: Kevin Evel-Kabler, Si-Yi Chen
Journal: Cancer Research (2006)

4880   Tumor vaccines represent a promising therapeutic approach to treat cancer, but thus far have achieved only limited success in the clinic. The major challenge is to find a means of overcoming inhibitory immune regulatory mechanisms and elicit effective T cell responses to antigens preferentially expressed by tumor cells. Dendritic cells (DCs) activate cytotoxic T-lymphocytes (CTLs) against target antigens by providing antigenic peptides in the context of MHC molecules, costimulation, and cytokines. Although the initiation of CTL responses has been well studied, little is known about how DCs regulate the magnitude and fate of CTL responses after their initial maturation and engagement with T cells. Here, we find that the stimulatory capacity of DCs and the magnitude of adaptive immunity are critically regulated by the suppressor of cytokine signaling (SOCS) 1 in DCs. Silencing SOCS1 in antigen-presenting DCs via small interfering (si)RNA technology drastically enhances DC sensitivity to stimulation and antigen-specific antitumor immunity. We further find that SOCS1-restricted cytokine signaling of mature DCs, not the peptide immunogenicity and costimulatory molecule level, plays a dominant role in controlling the magnitude and effectiveness of CTL responses. This study also indicates the necessity of silencing SOCS1 in DCs to break tolerance and induce effective CTL responses against naturally expressed self antigens. Our findings indicate that SOCS1 represents a novel inhibitory mechanism in DCs for qualitatively and quantitatively controlling the process of antigen presentation and the magnitude of adaptive immunity. This study has broad implications for understanding the regulation of antigen presentation, and for developing more effective tumor vaccines by silencing the critical brake in antigen presentation to break self-tolerance to natural, self-tumor associated antigens.
Sickle cell leg ulcers: a frequently disabling complication and a marker of severity
Authors: M. Halabi-Tawil, F. Lionnet, R. Girot, C. Bachmeyer, P.P. Lévy, S. Aractingi
Journal: British Journal of Dermatology (2007)

Leg ulcers are a poorly known and underestimated complication of sickle cell disease (SCD), but in our experience they often appear as a severely disabling condition, associated with the most severe forms of the disease.To assess the characteristics, complications, repercussion on quality of life and associations of SCD ulcers.Case series of 20 patients followed in a French referral centre for SCD and who had previous/present leg ulcers.Median ulcerated area was 12 cm2 and median time spent with ulcers was 29.5 months. Locoregional infections developed in 85%, ankle stiffness in 50% and mood disorders in 85%. Ninety per cent of patients needed analgesics, 20% being opioids. Median loss of time from work was 12.5 months. The Short Form 36 Health Survey showed physical and mental component summary scores of 41.5 and 40.7, respectively, indicating severe alteration close to that found in lung cancer or haemodialysis. Two categories of SCD leg ulcers were distinguished, defined by a 1-year duration cut off. The 'prolonged' ulcers had larger surfaces, tended to recur more frequently and led to more infection and depression. Several SCD complications were associated with leg ulcers, notably priapism, pulmonary hypertension, stroke and acute chest syndrome.Leg ulcers are a major complication of SCD, given their severe consequences and frequent association with other specific organ damage, and they constitute in their 'prolonged' form a severely disabling condition that remains an important therapeutic challenge.
Clinic-based testing for rectal and pharyngeal Neisseria gonorrhoeae and Chlamydia trachomatis infections by community-based organizations - five cities, United States, 2007.
Authors: J. D. Klausner, K. T. Bernstein, M. Pandori, C. Hall, S. Gibson, T. Ryan, R. Bolan, S. Tilekar, H. Khanlou, P. Kerndt, S. Guerry, C. Wigen, E. Rudy, G. Mayer, B. Gratzer, F. Swanson, M. Golden, C. Kent, K. A. Katz
Journal: MMWR Morbidity and Mortality Weekly Report (2009)
Abstract 15876: The Safety of Transesophageal Echocardiography in Patients With Gastroesophageal Varices
Authors: Ziad Alnabki, Wasiq F Rawasia, Gerald Dryden, Ali Usmani, Marcus F Stoddard
Journal: Circulation (2014)

Introduction: The presence of gastroesophageal varices (GEV) is considered a relative contraindication to performing Trans esophageal echocardiography (TEE) however; the safety of TEE in patients with GEV is unknown. Hypothesis: Bleeding complications related to TEE in patients with GEV are dependent on the severity of the GEV. Methods: 55 patients (G1) with GEV undergoing clinically indicated TEE were studied. Each patient was matched by age and gender to a control subject (C). GEV were graded using esophagogastroduodenoscopy (EGD). There were 39 males and 16 females in either group. Complications related to TEE were defined as upper gastrointestinal (GI) bleed, decline in hemoglobin by more than 2 g/dl, esophageal perforation, aspiration, respiratory compromise requiring intubation and/or need for sedative reversal agents that occurred within 48 hours of the procedure. Results: In G1 grade 1, grade 2, and grade 3 GEV were present in 21, 24, and 12 patients, respectively. Of the 12 patients with grade 3 GEV, one patient had GI bleed. TEE findings included vegetation in 8 patients of G1 and in — patients of C and thrombus in 3 patients of G1 and 3 patients of C. Conclusions: TEE appears safe in patient with grade 1 or 2 GEV. However, caution should be advised when performing TEE in patients with grade 3 GEV. TEE showed significant findings of vegetation or thromus in at least 20% of the patients with GEV.
Abstract 2679: Chest Pain: Characteristics of Children/Adolescents Evaluated in the Cardiac Exercise Laboratory
Authors: Michael J Danduran, David C Sheridan, Kathy A Mussatto, Lauren A Ewalt, Peter C Frommelt
Journal: Circulation (2006)

INTRODUCTION: Chest pain (CP) in children/adolescents is a common referral for the pediatric cardiologist. METHODS: A group of 263 patients (141 M/122 F, 13.4 yrs, R:5–22 yrs) with the primary comp...
Creativity and Disease: How Illness Affects Literature, Art, and Music.
Authors: Philip Sandblom
Journal: Annals of Internal Medicine (1988)

to do the reconstruction (only one biblio¬ graphic citation is provided and that one is not adequate). Tachdjian devotes 93 pages to four techniques of limb length¬ ening and 17 pages to that of Ilizarov, and each is illustrated by pages and pages of drawings. Yet there is no ade¬ quate discussion of questions such as how much of a discrepancy warrants any single procedure and what might be the influence of the patient's age on the result. However, in general, Tachdjian advocates a conservative approach to treatment, eg, open reduction and in¬ ternal fixation of fractures is rarely indicated. In distinct contrast, Morrissy's two volumes and 34 chapters are not or¬ dered to a logical plan. There are clus¬ ters of chapters that do havemeaningful relationships (disorders of the nonskeletal systems—endocrine, vascular, and neuromuscular—and lesions of the ana¬ tomical regions), but the book seems to be designed for the reading of, rather than reference to, each separate chap¬ ter as an overview of a restricted field. If the reader instead seeks material on certain details, the index serveswell. In contrast to Tachdjian's text, where the competent writings of a single author (superbly edited, too) are evidence of a painstaking devotion to the quality of the product, the texts ofMorrissy's nu¬ merous authors vary in literary excel¬ lence from quite good to bad, and the stylistic editing is abominable. As with most multiauthored books, the writers vary in their assessments as to the level of prior education and experience of their target audiences, somewriting for trained surgeons, albeit not in the pedi¬ atrie field, others seemingly for begin¬ ning residents or even medical stu¬ dents. For the latter groups, however, there does not seem to be much of an attempt by most of the authors to inte¬ grate recent advances in basic science (eg, in infection and immunity) into the time-honored clinical material of ortho¬ pedic surgeons. Yet, these criticisms aside, the use¬ fulness ofMorrissy's text resides in hav¬ ing available a collection of reviews, mostly of good quality, of all the sub¬ jects that constitute pediatrie orthope¬ dics—no need to single out the best ones, or the worst. If you start with the objective of a refresher course, Mor¬ rissy's text will serve well. If, instead, you want a good reference book on the shelf, Tachdjian's text is the one to choose.
Abstract 14806: Predictors of Survival and Favourable Functional Outcomes Following an Out of Hospital Cardiac Arrest in Patients Systematically Brought to a Dedicated Heart Attack Centre
Authors: M Bilal Iqbal, Abtehale Al-Hussaini, Gareth Rosser, Saleem Salehi, Maria Phylactou, Ramyah Rajakulasingham, Jayna Patel, Katharine Elliott, Poornima Mohan, Rebecca Green, Robert Smith, Charles Ilsley
Journal: Circulation (2014)

BACKGROUND: Despite advances in cardiopulmonary resuscitation, survival remains low after out of hospital cardiac arrest (OOHCA), with less than 20% of patients surviving to hospital discharge. Acute coronary ischaemia is the predominating cause and prompt delivery of patients to dedicated facilities may improve outcomes. Since 2011, all patients in London with OOHCA, in whom a cardiac aetiology is suspected, are brought to dedicated Heart Attack Centres (HACs). OBJECTIVES: We sought to determine the predictors for survival and favourable functional outcomes following OOHCA in this setting. METHODS: We analysed 182 consecutive OOHCA patients brought by the emergency services to Harefield Hospital - a designated HAC in London. Of these, 174 patients achieved return of spontaneous circulation. We analysed (a) all-cause mortality at 1 year; and (b) functional status at discharge using a modified Rankins score (mRS:0-6, where mRS0-3=favourable functional status). We used multivariate models to determine predictors of survival and favourable functional status. RESULTS: The overall survival rates were 66.7% at 30 days and 62.1% at 1 year. Of the 174 patients, 95 patients (54.5%) had favourable functional status at discharge. Patients with favourable functional status had significantly reduced mortality rates compared to those with poor functional status: 30 days (1.2% vs. 72.2%, p&lt;0.001) and 1 year (5.3% vs. 77.2%, p&lt;0.001). Multivariate analyses identified a shorter duration of resuscitation and absence of cardiogenic shock as consistent independent predictors of both favourable functional status and long-term survival (figure). CONCLUSIONS: The strategic delivery of OOHCA patients to HACs is associated with improved functional status and survival. Those with favourable functional status at discharge have significantly improved survival. Our study supports the standardisation of care for such patients with the widespread adoption of dedicated facilities.
842. Cell Permeable Peptides: Potential Use To Enhance Intracellular Gene Delivery
Authors: Valentina A. Anisimova, Igor G. Shemyakin
Journal: Molecular Therapy (2004)

For the present viruses remain to be the most effective gene delivery vehicles in comparing with non-viral ones due to the last lack one or more properties necessary for successful overcoming three membrane barriers of target cells. We have constructed multifunctional protein consisting of three parts: human protamine PI, responsible for binding, condensing and nuclear targeting of DNA; translocation domain of diphtheria toxin (DT) facilitating endosome escape and streptavidine (SA) as a mediator between DNA-protein complexes and biotinilated ligands/antibodies which interact with specific molecules on the surface of target cells. SA in this construction provides as well possibility for screening of the most effective for gene delivery surface molecules. Gene of PI has been assembled from synthetic oligonucleotides taking into account codon usage frequency by Escherichia coli cells. The fusion protein (PIΔDT388SA) has been expressed in soluble form in E. coli and in insect cells using baculoviral system and purified up to homogeneity. It interacts with anti-DT antibodies and biotinilated molecules. DNA binding studies by gel-retardation demonstrate highly efficient neutralization of negative charge of plasmid DNA. Cell targeting efficiency of the protein-DNA complexes is under investigation.
Effect of GERD on clinical severity and functional characteristics of lung function in asthma
Authors: Khalil Ansarin, Akbar Sharifi
Journal: European Respiratory Journal (2011)

Background: It is known that almost one third of patients with asthma have symptomatic evidence for coexisting gastroesophageal reflux disorder (GERD) which is thought to be aggravating factor in asthma at least in some cases.

Aims and objectives: We investigated the impact of coexisting GERD on the severity and functional characteristics of asthma.

Methods: Ninety-two patients with asthma diagnosed on the basis of ATS criteria were studied. Asthma clinical severity was measured in using asthma control test (ACT) and evidence for GERD was verified using standard questionnaire. Spirometry, impulse oscillometry, and lung volume studies (using body-plethysmograph and IOS both provide by Jaeger, Germany) were performed. The difference between total airway resistance (TAWR) indicated by resistance at 5Hz and central airway resistance (CAWR) as indicated by resistance at 20 Hz in oscillometry was calculated as representative of resistance of peripheral airways (PAWR). The relationship between the symptoms of GERD, ACT score and parameters of lung function were analyzed.

Results: PAWR and TAWR were both significantly higher in asthma patients with GERD symptoms than patients without GERD symptoms (mean ranks of 56.6 versus 41.9; P=0.01 and 55.8 versus 43.0 kpL/s; p=0.04, respectively). However, the values for ACT score, FEV1, FVC, PEF, RV, TLC, FRC/TLC were not significantly different in these two groups

Conclusion: Clinical severity of asthma measured by ACT score is not different in asthma patients with and without GERD symptoms and central and peripheral airway resistance is equally influenced by symptomatic GERD.