tbuckley/cabot-search huggingface dataset:
Preclinical Activity of the Liposomal Cisplatin Lipoplatin in Ovarian Cancer
Authors: Naike Casagrande, Marta Celegato, Cinzia Borghese, Maurizio Mongiat, Alfonso Colombatti, Donatella Aldinucci
Journal: Clinical Cancer Research (2014)

Cisplatin and its platinum derivatives are first-line chemotherapeutic agents in the treatment of ovarian cancer; however, treatment is associated with tumor resistance and significant toxicity. Here we investigated the antitumoral activity of lipoplatin, one of the most promising liposomal platinum drug formulations under clinical investigation.In vitro effects of lipoplatin were tested on a panel of ovarian cancer cell lines, sensitive and resistant to cisplatin, using both two-dimensional (2D) and 3D cell models. We evaluated in vivo the lipoplatin anticancer activity using tumor xenografts.Lipoplatin exhibited a potent antitumoral activity in all ovarian cancer cell lines tested, induced apoptosis, and activated caspase-9, -8, and -3, downregulating Bcl-2 and upregulating Bax. Lipoplatin inhibited thioredoxin reductase enzymatic activity and increased reactive oxygen species accumulation and reduced EGF receptor (EGFR) expression and inhibited cell invasion. Lipoplatin demonstrated a synergistic effect when used in combination with doxorubicin, widely used in relapsed ovarian cancer treatment, and with the albumin-bound paclitaxel, Abraxane. Lipoplatin decreased both ALDH and CD133 expression, markers of ovarian cancer stem cells. Multicellular aggregates/spheroids are present in ascites of patients and most contribute to the spreading to secondary sites. Lipoplatin decreased spheroids growth, vitality, and cell migration out of preformed spheroids. Finally, lipoplatin inhibited more than 90% tumor xenograft growth with minimal systemic toxicity, and after the treatment suspension, no tumor progression was observed.These preclinical data suggest that lipoplatin has potential for clinical assessment in aggressive cisplatin-resistant patients with ovarian cancer.
Microsatellite Instability and Epigenetic Inactivation of <i>MLH1</i> and Outcome of Patients With Endometrial Carcinomas of the Endometrioid Type
Authors: Israel Zighelboim, Paul J. Goodfellow, Feng Gao, Randall K. Gibb, Matthew A. Powell, Janet S. Rader, David G. Mutch
Journal: Journal of Clinical Oncology (2007)

Most studies of microsatellite instability (MSI) and outcomes in endometrial cancer patients have included varied histologic subtypes. Nonetheless, MSI occurs almost exclusively in endometrioid tumors. The impact of MSI on outcomes in patients with endometrial cancer is controversial. We sought to determine whether MSI and MLH1 methylation are associated with clinicopathologic variables and survival outcomes in a large series of patients with endometrial carcinomas of the endometrioid type.Tumor samples, blood, and clinicopathologic data were prospectively collected and analyzed for 446 patients with endometrioid carcinomas. MSI was determined using five National Cancer Institute (NCI) consensus panel markers, and the methylation status of the MLH1 promoter was determined by combined bisulfite restriction analysis (COBRA). Associations with clinicopathologic variables and survival outcomes were evaluated.MSI was identified in 147 cases (33%). MSI was associated with higher International Federation of Gynecology and Obstetrics (FIGO) grade (P < .0001). MSI+ tumors without MLH1 methylation were associated with younger age (P < .001). MSI was not associated with overall survival (OS; hazard ratio [HR], 1.011; 95% CI, 0.688 to 1.484; P = .96) or disease-free survival (DFS; HR 0.951; 95% CI, 0.554 to 1.635; P = .86). The combined MSI/MLH1 methylation status (treating MSI- as the reference) did not predict OS (MSI+/MLH1-U: HR, 0.62; 95% CI, 0.27 to 1.44; P = .26; MSI+/MLH1-M: HR, 0.95; 95% CI, 0.62 to 1.46; P = .82) or DFS (MSI+/MLH1-U: HR, 0.51; 95% CI, 0.22 to 1.19; P = .12; MSI+/MLH1-M: HR, 0.93; 95% CI, 0.62 to 1.40; P = .72).MSI is not associated with survival in patients with endometrioid endometrial cancer.
Judging the best of Indian healthcare
Authors: J. D'Silva
Journal: BMJ (2014)

We received an overwhelming number of nominations," said Anand Ekambaram, managing director of BMJ India.More than 500 individuals and teams throughout India have been put forward. 1 "The BMJ India Awards are a very prestigious recognition, and it is an honour to be among the nominees," said Sarman Singh, professor and head of the division of clinical microbiology and molecular medicine at the
A multifunctional bispecific antibody protects against <i>Pseudomonas aeruginosa</i>
Authors: Antonio DiGiandomenico, Ashley E. Keller, Cuihua Gao, Godfrey J. Rainey, Paul Warrener, Mareia M. Camara, Jessica Bonnell, Ryan Fleming, Binyam Bezabeh, Nazzareno Dimasi, Bret R. Sellman, Jamese Hilliard, Caitlin M. Guenther, Vivekananda Datta, Wei Zhao, Changshou Gao, Xiang-Qing Yu, JoAnn A. Suzich, C. Kendall Stover
Journal: Science Translational Medicine (2014)

A new antibody platform combining anti-Psl and anti-PcrV activities provides enhanced protection and acts synergistically with antibiotics against Pseudomonas aeruginosa .
'Astronaut' Emphasized Over 'Physician,' but Some Manage to Stay in Practice
Authors: Jeanette Smith
Journal: JAMA (1990)

DO PHYSICIAN-astronauts have opportunity to practice more conventional, earthbound medicine? Jeff Carr of the National Aeronautics and Space Administration (NASA), when asked about physician-astronauts' maintaining clinical skills, says: "They generally don't. When they come to work for [the] NASA, they are NASA astronauts, not NASA physicians." <h3>Some Do Clinical Work</h3> However, he adds, some find time for work in a local hospital emergency department or pursuing some other form of medical practice. One of the physician-astronauts who does work in an emergency department a few days a month is M. Rhea Seddon, MD. Says Seddon: "I have a pretty full job at [the] NASA but, to really feel like I can still diagnose a problem and treat a patient, I like to keep my hand in and do a little bit of emergency medicine." <h3>Young Person's Job?</h3> Another question that is asked about these physicians, and other astronauts, is: Is
Podocyte Differentiation and Hereditary Proteinuria/Nephrotic Syndromes
Authors: Marie-Claire Gubler
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The study of familial nephrotic syndromes (NS) and the analysis of murine models of glomerular diseases resulted in major progresses in the knowledge of podocyte physiology and pathology. Numerous proteins participating in the composition of the slit diaphragm region have been identified. The importance of several of them (nephrin, podocin, CD2AP, and Neph1) in the maintenance of the glomerular filtration barrier has been demonstrated by the occurrence of massive proteinuria when they are defective. The role of the cytoskeleton has been revealed by the development of proteinuria/NS in patients with ACTN4 mutation and the occurrence of early and severe NS in α-actinin-4–deficient mice. Given the genetic heterogeneity of familial NS and the many other genes to be identified, further insights in the molecular basis of the role of the podocyte in the maintenance of the glomerular filtration barrier may be expected in the near future. E-mail: [email protected]
Fugu Genome Analysis Provides Evidence for a Whole-Genome Duplication Early During the Evolution of Ray-Finned Fishes
Authors: Alan Christoffels, Esther G. L. Koh, Jer-ming Chia, Sydney Brenner, Samuel Aparicio, Byrappa Venkatesh
Journal: Molecular Biology and Evolution (2004)

With about 24,000 extant species, teleosts are the largest group of vertebrates. They constitute more than 99% of the ray-finned fishes (Actinopterygii) that diverged from the lobe-finned fish lineage (Sarcopterygii) about 450 MYA. Although the role of genome duplication in the evolution of vertebrates is now established, its role in structuring the teleost genomes has been controversial. At least two hypotheses have been proposed: a whole-genome duplication in an ancient ray-finned fish and independent gene duplications in different lineages. These hypotheses are, however, based on small data sets and lack adequate statistical and phylogenetic support. In this study, we have made a systematic comparison of the draft genome sequences of Fugu and humans to identify paralogous chromosomal regions ("paralogons") in the Fugu that arose in the ray-finned fish lineage ("fish-specific"). We identified duplicate genes in the Fugu by phylogenetic analyses of the Fugu, human, and invertebrate sequences. Our analyses provide evidence for 425 fish-specific duplicate genes in the Fugu and show that at least 6.6% of the genome is represented by fish-specific paralogons. We estimated the ages of Fugu duplicate genes and paralogons using the molecular clock. Remarkably, the ages of duplicate genes and paralogons are clustered, with a peak around 350 MYA. These data strongly suggest a whole-genome duplication event early during the evolution of ray-finned fishes, probably before the origin of teleosts.
Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury
Authors: Y. P. de Visser, F. J. Walther, E. H. Laghmani, S. van Wijngaarden, K. Nieuwland, G. T. M. Wagenaar
Journal: European Respiratory Journal (2007)

Phosphodiesterase-4 (PDE4) inhibitors may offer novel therapeutic strategies in respiratory diseases, including asthma and chronic obstructive pulmonary disease. Therefore, selective PDE4 inhibitors may also provide a therapeutic option for very pre-term infants with bronchopulmonary dysplasia (BPD). The anti-inflammatory effect of two PDE4 inhibitors was investigated in a pre-term rat model of hyperoxia-induced lung injury. Pre-term rat pups were exposed to room air, hyperoxia, or hyperoxia and one of two PDE4 inhibitors: rolipram and piclamilast. The anti-inflammatory effects of prolonged PDE4 inhibitor therapy were investigated by studying survival, histopathology, fibrin deposition, alveolar vascular leakage and differential mRNA expression (real-time RT-PCR) of key genes involved in inflammation, alveolar enlargement, coagulation and fibrinolysis. PDE4 inhibitor therapy prolonged median survival by up to 7 days and reduced alveolar fibrin deposition, lung inflammation and vascular leakage by decreasing the influx of monocytes and macrophages and protein efflux in bronchoalveolar lavage fluid. Analysis of mRNA expression of key genes involved in experimental BPD revealed a significant PDE4 inhibitor-induced improvement of genes involved in inflammation, fibrin deposition and alveolarisation. In conclusion, phosphodiesterase-4 inhibition prolongs survival by inhibiting inflammation and reducing alveolar fibrin deposition in pre-term rat pups with neonatal hyperoxic lung injury, whereby piclamilast outperformed rolipram.
Host lifestyle affects human microbiota on daily timescales
Authors: Lawrence A David, Arne C Materna, Jonathan Friedman, Maria I Campos-Baptista, Matthew C Blackburn, Allison Perrotta, Susan E Erdman, Eric J Alm
Journal: Genome biology (2014)

Disturbance to human microbiota may underlie several pathologies. Yet, we lack a comprehensive understanding of how lifestyle affects the dynamics of human-associated microbial communities.Here, we link over 10,000 longitudinal measurements of human wellness and action to the daily gut and salivary microbiota dynamics of two individuals over the course of one year. These time series show overall microbial communities to be stable for months. However, rare events in each subjects’ life rapidly and broadly impacted microbiota dynamics. Travel from the developed to the developing world in one subject led to a nearly two-fold increase in the Bacteroidetes to Firmicutes ratio, which reversed upon return. Enteric infection in the other subject resulted in the permanent decline of most gut bacterial taxa, which were replaced by genetically similar species. Still, even during periods of overall community stability, the dynamics of select microbial taxa could be associated with specific host behaviors. Most prominently, changes in host fiber intake positively correlated with next-day abundance changes among 15% of gut microbiota members.Our findings suggest that although human-associated microbial communities are generally stable, they can be quickly and profoundly altered by common human actions and experiences.
Do Molecular Markers Predict Survival in Non–Small-Cell Lung Cancer?
Authors: TODD M. GREATENS, GLORIA A. NIEHANS, JEFFREY B. RUBINS, JOSE JESSURUN, ROBERT A. KRATZKE, MICHAEL A. MADDAUS, DENNIS E. NIEWOEHNER
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Patients with non–small-cell lung cancer (NSCLC) survive for variable lengths of time, even when adjustment is made for pathological stage. Numerous reports suggest that biological markers predict survival in patients undergoing surgery for NSCLC with curative intent, but many of these claims are unconfirmed or conflicting. We postulated that the use of multiple putative markers might provide greater power in predicting survival. We studied 101 consecutive patients with NSCLC who underwent exploratory thoracotomy and who were followed for at least 2 yr. We assessed mutations in the p53 tumor suppressor gene (exons 5-8) and the K-ras oncogene (codons 12 and 13) by polymerase chain reaction amplification and single strand conformation polymorphism of the product. We identified 19 K-ras mutations (all adenocarcinomas except for two) and 40 p53 mutations among the 101 cases. We also evaluated p53 protein, bcl-2 protein, c-erbB-1 protein, c-erbB-2 protein, and MIA-15-5 antigen by standard immunocytochemical techniques, and we found that all of these antigens were variably expressed. As expected, we found a strong inverse association between surgical tumor stage and survival. Of the molecular markers studied, only MIA-15-5 antigen expression correlated strongly with survival by univariate analysis (p = 0.001) and it remained a significant predictor by multivariate analysis (p = 0.01). However, in this study, overexpression of MIA-15-5 antigen predicted an improved survival, whereas the original report showed a worse prognosis (N. Engl. J. Med. 1992;327:14). We conclude the multiple cell markers are not clinically useful in predicting survival among patients undergoing surgery for NSCLC. Differences between our results and prior reports may be due to chance, to true population differences, or to other factors.
Decreasing incidence of symptomatic gastrointestinal ulcers and ulcer complications in patients with rheumatoid arthritis
Authors: K S S Steen, M T Nurmohamed, I Visman, M Heijerman, M Boers, B A C Dijkmans, W F Lems
Journal: Annals of the Rheumatic Diseases (2007)

Non-steroidal anti-inflammatory drugs (NSAIDs) frequently cause gastrointestinal (GI) ulcers and complications of ulcers. In 1997 in Amsterdam, the incidence of symptomatic GI events was 2.1% (95% CI 1.0-3.1) in patients with rheumatoid arthritis (RA). We conducted a new prospective, observational study on the symptomatic GI events in our outpatient clinics, and compared the data to a previous study conducted by our group. Over the same time period, a decline of GI events over the last decade was reported for US patients.In 2003, three questionnaires were sent to all RA patients in Amsterdam at 4-month intervals, addressing medication use, dyspepsia, and symptomatic GI events in the previous 4 months.The incidence of GI events in high-risk patients, defined as age >or=60 and/or history of GI event) using NSAIDs or cyclo-oxygenase 2 specific inhibitors (COXIBs) was 1.2% (95% CI 0.2-2.3), which appears to be substantially lower than the 2.1% observed in 1997; however this difference did not reach statistical significance (p = 0.3). In 64% (95% CI 61-68) of the high-risk patients, acid-suppressive drugs (ie, proton pump inhibitors, prostaglandin analogues or high dose H2 antagonists) were used. In 1997 this percentage was significantly lower at 49% (45-52; p<0.001). The compliance to the Dutch guidelines for prevention of NSAID-related gastropathy was almost 75%, with 64% of the patients using acid-suppressive drugs and 11% using COXIBs.The present study reveals a decline of NSAID-induced gastrointestinal events, which is similar to the results observed in the US. This is most likely due to a more strict adherence to guidelines for prevention of NSAID gastropathy, and better treatment of rheumatoid arthritis.
From trial data to practical knowledge: qualitative study of how general practitioners have accessed and used evidence about statin drugs in their management of hypercholesterolaemia
Authors: K. Fairhurst, G. Huby
Journal: BMJ (1998)

<h3>Abstract</h3> <b>Objectives</b> To explore how general practitioners have accessed and evaluated evidence from trials on the use of statin lipid lowering drugs and incorporated this evidence into their practice. To draw out the practical implications of this study for strategies to integrate clinical evidence into general medical practice. <b>Design</b>Qualitative analysis of semistructured interviews. <b>Setting</b>General practices in Lothian. <b>Subjects</b>24&nbsp;general practitioners selected to obtain a heterogeneous sample. <b>Results</b> Respondents were generally aware of the evidence relating to the use of statins in secondary prevention of coronary heart disease, but they were less clear about the evidence in primary prevention. The benefits of statins in secondary prevention were clearer to them andthe social and economic issues less complex than was the case for use in primary prevention. Respondents rarely said they appraised the methods and content of trials, rather they judged the trustworthiness of the source of trial evidence and interpreted it within the context of the economic and social factors which impinge on their practice. Moreover, trial data become relevant for routinepractice only when underpinned by a consensus on these issues. <b>Conclusion</b> Strategies to promote incorporation of evidence from clinical trials into everyday practice are likely to be effective if they tap into and build on the process of local consensus building. Strategies such as teaching critical appraisal skills and guideline development may have little effect if they are separated from this process.
Grain dust-induced airflow obstruction and inflammation of the lower respiratory tract.
Authors: W D Clapp, S Becker, J Quay, J L Watt, P S Thorne, K L Frees, X Zhang, H S Koren, C R Lux, D A Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

To investigate the relationship between the physiologic and biologic effects of grain dust inhalation, we exposed 15 nonsmoking, nonasthmatic, nonatopic male grain handlers to buffered saline and aqueous corn dust extract by inhalation challenge in a crossover study. The inhalation challenges to buffered saline and corn dust extract were separated by at least 14 d. Compared with buffered saline, inhalation of corn dust extract resulted in significant airflow obstruction, which was observed within 30 min of exposure and persisted for 5 h. Inhalation of corn dust extract resulted in an acute inflammatory response characterized by higher concentrations of neutrophils (p = 0.001), IL-1 beta (p = 0.001), IL-1RA (p = 0.001), IL-6 (p = 0.001), IL-8 (p = 0.001), and TNF-alpha (p = 0.04) in bronchoalveolar lavage (BAL) fluid. mRNA levels specific for IL-1 beta, IL-1RA, IL-6, and IL-8 from cells present in the BAL fluid were significantly greater after challenge with corn dust extract than after challenge with buffered saline. Importantly, no significant differences were observed in the concentration of lymphocytes or eosinophils in the BAL fluid following inhalation of corn dust extract, and the concentrations of histamine and 15-HETE were similar in BAL fluid after the two challenges. The maximal percentage decrease in FEV1 was significantly associated with the absolute neutrophil concentration in the BAL fluid (p = 0.001), as well as the concentration of TNF-alpha (p = 0.03), IL-1 beta (p = 0.005), IL-1RA (p = 0.001), IL-6 (p = 0.001), and IL-8 (p = 0.001) in the BAL fluid.(ABSTRACT TRUNCATED AT 250 WORDS)
IRF3 balances killing and cleaning
Authors: Ruth Williams
Journal: The Journal of Experimental Medicine (2006)

A clean house is a sign of a boring life. When more interesting or urgent matters arise, the housework has to wait. Similarly, when the body needs to fight infection, the liver's clean-up work is impaired. Chow et al. (page 2589) now show why: switching on virus-fighting factor interferon also switches off the liver's detoxification pathway.

Viral infection can cause metabolic disorders, including cholesterol and bone metabolism defects as well as Reye's syndrome, a defect in which aspirin becomes toxic because the liver fails to break it down. Liver detoxification is partly regulated by a transcription factor called retinoid X receptor (RXR), which turns on drug metabolism genes. But RXR is turned off by viral infection, Chow and colleagues now find.

RXR gets down-regulated by interferon regulatory factor 3 (IRF3), the same factor responsible for promoting virus-killing interferon expression as part of the primary immune response.

The team's work reveals a mechanism for crosstalk between immunity and metabolism—but why might cells need such crosstalk? “Fighting infection costs energy, and so does metabolism,” explains Chow. The simultaneous switching of resources in favor of the immune response and away from metabolism might thus be the body's way of balancing the energy budget.
Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation
Authors: Jan R. Thiele, Jonathon Habersberger, David Braig, Yvonne Schmidt, Kurt Goerendt, Valentin Maurer, Holger Bannasch, Amelie Scheichl, Kevin J. Woollard, Ernst von Dobschütz, Frank Kolodgie, Renu Virmani, G. Bjoern Stark, Karlheinz Peter, Steffen U. Eisenhardt
Journal: Circulation (2014)

Background— The relevance of the dissociation of circulating pentameric C-reactive protein (pCRP) to its monomeric subunits (mCRP) is poorly understood. We investigated the role of conformational C-reactive protein changes in vivo. Methods and Results— We identified mCRP in inflamed human striated muscle, human atherosclerotic plaque, and infarcted myocardium (rat and human) and its colocalization with inflammatory cells, which suggests a general causal role of mCRP in inflammation. This was confirmed in rat intravital microscopy of lipopolysaccharide-induced cremasteric muscle inflammation. Intravenous pCRP administration significantly enhanced leukocyte rolling, adhesion, and transmigration via localized dissociation to mCRP in inflamed but not noninflamed cremaster muscle. This was confirmed in a rat model of myocardial infarction. Mechanistically, this process was dependent on exposure of lysophosphatidylcholine on activated cell membranes, which is generated after phospholipase A2 activation. These membrane changes could be visualized intravitally on endothelial cells, as could the colocalized mCRP generation. Blocking of phospholipase A2 abrogated C-reactive protein dissociation and thereby blunted the proinflammatory effects of C-reactive protein. Identifying the dissociation process as a therapeutic target, we stabilized pCRP using 1,6-bis(phosphocholine)-hexane, which prevented dissociation in vitro and in vivo and consequently inhibited the generation and proinflammatory activity of mCRP; notably, it also inhibited mCRP deposition and inflammation in rat myocardial infarction. Conclusions— These results provide in vivo evidence for a novel mechanism that localizes and aggravates inflammation via phospholipase A2–dependent dissociation of circulating pCRP to mCRP. mCRP is proposed as a pathogenic factor in atherosclerosis and myocardial infarction. Most importantly, the inhibition of pCRP dissociation represents a promising, novel anti-inflammatory therapeutic strategy.