tbuckley/cabot-search huggingface dataset:
“Less Is More” in Critically Ill Patients
Authors: Matthijs Kox, Peter Pickkers
Journal: JAMA Internal Medicine (2013)

The current view in intensive care medicine is that very sick patients need very intensive treatment. However, in this group of highly vulnerable patients, more intensive treatment may promote the chances of unwanted adverse effects and hence, iatrogenic damage. Therefore, we state that critically ill patients probably benefit from a more cautious approach. Using data from large clinical trials of previous years, we exemplify that less intensive treatment is associated with a better outcome in intensive care patients and suggest that we reappraise patient management as well as trial design in intensive care medicine while bearing in mind the “less is more” paradigm. We illustrate our case by describing the intensity of the most relevant treatment options for patients with septic shock, including mechanical ventilation, fluid management, blood pressure–targeted therapy, corticosteroids, patient monitoring, sedation, and nutrition. We conclude that treatment of critically ill patients while keeping in mind the “less is more” paradigm might not only benefit the patient but could also have a notable impact on the ever-increasing intensive care–related health care costs.
A cyanobacterial LPS antagonist prevents endotoxin shock and blocks sustained TLR4 stimulation required for cytokine expression
Authors: Annalisa Macagno, Monica Molteni, Andrea Rinaldi, Francesco Bertoni, Antonio Lanzavecchia, Carlo Rossetti, Federica Sallusto
Journal: The Journal of Experimental Medicine (2006)

Toll-like receptors (TLRs) function as primary sensors that elicit coordinated innate immune defenses through recognition of microbial products and induction of immune and proinflammatory genes. Here we report the identification and biological characterization of a lipopolysaccharide (LPS)-like molecule extracted from the cyanobacterium Oscillatoria Planktothrix FP1 (cyanobacterial product [CyP]) that is not stimulatory per se but acts as a potent and selective antagonist of bacterial LPS. CyP binds to MD-2 and efficiently competes with LPS for binding to the TLR4–MD-2 receptor complex. The addition of CyP together with LPS completely inhibited both MyD88- and TRIF-dependent pathways and suppressed the whole LPS-induced gene transcription program in human dendritic cells (DCs). CyP protected mice from endotoxin shock in spite of a lower capacity to inhibit LPS stimulation of mouse DCs. Interestingly, the delayed addition of CyP to DCs responding to LPS strongly inhibited signaling and cytokine production by immediate down-regulation of inflammatory cytokine mRNAs while not affecting other aspects of DC maturation, such as expression of major histocompatibility complex molecules, costimulatory molecules, and CCR7. Collectively, these results indicate that CyP is a potent competitive inhibitor of LPS in vitro and in vivo and reveal the requirement of sustained TLR4 stimulation for induction of cytokine genes in human DCs.
International variation in prevalence of rhinitis and its relationship with sensitisation to perennial and seasonal allergens
Authors: G. Weinmayr, F. Forastiere, S. K. Weiland, P. Rzehak, T. Abramidze, I. Annesi-Maesano, B. Björkstén, B. Brunekreef, G. Büchele, W. O. C. Cookson, E. von Mutius, R. Pistelli, D. P. Strachan
Journal: European Respiratory Journal (2008)

The relative importance of atopy in the aetiology of rhinitis is largely unknown. The present study investigated the geographical variations in rhinitis in relation to atopy. The cross-sectional study involved 54,178 children (aged 8–12 yrs) from 30 study centres in 22 countries worldwide. Symptoms of rhinoconjunctivitis and rhinitis without conjunctivitis in the last 12 months were reported in parental questionnaires and children were skin-prick tested. The prevalence of rhinoconjunctivitis and rhinitis without conjunctivitis varied widely (1.5–24.5% and 1.4–45.2%, respectively). For rhinoconjunctivitis, the population attributable fraction (PAF) varied 0–71% for a positive skin-prick test to one or more seasonal allergens and 0–41% for perennial allergens. The PAF for sensitisation to seasonal and perennial allergens was higher in affluent countries (36 and 25%, respectively) than nonaffluent countries (1.3 and 12.6%, respectively). For rhinitis without conjunctivitis, the PAF for perennial allergens was 8 and 4% for affluent and nonaffluent countries, respectively. No significant PAF was found for seasonal allergens. Overall, atopy explained only a limited proportion of rhinitis symptoms, suggesting that the importance of other environmental factors has been under emphasised, particularly in less affluent countries. Atopy seems to be only marginally relevant for rhinitis without conjunctivitis, which seems mainly to reflect nonatopic rhinitis.
Combinatorial Immunotherapy of Polyinosinic–Polycytidylic Acid and Blockade of Programmed Death-Ligand 1 Induce Effective CD8 T-cell Responses against Established Tumors
Authors: Toshihiro Nagato, Young-Ran Lee, Yasuaki Harabuchi, Esteban Celis
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Epitope-based cancer vaccines capable of inducing CD8 T-cell responses to tumor-associated antigens (TAA) expressed by tumor cells have been considered as attractive alternatives for the treatment of some types of cancer. However, reliable TAAs have not been identified for most malignant diseases, limiting the development of epitope-based vaccines. Herein, we report that the combinatorial therapy of polyinosinic–polycytidylic acid (poly-IC) and antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody (mAb) can be implemented with good results for tumors where no known TAAs have been identified. Experimental Design: Three cancer mouse models (melanoma, lung, and colon) were used to evaluate therapeutic efficacy and examine the immunologic mechanisms of the poly-IC/anti–PD-L1 mAb therapy. Results: The combined administration of poly-IC and anti–PD-L1 mAb into tumor-bearing mice generated potent immune responses resulting in the complete eradication or remarkable reduction of tumor growth. In some instances, the poly-IC/anti–PD-L1 mAb therapy induced long-lasting protection against tumor rechallenges. The results indicate that CD8 T cells but not CD4 T cells or NK cells mediated the therapeutic efficacy of this combinatorial therapy. Experiments using genetically deficient mice indicate that the therapeutic efficacy of this combinatorial therapy depended in part by the participation of type-I IFN, whereas IFN-γ did not seem to play a major role. Conclusions: The overall results suggest that immunotherapy consisting of the combination of poly-IC/anti–PD-L1 mAb could be a promising new approach for treating patients with cancer, especially those instances where no reliable TAAs are available as a therapeutic vaccine. Clin Cancer Res; 20(5); 1223–34. ©2014 AACR.
Pharmacogenetic Differences in Response to Albuterol between Puerto Ricans and Mexicans with Asthma
Authors: Shweta Choudhry, Ngim Ung, Pedro C. Avila, Elad Ziv, Sylvette Nazario, Jesus Casal, Alfonso Torres, Jennifer D. Gorman, Keyan Salari, Jose R. Rodriguez-Santana, Monica Toscano, Jody Senter Sylvia, MariaElena Alioto, Richard A. Castro, Michael Salazar, Ivan Gomez, Joanne K. Fagan, Jorge Salas, Suzanne Clark, Craig Lilly, Henry Matallana, Moises Selman, Rocio Chapela, Dean Sheppard, Scott T. Weiss, Jean G. Ford, Homer A. Boushey, Jeffrey M. Drazen, William Rodriguez-Cintron, Edwin K. Silverman, Esteban González Burchard
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

In the United States, Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity, and mortality, respectively. Ethnic-specific differences in the response to drug treatment may contribute to differences in disease outcomes. Genetic variants at the beta(2)-adrenergic receptor (beta(2)AR) may modify asthma severity and albuterol responsiveness. We tested the association of beta(2)AR genotypes with asthma severity and bronchodilator response to albuterol in Puerto Ricans and Mexicans with asthma.We used both family-based and cross-sectional tests of association with 8 beta(2)AR single nucleotide polymorphisms in 684 Puerto Rican and Mexican families. Regression analyses were used to determine the interaction between genotype, asthma severity, and bronchodilator drug responsiveness.Among Puerto Ricans with asthma, the arginine (Arg) 16 allele was associated with greater bronchodilator response using both family-based and cross-sectional tests (p = 0.00001-0.01). We found a strong interaction of baseline FEV(1) with the Arg16Glycine (Gly) polymorphism in predicting bronchodilator response. Among Puerto Ricans with asthma with baseline FEV(1) < 80% of predicted, but not in those with FEV(1) > 80%, there was a very strong association between the Arg16 genotype and greater bronchodilator responsiveness. No association was observed between Arg16Gly genotypes and drug responsiveness among Mexicans with asthma.Ethnic-specific pharmacogenetic differences exist between Arg16Gly genotypes, asthma severity, and bronchodilator response in Puerto Ricans and Mexicans with asthma. These findings underscore the need for additional research on racial/ethnic differences in asthma morbidity and drug responsiveness.
Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia
Authors: Kathryn G. Roberts, Yongjin Li, Debbie Payne-Turner, Richard C. Harvey, Yung-Li Yang, Deqing Pei, Kelly McCastlain, Li Ding, Charles Lu, Guangchun Song, Jing Ma, Jared Becksfort, Michael Rusch, Shann-Ching Chen, John Easton, Jinjun Cheng, Kristy Boggs, Natalia Santiago-Morales, Ilaria Iacobucci, Robert S. Fulton, Ji Wen, Marcus Valentine, Cheng Cheng, Steven W. Paugh, Meenakshi Devidas, I-Ming Chen, Shalini Reshmi, Amy Smith, Erin Hedlund, Pankaj Gupta, Panduka Nagahawatte, Gang Wu, Xiang Chen, Donald Yergeau, Bhavin Vadodaria, Heather Mulder, Naomi J. Winick, Eric C. Larsen, William L. Carroll, Nyla A. Heerema, Andrew J. Carroll, Guy Grayson, Sarah K. Tasian, Andrew S. Moore, Frank Keller, Melissa Frei-Jones, James A. Whitlock, Elizabeth A. Raetz, Deborah L. White, Timothy P. Hughes, Jaime M. Guidry Auvil, Malcolm A. Smith, Guido Marcucci, Clara D. Bloomfield, Krzysztof Mrózek, Jessica Kohlschmidt, Wendy Stock, Steven M. Kornblau, Marina Konopleva, Elisabeth Paietta, Ching-Hon Pui, Sima Jeha, Mary V. Relling, William E. Evans, Daniela S. Gerhard, Julie M. Gastier-Foster, Elaine Mardis, Richard K. Wilson, Mignon L. Loh, James R. Downing, Stephen P. Hunger, Cheryl L. Willman, Jinghui Zhang, Charles G. Mullighan
Journal: New England Journal of Medicine (2014)

Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR–ABL1–positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.
Novel Breast Tissue Feature Strongly Associated With Risk of Breast Cancer
Authors: Kevin P. McKian, Carol A. Reynolds, Daniel W. Visscher, Aziza Nassar, Derek C. Radisky, Robert A. Vierkant, Amy C. Degnim, Judy C. Boughey, Karthik Ghosh, Stephanie S. Anderson, Douglas Minot, Jill L. Caudill, Celine M. Vachon, Marlene H. Frost, V. Shane Pankratz, Lynn C. Hartmann
Journal: Journal of Clinical Oncology (2009)

Accurate, individualized risk prediction for breast cancer is lacking. Tissue-based features may help to stratify women into different risk levels. Breast lobules are the anatomic sites of origin of breast cancer. As women age, these lobular structures should regress, which results in reduced breast cancer risk. However, this does not occur in all women.We have quantified the extent of lobule regression on a benign breast biopsy in 85 patients who developed breast cancer and 142 age-matched controls from the Mayo Benign Breast Disease Cohort, by determining number of acini per lobule and lobular area. We also calculated Gail model 5-year predicted risks for these women.There is a step-wise increase in breast cancer risk with increasing numbers of acini per lobule (P = .0004). Adjusting for Gail model score, parity, histology, and family history did not attenuate this association. Lobular area was similarly associated with risk. The Gail model estimates were associated with risk of breast cancer (P = .03). We examined the individual accuracy of these measures using the concordance (c) statistic. The Gail model c statistic was 0.60 (95% CI, 0.50 to 0.70); the acinar count c statistic was 0.65 (95% CI, 0.54 to 0.75). Combining acinar count and lobular area, the c statistic was 0.68 (95% CI, 0.58 to 0.78). Adding the Gail model to these measures did not improve the c statistic.Novel, tissue-based features that reflect the status of a woman's normal breast lobules are associated with breast cancer risk. These features may offer a novel strategy for risk prediction.
RNA editing of human microRNAs.
Authors: Matthew J Blow, Russell J Grocock, Stijn van Dongen, Anton J Enright, Ed Dicks, P Andrew Futreal, Richard Wooster, Michael R Stratton
Journal: Genome biology (2006)

Abstract Background MicroRNAs (miRNAs) are short RNAs of around 22 nucleotides that regulate gene expression. The primary transcripts of miRNAs contain double-stranded RNA and are therefore potential substrates for adenosine to inosine (A-to-I) RNA editing. Results We have conducted a survey of RNA editing of miRNAs from ten human tissues by sequence comparison of PCR products derived from matched genomic DNA and total cDNA from the same individual. Six out of 99 (6%) miRNA transcripts from which data were obtained were subject to A-to-I editing in at least one tissue. Four out of seven edited adenosines were in the mature miRNA and were predicted to change the target sites in 3' untranslated regions. For a further six miRNAs, we identified A-to-I editing of transcripts derived from the opposite strand of the genome to the annotated miRNA. These miRNAs may have been annotated to the wrong genomic strand. Conclusion Our results indicate that RNA editing increases the diversity of miRNAs and their targets, and hence may modulate miRNA function.
Update in Diffuse Parenchymal Lung Disease 2011
Authors: Tracy R. Luckhardt, Joachim Müller-Quernheim, Victor J. Thannickal
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Over the past year, we have witnessed considerable progress in the clinical evaluation/management of diffuse parenchymal lung diseases (DPLDs) and in the elucidation of pathobiological mechanisms. Studies in idiopathic pulmonary fibrosis (IPF), sarcoidosis, and other less common DPLDs, published in this journal and elsewhere, have advanced our understanding of these complex lung diseases. Clinical trials have aided in understanding the natural history of the disease, defining clinical (sub)phenotypes, and informing better study design. Several studies explored the pathophysiologic underpinnings in the development of lung inflammation and fibrosis. A joint consensus statement from multiple international medical societies on the diagnosis and management of IPF was published in 2011. In this update article, we highlight important clinical and basic research advances made over the past year, with a primary focus on those published in this journal.
Co-Targeting Insulin-Like Growth Factor I Receptor and HER2: Dramatic Effects of HER2 Inhibitors on Nonoverexpressing Breast Cancer
Authors: Ashok K. Chakraborty, Ke Liang, Michael P. DiGiovanna
Journal: Cancer Research (2008)

Abstract The insulin-like growth factor I receptor (IGFIR) and HER2 display important signaling interactions in breast cancer. We examined the effect of combinations of antagonists of these receptors using two human breast cancer cell lines: BT474 (HER2+, IGFIR low) and MCF7 (HER2 low, IGFIR high). In BT474 cells, growth was inhibited by HER2 antagonists but not by IGFIR antagonists; however, IGFIR antagonists enhanced the effect of HER2 inhibitors. In MCF7 cells, growth was inhibited by IGFIR antagonists but not by HER2 antagonists; however, HER2 antagonism enhanced the effect of IGFIR inhibitors. Synergistic inhibition of soft agar growth was also observed. Although HER2 and IGFIR antagonists individually only minimally affected cell cycle, their combination gave a small enhancement of their effects. No single receptor-targeting drug was capable of inducing apoptosis, but combining antagonists of both receptors induced a dramatic degree of apoptosis in both cell lines. Induction of apoptosis was most striking in MCF7 cells using a Herceptin/IGFIR antagonist combination despite these cells being HER2 nonoverexpressing. Toward understanding the mechanism of these effects, we detected coassociation IGFIR and HER2 in both cell lines. Specific inhibitors of one of these receptors could cross-inhibit the activity of the other. Targeting both receptors gave the maximal inhibition of their downstream extracellular signal-regulated kinase 1/2 and AKT signaling pathways. Hence, such drug combinations may be clinically useful and may be beneficial even in tumors in which single drugs are inactive, as exemplified by the effect of the HER2/IGFIR inhibitor combination in HER2 nonoverexpressing MCF7 cells. [Cancer Res 2008;68(5):1538–45]
Sirolimus for Retinal Astrocytic Hamartoma Associated with Tuberous Sclerosis Complex
Authors: Zhi-Qiao Zhang, Cheng Shen, Qin Long, Zhi-Kun Yang, Rong-Ping Dai, Jun Wang, Weihong Zhang, Qingqing Pan, Zhaohui Zhu, Kai-Feng Xu
Journal: Ophthalmology (2015)
Collagen degradation in a murine myocarditis model: relevance of matrix metalloproteinase in association with inflammatory induction
Authors: J LI, P LOTHARSCHWIMMBECK, C TSCHOPE, S LESCHKA, L HUSMANN, S RUTSCHOW, F REICHENBACH, M NOUTSIAS, U KOBALZ, W POLLER
Journal: Cardiovascular Research (2002)

Objective: Myocardial collagen degradation is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs). The possible relevance of MMPs in association with the inflammatory induction was investigated in a murine coxsackievirus B3 myocarditis model. Methods: Hearts from viral infected and sham-infected BALB/c mice were analyzed by semi-quantitative RT-PCR, picrosirius red staining, Western blot analysis, and immunohistochemistry. Results: In viral infected mice, both mRNA and protein abundance for collagen type I remained unaltered. In addition, picrosirius red staining showed the unchanged total collagen content. However, degraded soluble fraction of collagen type I protein was increased. Moreover, the mRNA abundance for MMP-3 and MMP-9 was upregulated, whereas the mRNAs for TIMP-1 and TIMP-4 were downregulated, respectively. The upregulation of MMP-3/MMP-9 and downregulation of TIMP-4 were confirmed at the protein level, and were associated with significantly increased mRNA levels of interleukin 1β, tumor necrosis factor-α, transforming growth factor-β1 and interleukin-4. Conclusion: The increment of MMPs in the absence of counterbalance by TIMPs may lead to a functional defect of the myocardial collagen network by posttranslational mechanisms. This may contribute significantly to the development of left ventricular dysfunction in murine viral myocarditis. The inflammatory response with induction of cytokines may mediate the dysregulation of the myocardial MMP/TIMP systems.
Incidence of High-Strain Patterns in Human Coronary Arteries
Authors: Johannes A. Schaar, Evelyn Regar, Frits Mastik, Eugene P. McFadden, Francesco Saia, Clemens Disco, Chris L. de Korte, Pim J. de Feyter, Antonius F.W. van der Steen, Patrick W. Serruys
Journal: Circulation (2004)

Rupture of thin-cap fibroatheromatous plaques is a major cause of acute myocardial infarction (AMI). Such plaques can be identified in vitro by 3D intravascular palpography with high sensitivity and specificity. We used this technique in patients undergoing percutaneous intervention to assess the incidence of mechanically deformable regions. We further explored the relation of such regions to clinical presentation and to C-reactive protein levels.Three-dimensional palpograms were derived from continuous intravascular ultrasound pullbacks. Patients (n=55) were classified by clinical presentation as having stable angina, unstable angina, or AMI. In every patient, 1 coronary artery was scanned (culprit vessel in stable and unstable angina, nonculprit vessel in AMI), and the number of deformable plaques assessed. Stable angina patients had significantly fewer deformable plaques per vessel (0.6+/-0.6) than did unstable angina patients (P=0.0019) (1.6+/-0.7) or AMI patients (P<0.0001) (2.0+/-0.7). Levels of C-reactive protein were positively correlated with the number of mechanically deformable plaques (R2=0.65, P<0.0001).Three-dimensional intravascular palpography detects strain patterns in human coronary arteries that represent the level of deformation in plaques. The number of highly deformable plaques is correlated with both clinical presentation and levels of C-reactive protein. Further studies will assess the potential role of the technique to identify patients at risk of future clinical events
Intrahepatic Fat Accumulation and Alterations in Lipoprotein Composition in Obese Adolescents
Authors: Anna M.G. Cali, Tosca L. Zern, Sara E. Taksali, Ana Mayra de Oliveira, Sylvie Dufour, James D. Otvos, Sonia Caprio
Journal: Diabetes Care (2007)

Among other metabolic consequences, a dyslipidemic profile often accompanies childhood obesity. In adults, type 2 diabetes and hepatic steatosis have been shown to alter lipoprotein subclass distribution and size; however, these alterations have not yet been shown in children or adolescents. Therefore, our objective was to determine the effect of hepatic steatosis on lipoprotein concentration and size in obese adolescents.Using fast magnetic resonance imaging, we measured intrahepatic fat content in 49 obese adolescents with normal glucose tolerance. The presence or absence of hepatic steatosis was determined by a threshold value for hepatic fat fraction (HFF) of 5.5%; therefore, the cohort was divided into two groups (HFF > or <5.5%). Fasting lipoprotein subclasses were determined using nuclear magnetic resonance spectroscopy.Overall, the high-HFF group had 88% higher concentrations of large VLDL compared with the low-HFF group (P < 0.001). Likewise, the high-HFF group had significantly higher concentrations of small dense LDL (P < 0.007); however, the low-HFF group had significantly higher concentrations of large HDL (P < 0.001). Stepwise multiple regression analysis revealed that high HFF was the strongest single correlate, accounting for 32.6% of the variance in large VLDL concentrations (P < 0.002).The presence of fatty liver was associated with a pronounced dyslipidemic profile characterized by large VLDL, small dense LDL, and decreased large HDL concentrations. This proatherogenic phenotype was strongly related to the intrahepatic lipid content.