tbuckley/cabot-search huggingface dataset:
Abstract 3786: Gambogic acid inhibits chemokine receptor CXCR4 signaling pathways and osteoclastogenesis in multiple myeloma
Authors: Manoj K. Pandey, Vijay P. Kale, Chunhua Song, Shen-shu Sung, Arun K. Sharma, Sinisa Dovat, Shantu G. Amin
Journal: Cancer Research (2014)

Abstract Bone disease, characterized by the presence of lytic lesions and osteoporosis is the hallmark of multiple myeloma (MM). Stromal cell-derived factor 1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4), has been implicated as a regulator of bone resorption, suggesting that agents that can suppress SDF1α/CXCR4 signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We, therefore, investigated whether gambogic acid (GA), a xanthone, could inhibit CXCR4 signaling and suppress osteoclastogenesis induced by MM cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on MM cells in a dose- and time-dependent manner. The down-regulation of CXCR4 was not due to proteolytic degradation but rather to transcriptional regulation, as indicated by down-regulation of CXCR4 mRNA expression, inhibition of nuclear factor-kappa B (NF-κB) activity, and suppression of p65 binding at CXCR4 promoter analyzed by quantitative chromatin immunoprecipitation (qChIP) assay. Suppression of CXCR4 expression by GA correlated with both inhibition of SDF-1α-induced invasion of MM cells. GA also inhibited phosphorylation of Akt, p38, and Erk1/2 in MM cells. GA suppressed the RANKL-induced differentiation of macrophages to osteoclasts in a dose- and time-dependent manner. Finally, we found that MM cells, induced differentiation of macrophages to osteoclasts, and that GA suppressed this process. Overall, our results show that GA is a novel inhibitor of CXCR4 expression and thus has a strong potential to suppress osteoclastogenesis mediated by MM cells. Citation Format: Manoj K. Pandey, Vijay P. Kale, Chunhua Song, Shen-shu Sung, Arun K. Sharma, Sinisa Dovat, Shantu G. Amin. Gambogic acid inhibits chemokine receptor CXCR4 signaling pathways and osteoclastogenesis in multiple myeloma. [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 3786. doi:10.1158/1538-7445.AM2014-3786
Child Mortality Report
Authors: Jennifer Stephenson
Journal: JAMA (2004)

Nearly 100 countries are falling short of a goal to reduce child mortality adopted by world leaders at the United Nations' Millennium Summit in 2000, according to a report by the United Nation's Children's Fund. One in 12 children worldwide does not live to age 5 years. The group reported alarmingly slow progress on reducing child deaths despite the availability of proven, low-cost interventions. At the current rate of progress, by 2015, the global average child mortality rate will have decreased by about one quarter since 1990 (the baseline year), rather than by the goal of a two thirds reduction. In 2002, industrialized countries had 7 deaths per 1000 births compared with 158 deaths per 1000 for the poorest countries. Poor neonatal care, infections, malnutrition, and poor sanitation are major factors in child mortality.
Community-Acquired Methicillin-Resistant
Authors: Cassandra D Salgado, Barry M Farr
Journal: JAMA (2004)

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A viral PAMP double‐stranded RNA induces allergen‐specific Th17 cell response in the airways which is dependent on VEGF and IL‐6
Authors: J.‐P. Choi, Y.‐S. Kim, Y.‐M. Tae, E.‐J. Choi, B.‐S. Hong, S. G. Jeon, Y. S. Gho, Z. Zhu, Y.‐K. Kim
Journal: Allergy (2010)

Innate immune response by a viral pathogen-associated molecular pattern dsRNA modulates the subsequent development of adaptive immune responses. Although virus-associated asthma is characterized by noneosinophilic inflammation, the role of Th17 cell response in the development of virus-associated asthma is still unknown.To evaluate the role of the Th17 cell response and its underlying polarizing mechanisms in the development of an experimental virus-associated asthma.An experimental virus-associated asthma was created via airway sensitization with ovalbumin (OVA, 75 μg) and a low (0.1 μg) or a high (10 μg) doses of synthetic dsRNA [polyinosine-polycytidylic acid; poly(I:C)]. Transgenic (IL-17-, IL-6-deficient mice) and pharmacologic [a vascular endothelial growth factor receptor (VEGFR) inhibitor] approaches were used to evaluate the roles of Th17 cell responses.After cosensitization with OVA and low-dose poly(I:C), but not with high-dose poly(I:C), inflammation scores after allergen challenge were lower in IL-17-deficient mice than in wild-type (WT) mice. Moreover, inflammation enhanced by low-dose poly(I:C), but not by high-dose poly(I:C), was impaired in IL-6-deficient mice; this phenotype was accompanied by the down-regulation of IL-17 production from T cells from both lymph nodes and lung tissues. Airway exposure of low-dose poly(I:C) enhanced the production of VEGF and IL-6, and the production of IL-6 was blocked by treatment with a VEGFR inhibitor (SU5416). Moreover, the allergen-specific Th17 cell response and subsequent inflammation in the low-dose poly(I:C) model were impaired by the VEGFR inhibitor treatment during sensitization.Airway exposure of low-level dsRNA induces an allergen-specific Th17 cell response, which is mainly dependent on VEGF and IL-6.
Prague's health services prepare for Seattle-style riots
Authors: Katka Krosnar
Journal: BMJ (2000)

With fears that Prague could be transformed into a battle ground as up to 50 000 anti-globalisation protesters, as well as 18 000 delegates, descend on the city ahead of next week's International Monetary Fund and World Bank annual meetings, health workers are gearing up for the expected increased demand on medical services.

Accepting that medical services will be more stretched, emergency plans have been updated, annual leave has been cancelled, routine operations have been postponed, and hospital beds have been set aside at the city's state hospitals.

Jaromir Moravek, spokesman for Prague's Motol Teaching Hospital, told the BMJ : “We expect to be much busier than normal. Every hospital department will set aside at least two …
Celecoxib for prevention of sporadic colorectal adenomas: Patient selection to optimize efficacy and safety
Authors: Monica Bertagnolli
Journal: Clinical Cancer Research (2008)

PL06-01   Celecoxib is a selective cyclooxygenase-2 inhibitor used for treatment of severe arthritis and for reduction of colorectal adenoma burden in patients with familial adenomatous polyposis. Recent randomized trials also showed that celecoxib reduced formation of sporadic adenomas in patients at risk for colorectal cancer. The Adenoma Prevention with Celecoxib (APC) Trial randomized 2035 patients to receive either placebo, celecoxib 200 mg bid or celecoxib 400 mg bid for 3 years, with a total observation period of 5 years following randomization. A dose-dependent decrease in sporadic adenoma incidence was observed over the 3-year treatment interval. Celecoxib treatment was also associated with an increased risk of serious cardiovascular events.  The APC Trial prospectively collected data on patient family history, co-morbid conditions, and concomitant medication use. In addition, participants provided blood and tissue specimens for analyses of factors influencing treatment response and toxicity. We hypothesized (prospectively) that celecoxib efficacy would be influenced by patient medical history, with greatest efficacy observed in those at high cancer risk due to the presence of advanced adenomas at baseline. We also predicted (retrospectively) that patients with a baseline history of cardiovascular disease would be more likely to experience cardiovascular adverse events while taking celecoxib.  Genetic variants in the cytochrome p450 2C9 (CYP2C9) enzyme, particularly the I359L allele, are associated with impaired metabolism of celecoxib. Because both efficacy and toxicity of celecoxib were associated with dose in the APC Trial, we hypothesized that these outcomes would also be influenced by CYP2C9 genotype. Specifically, we predicted that APC Trial patients bearing the I359L allele would demonstrate both greater reduction in adenoma incidence and greater risk for cardiovascular toxicity.  Our results showed that treatment with celecoxib is associated with a significant reduction in advanced adenoma incidence during a 3 year treatment interval, with efficacy that persisted over a 5 year total observation period. We also found that dose-related benefits and cardiovascular toxicity of celecoxib appear to be modified by genetic variation in its metabolism.   References  1. Arber N, Kuwada S, Leshno M, Sjodahl R, Hultcrantz R, Rex D. Sporadic adenomatous polyp regression with exisulind is effective but toxic: A randomized, double-blind, placebo controlled, dose-response study. Gut 2006;55:367-73.  2. Bertagnolli MM, Eagle CJ, Zauber AG ,  et al. A randomized trial of celecoxib to prevent sporadic colorectal adenomas. N Engl J Med 2006;355:873-84.  3. Solomon SD, McMurray JJ, Pfeffer MA ,  et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention .  N Engl J Med 2005;352:1071-80.
Abstract 14928: Adverse Outcomes Following Transcatheter Aortic Valve Replacement (TAVR) in Patients with Low Flow-Low Gradient (LFLG) Aortic Stenosis (AS)
Authors: Jay N Patel, Sonya Gadhvi, Michael Salama, Lilana Rios-Rojas, Shahidul Islam, Joseph Mattana, John Goncalves, Richard Schwartz, Kevin Marzo, Abdul M Hafiz
Journal: Circulation (2014)

Introduction: LFLG severe AS (stroke volume index &lt;35 mL/m2 or cardiac index &lt;3.0 L/min/m2 and transvalvular aortic gradient &lt;40 mmHg) is associated with worse clinical outcomes following surgical aortic valve replacement. However, there is paucity of data regarding impact of low left ventricular flow and transvalvular gradient on outcomes following TAVR. We evaluated the impact of baseline LFLG on outcomes following TAVR in patients with severe AS at our institution. Hypothesis: Patients with LFLG severe AS undergoing TAVR will have a higher rate of adverse clinical outcomes. Methods: In a retrospective single center registry, we analyzed the clinical, 2D doppler-echocardiographic and outcome data in consecutive patients who underwent TAVR with the Edwards Sapien transcatheter aortic valve for symptomatic severe AS at our tertiary care hospital from March 2012 to April 2014. Patients with LFLG were compared to non-LFLG patients. Background medical data, clinical endpoints (defined by the Valve Academic Research Consortium-2), length of stay (LOS), readmissions and mortality, were compared between the two groups. Wilcoxon rank-sum and Fisher’s exact tests were used to evaluate the hypothesis. Results: LFLG was found in 66 (32%) out of 206 patients. Baseline characteristics were comparable between the LFLG and non-LFLG group, except significant difference in STS scores (12.1±8 vs. 9.9±8, p=0.011), prior aortic valve surgery (16.7% vs. 6.4%, p=0.041) and atrial fibrillation/flutter (57.6% vs. 29.3% (p&lt;0.001). Overall, peri-procedural complications were similar between both groups, however, LFLG patients required: longer ICU monitoring (113.8±175 vs. 67.3±97 hours, p=0.01), longer hospital LOS (14.2±11.7 vs. 10.5±7.7 days, p=0.032). These patients had a non-significant trend toward 30 day mortality (7.6 vs. 4.3%, p=0.335) but a significantly higher 1-year all-cause mortality (19.7% vs. 9.3% p=0.044). Conclusions: LFLG patients had higher co-morbidities but comparable peri-procedural complications and short-term mortality. However this group was associated with longer hospitalizations and higher 1-year all-cause-mortality following TAVR. Further studies are needed to fully define outcomes in LFLG patients.
Abstract 4221: HSP90 as a therapeutic target in colorectal cancer
Authors: Ganji Purnachandra Nagaraju, Field F. Willingham, Kevin E. Woods, Patrick Sullivan, Jerome C. Landry, Roberto Diaz, Bassel F. El-Rayes
Journal: Cancer Research (2014)

Abstract Purpose/Objectives: Activation of PI3K /Akt/ NF-κB and MAPK signaling pathway contributes to colorectal cancer cell growth, survival and resistance to therapy. HSP90 is required for PI3K/Akt and MAPK stability, folding and trafficking. Ganetespib is a potent functional inhibitor of HSP90 currently under evaluation in clinical trials. We tested the hypothesis that HSP90 functional inhibition by ganetespib can inhibit PI3K/Akt/ NF-κB and MAPK signaling pathways in colorectal cell lines. Methods: Two colorectal cancer (CRC) cell lines were used, HCT-116 and HT-29. Cells were either untreated (control) or treated with ganetespib at 50nM for 24 hours. Western blot and RT-PCR analyses were carried out to determine the effect of ganetespib on protein molecules involved in cell survival and proliferation. Electrophoretic mobility shift assay (EMSA) was performed in CRC cells to evaluate the effects of ganetespib on NF-κB activity. A subcutaneous xenograft mouse model was used to evaluate the in vivo effects of ganetespib. Results: Treatment of HCT-116 and HT-29 CRC cell lines with ganetespib inhibited survival signaling (PI3K/Akt) and proliferative signaling (MAPK) at the transcriptional and translational level. As validation, HSP90 knockdown similarly inhibited PI3K/Akt and MAPK protein and mRNA levels in both cell lines. Functional inhibition of HSP90 resulted in inhibition of PI3K/Akt and MAPK transcription. Functional inhibition or down regulation of HSP90 was associated with inhibition of NF-κB trafficking (downregulation of NF-κB in nucleus). Ganetespib sensitized colon cancer cell lines to the effects of oxaliplatin and 5FU. Similar effects were also observed in tumors from animals treated with ganetespib. Conclusion: In this study, we present in vitro and animal data supporting the targeting of HSP90 as a method to inhibit the PI3K/Akt/ NF-κB and MAPK signaling pathways in colorectal cancer. We demonstrate that inhibition of HSP90 downregulates PI3K/Akt/ NF-κB and MAPK leading to a decrease in colon cancer cell survival and proliferation, as well as sensitization to chemotherapy. Combining HSP90 inhibitors with chemotherapy is a rational approach for future drug development in colorectal cancer. Citation Format: Ganji Purnachandra Nagaraju, Field F. Willingham, Kevin E. Woods, Patrick Sullivan, Jerome C. Landry, Roberto Diaz, Bassel F. El-Rayes. HSP90 as a therapeutic target in colorectal cancer. [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 4221. doi:10.1158/1538-7445.AM2014-4221
Science, medicine, and the future: The search for an HIV vaccine
Authors: M. W. Makgoba
Journal: BMJ (2002)

See also Education and debate p 226 

HIV infections and deaths from AIDS continue to ravage many countries around the world, with most infected people living in the poorest nations.1 In terms of morbidity and mortality, the HIV/AIDS pandemic is worse than the Black Death of the 14th century. The search for an HIV vaccine was seen as the logical solution to the burgeoning epidemic soon after the discovery of HIV, but early enthusiasm became muted as the realities of the challenge became evident.2–4

Nevertheless, there are scientific reasons why there is hope that an HIV vaccine will ultimately be developed. Firstly, studies of non-human primates that were given candidate vaccines based on HIV or SIV (simian immunodeficiency virus) have shown either complete or partial protection against infection with the wild type virus. 5 6 Secondly, successful vaccines have been developed against other retroviruses.7 Thirdly, almost all humans develop some form of immune response to HIV infection, with some exposed people remaining uninfected or developing immune responses that are protective or that are able to control the viral infection over long periods.8 Some people have remained free of disease for up to 20 years, often with undetectable viral loads. 9 10 A group of sex workers from Nairobi and South Africa has remained HIV negative despite continuing high risk exposure; resistance to HIV infection in these people is thought to be due to their ability to mount protective immune responses to HIV, rather than to any innate host genetic factors. 11 12 This group has provided insights into strategies for developing a vaccine.

#### Potential developments

An effective, affordable, and accessible HIV vaccine is within reach

Equitable public-private partnerships between researchers, manufacturers, and distributors and partnerships between rich and poor countries are the best strategy for the …
Abstract 837: A Novel -1364A/C Aquaporin 5 Gene Promoter Polymorphism Influences the Regulation of the Renin-Angiotensin-Aldosterone System in Young Healthy Men and Individuals with Coronary Artery Disease
Authors: Michael Adamzik, Ulrich Frey, Roland Schmieder, Gerd Heusch, Juergen Peters, Winfried Siffert
Journal: Circulation (2008)

Background: The family of aquaporin water channels contributes to water and salt homeostasis. AQP5 is an ubiquitously expressed exocrine-type water channel. Functional single nucleotide polymorphisms in AQP5 which alter gene transcription have not yet been described. We, therefore, sequenced the human AQP5 promoter to detect novel sequence variants which could impact upon AQP5 expression and contribute to the phenotypic variability of the renin-angiotensin-aldosterone system (RAAS). Method and Results : Sequencing of the whole AQP5 promoter revealed a novel -1364A/C polymorphism. Substitution of C for A was associated with increased transcription factor binding as tested by electrophoretic mobility shift assay, but significantly reduced transcriptional activation of the AQP5 gene by cAMP and serum. The C allele was associated with significantly decreased mRNA in human heart and with decreased protein expression in erythrocyte membranes. Finally, we investigated the phenotypic variability of the RAAS in two different independent study cohorts. First, we studied the phenotypic variability of the RAAS in 103 young (26 ± 3 years) healthy males under an increased salt diet. Increasing dietary salt intake decreased plasma angiotensin II by 25% in AC/CC genotypes but only by 2% in AA genotypes (p=0.012), and decreased serum aldosterone by 34% in subjects with AC/CC genotypes but only by 19% in the AA genotypes (p =0.005). Both genotypes had increased blood pressure under salt diet (p&lt;0.01), which was significantly more pronounced in AA genotypes (p =0.029). Second, we investigated associations with the phenotypic variability of the RAAS in 96 old patients (68 ± 10 years) with coronary artery disease scheduled for coronary artery bypass grafting. ADH plasma concentrations did not differ between genotypes. However, aldosteron serum concentrations were 2-fold (p&lt;0.001) and angiotensin II plasma concentrations were 4-fold higher in AA genotypes in comparison to the AC/CC genotypes. Conclusion: A novel single nucleotide polymorphism in the AQP5 gene promoter evokes an alteration of both AQP5 expression in different in vitro systems and cells, and the regulation of the Renin-Angiotensin-Aldosterone System.
Case Presentations in Clinical Tuberculosis
Authors: P. D. O. Davies, L. P. Ormerod
Journal: Thorax (2000)

The spectrum of nitrofurantoin lung injury continues to widen.The case histories are presented of two patients who developed lung disease associated with the use of nitrofurantoin with histological features of bronchiolitis obliterans organising pneumonia (BOOP), a rare but recognised form of drug induced injury.The two middle aged women presented with respiratory symptoms after prolonged treatment with nitrofurantoin.Both had impaired lung function and abnormal computed tomographic scans, and their condition improved when nitrofurantoin was withdrawn and corticosteroid treatment commenced.The favourable outcome in these two patients contrasts with the fatal outcome of the two other reported cases of nitrofurantoin induced BOOP.We suggest that the previous classification of nitrofurantoin induced lung injury into "acute" and "chronic" injury is an oversimplification in view of the wide variety of pathological entities that have subsequently emerged.
Abstract 19265: Adipose Tissue Overexpression of a Constitutively Active Isoform of Chrebp Protects Against Obesity and Insulin Resistance in Mice
Authors: Alli Nuotio-Antar, Naravat Poungvarin, Ming Li, Lawrence Chan
Journal: Circulation (2012)

Obesity is associated with increased risk for T2DM and CVD in humans, and nutrients typically consumed in excess in the Western diet, such as various saturated fats, cholesterol, and simple sugars, are thought to regulate the activity of metabolic genes that modulate risk for obesity and insulin resistance. The glucose-sensing transcription factor carbohydrate response element binding protein (ChREBP) has been shown to regulate hepatic intracellular glucose and lipid homeostasis independent of the effects of insulin. Recent publications have reported that white adipose tissue (WAT) and brown adipose tissue (BAT) depots also highly express ChREBP, that ChREBP expression is upregulated during adipocyte differentiation, and that increased ChREBP activation in adipocytes is associated with obesity, but not insulin resistance, in the context of adipose tissue-specific GLUT4 overexpression in mice. However, independent modulation of ChREBP expression in adipose tissue has not yet been achieved. To better understand the impact of adipocyte-specific ChREBP activity on intracellular and whole-body metabolism, we have generated a novel transgenic mouse model that overexpresses a constitutively active ChREBP (caChREBP) isoform in adipose tissue (ap2-Cre;eGFPflox-caChREBP mice). When fed either standard chow diet or Western-type diet (WD) for 10 weeks, total fat mass, but not lean mass, was significantly decreased in male ap2-Cre;eGFPflox-caChREBP mice versus ap2-Cre littermate controls. Both glucose tolerance testing and insulin tolerance testing revealed no differences between groups of chow-fed mice, but significantly improved insulin sensitivity in WD-fed male ap2-Cre;eGFPflox-caChREBP mice. RER during the daily active cycle was increased in WD-fed ap2-Cre;eGFPflox-caChREBP mice, implying greater utilization of carbohydrate for energy expenditure. Transgenic overexpression of caChREBP resulted in increased expression of lipogenic genes, but not genes involved in adipocyte differentiation, in gonadal fat. Taken together, these data indicate that upregulation of ChREBP activity in adipose tissue may defend against WD-induced obesity and insulin resistance, despite increased adipocyte expression of lipogenic genes.