tbuckley/cabot-search huggingface dataset:
VR23: A Quinoline–Sulfonyl Hybrid Proteasome Inhibitor That Selectively Kills Cancer via Cyclin E–Mediated Centrosome Amplification
Authors: Sheetal Pundir, Hai-Yen Vu, V. Raja Solomon, Rebecca McClure, Hoyun Lee
Journal: Cancer Research (2015)

The proteasome is clinically validated as a target for cancer therapeutics. However, proteasome-inhibitory agents that are cancer selective have yet to be developed. In this study, we report the identification of a safe and effective proteasome inhibitor with selective anticancer properties. We screened a chemical library constructed using a hybrid approach that incorporated a 4-piperazinylquinoline scaffold and a sulfonyl phamarcophore. From this library, we identified 7-chloro-4-(4-(2,4-dinitrophenylsulfonyl)piperazin-1-yl)quinoline (VR23) as a small molecule that potently inhibited the activities of trypsin-like proteasomes (IC50 = 1 nmol/L), chymotrypsin-like proteasomes (IC50 = 50-100 nmol/L), and caspase-like proteasomes (IC50 = 3 μmol/L). Data from molecular docking and substrate competition assays established that the primary molecular target of VR23 was β2 of the 20S proteasome catalytic subunit. Notably, VR23 was structurally distinct from other known proteasome inhibitors and selectively killed cancer cells by apoptosis, with little effect on noncancerous cells. Mechanistic investigations showed that cancer cells exposed to VR23 underwent an abnormal centrosome amplification cycle caused by the accumulation of ubiquitinated cyclin E. In combinations with the clinically approved chymotrypsin-like proteasome inhibitor bortezomib, VR23 produced a synergistic effect in killing multiple myeloma cells, including those that were resistant to bortezomib. VR23 was effective in vivo in controlling multiple myelomas and metastatic breast cancer cells, in the latter case also enhancing the antitumor activity of paclitaxel while reducing its side effects. Overall, our results identify VR23 as a structurally novel proteasome inhibitor with desirable properties as an anticancer agent.
Responsibility deal for alcohol has failed, says report
Authors: J. Wise
Journal: BMJ (2015)

A highly critical report by the Institute of Alcohol Studies has said that the UK government’s public health “responsibility deal” on alcohol has been a failure and has actually worsened the nation’s health.1

The responsibility deal for alcohol, launched in 2011, relies on voluntary action by alcohol firms to tackle drink related harm. Despite being designed as a partnership, most public health organisations, including the Royal College of Physicians and the BMA, rejected the deal.2 Its current status is uncertain, as its alcohol network has not met in over a year, and the government has not explicitly committed itself to its renewal since the general election in May.

The new report said that the responsibility deal had pursued …
A Partisan Assault on Science — The Threat to the CDC
Authors: Jerome P. Kassirer
Journal: New England Journal of Medicine (1995)

One of the agencies singled out for elimination in the recent spate of Congressional budget cutting was the National Center for Injury Prevention and Control (NCIPC), a part of the Centers for Disease Control and Prevention (CDC).1 Given the wide swath of the cuts under consideration, perhaps this relatively new center was just one more to get in the way of the congressional scythes. Yet, there is reason to believe that the NCIPC, which conducts and supports research on injury, was far more selectively targeted.Ten years ago an Institute of Medicine report cited injuries as a critical threat to . . .
Characterization of DNA Demethylation Effects Induced by 5-Aza-2′-Deoxycytidine in Patients with Myelodysplastic Syndrome
Authors: Cora Mund, Björn Hackanson, Carlo Stresemann, Michael Lübbert, Frank Lyko
Journal: Cancer Research (2005)

Azanucleoside drugs such as 5-azacytidine (Vidaza) and 5-aza-2'-deoxycytidine (decitabine, Dacogen) function as DNA methyltransferase inhibitors in vitro and represent promising new drugs for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia. In this study, we aimed to determine the effect of decitabine on the genomic methylation level in MDS patients. Comparison of different assays established micellar electrokinetic chromatography as a reliable method for the analysis of genomic methylation levels. When used for the determination of DNA methylation levels in bone marrow DNA from MDS patients during various time points of decitabine treatment, the results revealed a significant (up to 70%) demethylation in five of seven patients. Interestingly, genome-wide demethylation appeared after karyotype normalization, which suggests demethylation of nonclonal cells. Drug-induced demethylation dynamics were also confirmed by bisulfite sequencing of pericentromeric satellite elements. Our results are the first to show a genome-wide demethylating activity of decitabine in tumor material. In addition, our data uncovers novel targets of decitabine-mediated demethylation that are important for the refinement of treatment schedules with demethylating drugs.
Visfatin (pre-B cell colony-enhancing factor) gene expression in patients with rheumatoid arthritis: Figure 1
Authors: H Matsui, A Tsutsumi, M Sugihara, T Suzuki, K Iwanami, M Kohno, D Goto, I Matsumoto, S Ito, T Sumida
Journal: Annals of the Rheumatic Diseases (2008)

Visfatin, also known as pre-B cell colony enhancing factor, is a cytokine-like protein originally cloned from peripheral blood mononuclear cells (PBMC) as a factor that enhances differentiation of pre-B cells in synergy with interleukin 7 (IL-)7 and stem cell factor.1 Visfatin is mainly produced in visceral white adipose tissues, and shows an insulin-like effect by binding to insulin receptors.2 Generally, visfatin is regarded as an adipokine, and elevated levels of serum visfatin in patients with type 2 diabetes,3 and obesity,4 have been reported. Interestingly, in visceral adipose tissues, macrophages seem to be the major source …
MET Is a Potential Target across All Papillary Renal Cell Carcinomas: Result from a Large Molecular Study of pRCC with CGH Array and Matching Gene Expression Array
Authors: Laurence Albiges, Justine Guegan, Audrey Le Formal, Virginie Verkarre, Nathalie Rioux-Leclercq, Mathilde Sibony, Jean-Christophe Bernhard, Philippe Camparo, Zahira Merabet, Vincent Molinie, Yves Allory, Cedric Orear, Sophie Couvé, Sophie Gad, Jean-Jacques Patard, Bernard Escudier
Journal: Clinical Cancer Research (2014)

Papillary renal cell carcinomas (pRCC) are the most common nonclear cell RCC subtype. Germline mutations of the MET oncogene at 7q31 have been detected in patients with hereditary type I pRCC and in 13% of sporadic type I pRCC. Recent report of MET inhibition strengthened the role of c-Met inhibition across pRCC.We collected 220 frozen samples of sporadic pRCC through the French RCC Network and quality controlled for percentage of malignant cells >70%. Gene expression was assessed on 98 pRCC using human whole-genome Agilent 8 × 60K arrays. Copy number alterations were analyzed using Agilent Human 2 × 400K and 4× 180K array for type II pRCC and comparative genomic microarray analysis method for type I pRCC. MET gene sequencing was performed on type I pRCC.MET expression level was high across all pRCC. We identified copy number alterations (gain) in 46% of type II pRCC and in 81% of type I pRCC. Correlation between DNA copy number alterations and mRNA expression level was highly significant. Eleven somatic mutations of MET gene were identified amongst 51 type I pRCC (21.6%), including 4 new mutations. We validated LRRK2 cokinase as highly correlated to MET expression.The present report expands the role of MET activation as a potential target across all pRCC subtypes. These data support investigating MET inhibitors in pRCC in correlation with MET activation status.
Prevention of Aromatase Inhibitor–Induced Bone Loss Using Risedronate: The SABRE Trial
Authors: Catherine Van Poznak, Rosemary A. Hannon, John R. Mackey, Mario Campone, Justus P. Apffelstaedt, Glen Clack, David Barlow, Andreas Makris, Richard Eastell
Journal: Journal of Clinical Oncology (2010)

Purpose To investigate the management of bone health in women with early breast cancer (EBC) who were scheduled to receive anastrozole. Patients and Methods Postmenopausal women with hormone receptor–positive EBC were assigned to one of three strata by risk of fragility fracture. Patients with the highest risk (H) received anastrozole 1 mg/d plus risedronate 35 mg/wk orally. Patients with moderate-risk (M) were randomly assigned in a double-blind manner to anastrozole and risedronate (A + R) or to anastrozole and placebo (A + P). Patients with lower-risk (L) received anastrozole (A) alone. Calcium and vitamin D were recommended for all patients. Lumbar spine and total hip bone mineral density (BMD) were assessed at baseline, 12 months, and 24 months. Results At 24 months, in the M group, treatment with A + R resulted in a significant increase in lumbar spine and total hip BMD compared with A + P treatment (2.2% v −1.8%; treatment ratio, 1.04; P &lt; .0001; and 1.8% v −1.1%; treatment ratio, 1.03; P &lt; .0001, respectively). In the H stratum, lumbar spine and total hip BMD increased significantly (3.0%; P = .0006; and 2.0%; P = .0104, respectively). Patients in the L stratum showed a significant decrease in lumbar spine BMD (−2.1%; P = .0109) and a numerical decrease in total hip BMD (−0.4%; P = .5988). Safety profiles for anastrozole and risedronate were similar to those already established. Conclusion In postmenopausal women at risk of fragility fracture who were receiving adjuvant anastrozole for EBC, the addition of risedronate at doses established for preventing and treating osteoporosis resulted in favorable effects in BMD during 24 months.
Oncogenic Role of MPHOSPH1, a Cancer-Testis Antigen Specific to Human Bladder Cancer
Authors: Mitsugu Kanehira, Toyomasa Katagiri, Arata Shimo, Ryo Takata, Taro Shuin, Tsuneharu Miki, Tomoaki Fujioka, Yusuke Nakamura
Journal: Cancer Research (2007)

Abstract To disclose the molecular mechanism of bladder cancer, the second most common genitourinary tumor, we had previously done genome-wide expression profile analysis of 26 bladder cancers by means of cDNA microarray representing 27,648 genes. Among genes that were significantly up-regulated in the majority of bladder cancers, we here report identification of M-phase phosphoprotein 1 (MPHOSPH1) as a candidate molecule for drug development for bladder cancer. Northern blot analyses using mRNAs of normal human organs and cancer cell lines indicated this molecule to be a novel cancer-testis antigen. Introduction of MPHOSPH1 into NIH3T3 cells significantly enhanced cell growth at in vitro and in vivo conditions. We subsequently found an interaction between MPHOSPH1 and protein regulator of cytokinesis 1 (PRC1), which was also up-regulated in bladder cancer cells. Immunocytochemical analysis revealed colocalization of endogenous MPHOSPH1 and PRC1 proteins in bladder cancer cells. Interestingly, knockdown of either MPHOSPH1 or PRC1 expression with specific small interfering RNAs caused a significant increase of multinuclear cells and subsequent cell death of bladder cancer cells. Our results imply that the MPHOSPH1/PRC1 complex is likely to play a crucial role in bladder carcinogenesis and that inhibition of the MPHOSPH1/PRC1 expression or their interaction should be novel therapeutic targets for bladder cancers. [Cancer Res 2007;67(7):3276–85]
Hyperbaric oxygenation upregulates rat lung Na,K-ATPase
Authors: ZL Harris, KM Ridge, B Gonzalez-Flecha, L Gottlieb, A Zucker, JI Sznajder
Journal: European Respiratory Journal (1996)

Exposure of rats to hyperoxia is associated with increased active Na+ transport in rat lungs and increased Na,K-adenosine triphosphate (ATPase) expression in alveolar epithelial cells. Hyperbaric oxygenation (HBO) has been reported to act as an accelerated model of hyperoxic cell damage. Sublethal and intermittent exposure to HBO, however, has been suggested to upregulate endogenous protective mechanisms. In the present study, we tested whether short-term HBO, prior to inducing lung injury, would upregulate lung Na,K-ATPase. The results show that HBO, either intermittent or single 2.5 h exposure, increased lung Na,K-ATPase alpha-1 and beta-1 messenger ribonucleic acid (mRNA) transcript levels up to fourfold. Na,K-ATPase activity in lungs of rats exposed to HBO increased twofold during the first 2 h following removal from the hyperbaric chamber, and remained elevated for up to 6 h following HBO. Conceivably, the increase in Na,K-ATPase activity following HBO is due to an increase in activity from a basal to a higher rate, or possibly due to recruitment/translocation of Na,K-ATPases from inner membranes to the plasma membrane.
Group B streptococcal β-hemolysin/cytolysin activates neutrophil signaling pathways in brain endothelium and contributes to development of meningitis
Authors: Kelly S. Doran, George Y. Liu, Victor Nizet
Journal: Journal of Clinical Investigation (2003)

Meningitis occurs when blood-borne pathogens cross the blood-brain barrier (BBB) in a complex interplay between endothelial cells and microbial gene products. We sought to understand the initial response of the BBB to the human meningeal pathogen group B Streptococcus (GBS) and the organism’s major virulence factors, the exopolysaccharide capsule and the β-hemolysin/cytolysin toxin (β-h/c). Using oligonucleotide microarrays, we found that GBS infection of human brain microvascular endothelial cells (HBMEC) induced a highly specific and coordinate set of genes including IL-8, Groα, Groβ, IL-6, GM-CSF, myeloid cell leukemia sequence-1 (Mcl-1), and ICAM-1, which act to orchestrate neutrophil recruitment, activation, and enhanced survival. Most strikingly, infection with a GBS strain lacking β-h/c resulted in a marked reduction in expression of genes involved in the immune response, while the unencapsulated strain generally induced similar or greater expression levels for the same subset of genes. Cell-free bacterial supernatants containing β-h/c activity induced IL-8 release, identifying this toxin as a principal provocative factor for BBB activation. These findings were further substantiated in vitro and in vivo. Neutrophil migration across polar HBMEC monolayers was stimulated by GBS and its β-h/c through a process involving IL-8 and ICAM-1. In a murine model of hematogenous meningitis, mice infected with β-h/c mutants exhibited lower mortality and decreased brain bacterial counts compared with mice infected with the corresponding WT GBS strains.
Spontaneous rupture of an intercostal artery aneurysm during air flight
Authors: S Y Sundram-Novelend, D S Appleton, N J Screaton, R J Davies, E R Chilvers
Journal: Thorax (2008)

Pleural haematoma secondary to spontaneous rupture of an intercostal artery aneurysm is extremely rare but can be life-threatening. Most documented cases have been associated with coarctation of the aorta or neurofibromatosis type 1,1 or occur following trauma …
Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK
Authors: Eszter Doma, Christian Rupp, Andrea Varga, Florian Kern, Bettina Riegler, Manuela Baccarini
Journal: Cancer Research (2013)

RAF inhibitors achieve unprecedented but mainly transient clinical responses in patients with melanoma whose tumors harbor an activating BRAF mutation. One notable side-effect of RAF inhibitors is the stimulation of cutaneous skin tumors, arising in about 30% of patients receiving these drugs, which are thought to develop as a result of inhibitor-induced activation of wild-type Raf in occult precursor skin lesions. This effect raises the possibility that less manageable tumors might also arise in other epithelial tissues. Here we provide preclinical evidence supporting this disquieting hypothesis by showing that the RAF inhibitors PLX-4032 (vemurafenib) and GDC-0879 precipitate the development of cell-autonomous, Ras-driven tumors in skin and gastric epithelia. The magnitude of the effects correlated with the inhibitors' relative abilities to induce ERK activation. Epidermis-restricted ablation of either B-Raf or C-Raf prevented PLX-4032-induced ERK activation and tumorigenesis. In contrast, GDC-0879 induced ERK activation and tumorigenesis in B-Raf-deficient epidermis, whereas C-Raf ablation blocked GDC-0879-induced tumorigenesis (despite strong ERK activation) by preventing Rokα-mediated keratinocyte dedifferentiation. Thus, inhibitor-induced ERK activation did not require a specific Raf kinase. ERK activation was necessary, but not sufficient for Ras + Raf inhibitor-induced tumorigenesis, whereas C-Raf downregulation of Rokα was essential even in the face of sustained ERK signaling to prevent differentiation and promote tumorigenesis. Taken together, our findings suggest that combination therapies targeting ERK-dependent and -independent functions of Raf may be more efficient but also safer for cancer treatment.
Lysosomal β-glucuronidase regulates Lyme and rheumatoid arthritis severity
Authors: Kenneth K.C. Bramwell, Ying Ma, John H. Weis, Xinjian Chen, James F. Zachary, Cory Teuscher, Janis J. Weis
Journal: Journal of Clinical Investigation (2013)

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent arthropod-borne illness in the United States and remains a clinical and social challenge. The spectrum of disease severity among infected patients suggests that host genetics contribute to pathogenic outcomes, particularly in patients who develop arthritis. Using a forward genetics approach, we identified the lysosomal enzyme β-glucuronidase (GUSB), a member of a large family of coregulated lysosomal enzymes, as a key regulator of Lyme-associated arthritis severity. Severely arthritic C3H mice possessed a naturally occurring hypomorphic allele, Gusbh. C57BL/6 mice congenic for the C3H Gusb allele were prone to increased Lyme-associated arthritis severity. Radiation chimera experiments revealed that resident joint cells drive arthritis susceptibility. C3H mice expressing WT Gusb as a transgene were protected from severe Lyme arthritis. Importantly, the Gusbh allele also exacerbated disease in a serum transfer model of rheumatoid arthritis. A known GUSB function is the prevention of lysosomal accumulation of glycosaminoglycans (GAGs). Development of Lyme and rheumatoid arthritis in Gusbh-expressing mice was associated with heightened accumulation of GAGs in joint tissue. We propose that GUSB modulates arthritis pathogenesis by preventing accumulation of proinflammatory GAGs within inflamed joint tissue, a trait that may be shared by other lysosomal exoglycosidases.
Bronchial and Arterial Anomalies with Drainage of the Right Lung into the Inferior Vena Cava
Authors: NICHOLAS A. HALASZ, KATHERINE H. HALLORAN, AVERILL A. LIEBOW
Journal: Circulation (1956)

Three cases of anomalous pulmonary venous return to the inferior vena cava are presented and 18 previously reported cases are also analyzed. The clinical, radiographic, circulatory and pulmonary function, and anatomic features are carefully detailed. In particular, associated vascular and bronchial anomalies in the lungs were found by preparation of vinylite casts of the pulmonary vessels and bronchial casts; they are of great significance in planning and executing surgical therapy.
Inspiratory flow limitation during sleep in pre-eclampsia: comparison with normal pregnant and nonpregnant women
Authors: G. Connolly, A.R.A. Razak, A. Hayanga, A. Russell, P. McKenna, W.T. McNicholas
Journal: European Respiratory Journal (2001)

Self-reported snoring is common in pregnancy, particularly in females with pre-eclampsia. The prevalence of inspiratory flow limitation during sleep in pre-eclamptic females was objectively assessed and compared with normal pregnant and nonpregnant females. Fifteen females with pre-eclampsia were compared to 15 females from each of the three trimesters of pregnancy, as well as to 15 matched nonpregnant control females (total study population, 75 subjects). All subjects had overnight monitoring of respiration, oxygen saturation, and blood pressure (BP). No group had evidence of a clinically significant sleep apnoea syndrome, but patients with pre-eclampsia spent substantially more time (31±8.4% of sleep period time, mean±sd) with evidence of inspiratory flow limitation compared to 15.5±2.3% in third trimester subjects and &lt;5% in the other three groups (p=0.001). In the majority of pre-eclamptics, the pattern of flow limitation was of prolonged episodes lasting several minutes without associated oxygen desaturation. As expected, systolic and diastolic BPs were significantly higher in the pre-eclamptic group (p&lt;0.001), but all groups showed a significant fall (p≤0.05) in BP during sleep. Inspiratory flow limitation is common during sleep in patients with pre-eclampsia, which may have implications for the pathophysiology and treatment of this disorder.
Trauma Exposure and Posttraumatic Stress Disorder Symptoms Predict Onset of Cardiovascular Events in Women
Authors: Jennifer A. Sumner, Laura D. Kubzansky, Mitchell S.V. Elkind, Andrea L. Roberts, Jessica Agnew-Blais, Qixuan Chen, Magdalena Cerdá, Kathryn M. Rexrode, Janet W. Rich-Edwards, Donna Spiegelman, Shakira F. Suglia, Eric B. Rimm, Karestan C. Koenen
Journal: Circulation (2015)

Background— Psychological stress is a proposed risk factor for cardiovascular disease (CVD), and posttraumatic stress disorder (PTSD), the sentinel stress-related mental disorder, occurs twice as frequently in women as men. However, whether PTSD contributes to CVD risk in women is not established. Methods and Results— We examined trauma exposure and PTSD symptoms in relation to incident CVD over a 20-year period in 49 978 women in the Nurses’ Health Study II. Proportional hazards models estimated hazard ratios and 95% confidence intervals for CVD events confirmed by additional information or medical record review (n=548, including myocardial infarction [n=277] and stroke [n=271]). Trauma exposure and PTSD symptoms were assessed by using the Brief Trauma Questionnaire and a PTSD screen. In comparison with no trauma exposure, endorsing ≥4 PTSD symptoms was associated with increased CVD risk after adjusting for age, family history, and childhood factors (hazard ratio,1.60; 95% confidence interval, 1.20–2.13). Being trauma-exposed and endorsing no PTSD symptoms was associated with elevated CVD risk (hazard ratio, 1.45; 95% confidence interval, 1.15–1.83), although being trauma-exposed and endorsing 1 to 3 PTSD symptoms was not. After adjusting for adult health behaviors and medical risk factors, this pattern of findings was maintained. Health behaviors and medical risk factors accounted for 14% of the trauma/no symptoms–CVD association and 47% of the trauma/4+ symptoms–CVD association. Conclusion— Trauma exposure and elevated PTSD symptoms may increase the risk of CVD in this population of women. These findings suggest that screening for CVD risk and reducing health risk behaviors in trauma-exposed women may be promising avenues for prevention and intervention.