tbuckley/cabot-search huggingface dataset:
Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy
Authors: Sherif Daouti, Huisheng Wang, Wen-hui Li, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, Anthony Specian, Norman Kong, Nicholas Huby, Yang Wen, Qing Xiang, Frank J. Podlaski, Yang He, Nader Fotouhi, David Heimbrook, Huifeng Niu
Journal: Cancer Research (2009)

Abstract The mitogen-activated protein kinase (MAPK) signal transduction pathway plays a central role in regulating tumor cell growth, survival, differentiation, and angiogenesis. The key components of the Ras/Raf/MEK/ERK signal module are frequently altered in human cancers. Targeting this pathway represents a promising anticancer strategy. Small molecule inhibitors targeting MEK1/2 have shown promise in the clinic; however, ultimate clinical proof-of-concept remains elusive. Here, we report a potent and highly selective non–ATP-competitive MEK1/2 inhibitor, RO4927350, with a novel chemical structure and unique mechanism of action. It selectively blocks the MAPK pathway signaling both in vitro and in vivo, which results in significant antitumor efficacy in a broad spectrum of tumor models. Compared with previously reported MEK inhibitors, RO4927350 inhibits not only ERK1/2 but also MEK1/2 phosphorylation. In cancer cells, high basal levels of phospho-MEK1/2 rather than phospho-ERK1/2 seem to correlate with greater sensitivity to RO4927350. Furthermore, RO4927350 prevents a feedback increase in MEK phosphorylation, which has been observed with other MEK inhibitors. We show that B-Raf rather than C-Raf plays a critical role in the feedback regulation. The unique MAPK signaling blockade mediated by RO4927350 in cancer may reduce the risk of developing drug resistance. Thus, RO4927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation. [Cancer Res 2009;69(5):1924–32
A Prospective Study of Triglyceride Level, Low-Density Lipoprotein Particle Diameter, and Risk of Myocardial Infarction
Authors: Meir J. Stampfer
Journal: JAMA (1996)

To test whether a predominance of small, dense low-density lipoprotein (LDL) particles and elevated triglyceride levels are independent risk factors for myocardial infarction (MI).Nested case-control study with prospectively collected samples.Prospective cohort study.Blood samples were collected at baseline (85% nonfasting samples) from 14916 men aged 40 to 84 years in the Physicians' Health Study.Myocardial infarction diagnosed during 7 years of follow-up.Cases (n=266) had a significantly smaller LDL diameter (mean [SD], 25.6 [0.9] nm) than did controls (n=308) matched on age and smoking (mean [SD], 25.9 [8] nm; P<.001). Cases also had higher median triglyceride levels (1.90 vs 1.49 mmol/L [168 vs 132 mg/dL]; P<.001). The LDL diameter had a high inverse correlation with triglyceride level (r=-0.71), and a high direct correlation with high-density lipoprotein cholesterol (HDL-C) level (r=0.60). We observed a significant multiplicative interaction between triglyceride and total cholesterol (TC) levels (P=.01). After simultaneous adjustment for lipids and a variety of coronary risk factors, LDL particle diameter was no longer a statistically significant risk indicator, with a relative risk (RR) of 1.09 (95% confidence interval [CI], 0.85-1.40) per 0.8-nm decrease. However, triglyceride level remained significant with an RR of 1.40 (95% CI, 1.10-1.77) per 1.13 mmol/L (100-mg/dL) increase. The association between triglyceride level and MI risk appeared linear across the distribution; men in the highest quintile had a risk about 2.5 times that of those in the lowest quintile. The TC level, but not HDL-C level, also remained significant, with an RR of 1.80 (95% CI, 1.44-2.26) per 1.03-mmol/L (40-mg/dL) increase.These findings indicate that nonfasting triglyceride levels appear to be a strong and independent predictor of future risk of MI, particularly when the total cholesterol level is also elevated. In contrast, LDL particle diameter is associated with risk of MI, but not after adjustment for triglyceride level. Increased triglyceride level, small LDL particle diameter, and decreased HDL-C levels appear to reflect underlying metabolic perturbations with adverse consequences for risk of MI; elevated triglyceride levels may help identify high-risk individuals.
Sutures versus staples for skin closure in orthopaedic surgery: meta-analysis
Authors: T. O Smith, D. Sexton, C. Mann, S. Donell
Journal: BMJ (2010)

<b>Objective</b> To compare the clinical outcomes of staples versus sutures in wound closure after orthopaedic surgery. <b>Design</b> Meta-analysis. <b>Data sources</b> Medline, CINAHL, AMED, Embase, Scopus, and the Cochrane Library databases were searched, in addition to the grey literature, in all languages from 1950 to September 2009. Additional studies were identified from cited references. <b>Selection criteria</b> Two authors independently assessed papers for eligibility. Included studies were randomised and non-randomised controlled trials that compared the use of staples with suture material for wound closure after orthopaedic surgery procedures. All studies were included, and publications were not excluded because of poor methodological quality. <b>Review methods</b> Two authors independently reviewed studies for methodological quality and extracted data from each paper. Final data for analysis were collated through consensus. The primary outcome measure was the assessment of superficial wound infection after wound closure with staples compared with sutures. Relative risk and mean difference with 95% confidence intervals were calculated and pooled with a random effects model. Heterogeneity was assessed with I<sup>2</sup> and χ<sup>2</sup> statistical test. <b>Results</b> Six papers, which included 683 wounds, were identified; 332 patients underwent suture closure and 351 staple closure. The risk of developing a superficial wound infection after orthopaedic procedures was over three times greater after staple closure than suture closure (relative risk 3.83, 95% confidence interval 1.38 to 10.68; P=0.01). On subgroup analysis of hip surgery alone, the risk of developing a wound infection was four times greater after staple closure than suture closure (4.79, 1.24 to 18.47; P=0.02). There was no significant difference between sutures and staples in the development of inflammation, discharge, dehiscence, necrosis, and allergic reaction. The included studies had several major methodological limitations, including the recruitment of small, underpowered cohorts, poorly randomising patients, and not blinding assessors to the allocated methods of wound closure. Only one study had acceptable methodological quality. <b>Conclusions</b> After orthopaedic surgery, there is a significantly higher risk of developing a wound infection when the wound is closed with staples rather than sutures. This risk is specifically greater in patients who undergo hip surgery. The use of staples for closing hip or knee surgery wounds after orthopaedic procedures cannot be recommended, though the evidence comes from studies with substantial methodological limitations. Though we advise orthopaedic surgeons to reconsider their use of staples for wound closure, definitive randomised trials are still needed to assess this research question.
Early Events in T-Cell Maturation
Authors: B Adkins, C Mueller, C Y Okada, R A Reichert, I L Weissman, G J Spangrude
Journal: Annual Review of Immunology (1987)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
The Role of Recombination Activating Gene (<i>RAG</i>) Reinduction in Thymocyte Development in Vivo
Authors: Nikos Yannoutsos, Patrick Wilson, Wong Yu, Hua Tang Chen, Andre Nussenzweig, Howard Petrie, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2001)

Assembly of T cell receptor (TCR)α/β genes by variable/diversity/joining (V[D]J) rearrangement is an ordered process beginning with recombination activating gene (RAG) expression and TCRβ recombination in CD4−CD8−CD25+ thymocytes. In these cells, TCRβ expression leads to clonal expansion, RAG downregulation, and TCRβ allelic exclusion. At the subsequent CD4+CD8+ stage, RAG expression is reinduced and V(D)J recombination is initiated at the TCRα locus. This second wave of RAG expression is terminated upon expression of a positively selected α/β TCR. To examine the physiologic role of the second wave of RAG expression, we analyzed mice that cannot reinduce RAG expression in CD4+CD8+ T cells because the transgenic locus that directs RAG1 and RAG2 expression in these mice is missing a distal regulatory element essential for reinduction. In the absence of RAG reinduction we find normal numbers of CD4+CD8+ cells but a 50–70% reduction in the number of mature CD4+CD8− and CD4−CD8+ thymocytes. TCRα rearrangement is restricted to the 5′ end of the Jα cluster and there is little apparent secondary TCRα recombination. Comparison of the TCRα genes expressed in wild-type or mutant mice shows that 65% of all α/β T cells carry receptors that are normally assembled by secondary TCRα rearrangement. We conclude that RAG reinduction in CD4+CD8+ thymocytes is not required for initial TCRα recombination but is essential for secondary TCRα recombination and that the majority of TCRα chains expressed in mature T cells are products of secondary recombination.
Heat Shock Protein 90 Regulates the Metaphase-Anaphase Transition in a Polo-Like Kinase-Dependent Manner
Authors: Guillermo de Cárcer
Journal: Cancer Research (2004)

Abstract We have shown previously that the molecular chaperone heat shock protein 90 (Hsp90) is required for a proper centrosome function. Indeed, this Hsp90 function seems to be reflected in Polo-like kinase stability. Inhibition of Hsp90 in HeLa cells results in cell cycle arrest either in G2 stage or at the metaphase-anaphase transition. Here, we show that this inhibition leads to inactivation of the anaphase-promoting complex or cyclosome by both dephosphorylation and induction of the spindle assembly checkpoint. Hsp90 inhibition compromises two of the main mitotic kinases, Polo-like kinase 1 (Plk1) and cdc2. Interestingly, this mitotic arrest does not occur in certain tumor cell lines where Hsp90 and Plk1 are not associated. Those cells are able to process mitosis successfully and have an active Plk1 despite Hsp90 inactivation. Therefore, it seems that Hsp90 regulates completion of mitosis depending on its association with Plk1.
Unexpected toxicity of cetuximab combined with conventional chemoradiotherapy in patients with locally advanced anal cancer: results of the UNICANCER ACCORD 16 phase II trial
Authors: E. Deutsch, C. Lemanski, J.P. Pignon, A. Levy, A. Delarochefordiere, I. Martel-Lafay, E. Rio, D. Malka, T. Conroy, L. Miglianico, Y. Becouarn, K. Malekzadeh, E. Paris, B. Juzyna, P. Ezra, D. Azria
Journal: Annals of Oncology (2013)
M13 bacteriophage DNA inhibits duck hepatitis B virus during acute infection
Authors: Akira Iizuka, Tatsuro Watanabe, Toshiyuki Kubo, Masahiro Yamamoto, Kazuo Ogawa, Tetsuo Ohkuma, Akira Kaji
Journal: Hepatology (1994)

We investigated effects of various DNAs on duck hepatitis B virus replication in vivo. One-day-old ducks were infected intravenously with DHBV. Various DNAs were then injected intravenously, and duck hepatitis B virus levels were followed for up to 20 days after the inoculation. When M13 bacteriophage DNA (M13 DNA), heat-denatured Escherichia coli DNA or phi X 174 phage DNA was injected intravenously at a dose of 2.45 mg/kg body wt daily for 10 days, a significant decrease of serum duck hepatitis B virus DNA was detected within 10 days. The efficacy was twice that reported with antisense DNA on a weight basis and far more than that reported on a molar basis. M13 DNA was superior, on the basis of effective dose, to acyclovir as an anti-duck hepatitis B virus agent. On treatment with M13 DNA, serum 2-5 A synthetase level was increased five to six times, suggesting that the antiviral effect of M13 DNA is at least partly due to induction of endogenous interferon, which in turn induces 2-5 A synthetase. No significant inhibitory effect on replication of duck hepatitis B virus was demonstrated by DNAs obtained from herring testes, herring sperm, salmon testes, human placenta or calf thymus. On discontinuation of M13 DNA injection on day 10, duck hepatitis B virus reappeared in the serum at later time points. Digestion of M13 DNA with S1 nuclease resulted in marked reduction of antiviral activity. These results show that M13 DNA, not its digested product, has potent antiviral activity.
An analysis of dynamic forces transmitted through the foot in diabetic neuropathy.
Authors: J E Shaw, C H van Schie, A L Carrington, C A Abbott, A J Boulton
Journal: Diabetes Care (1998)

OBJECTIVE: Biomechanical studies in diabetic neuropathy have clearly demonstrated abnormal foot pressures, but information on other aspects of gait is limited. This study aimed to investigate and describe the forces transmitted through the foot during walking in diabetic subjects with varying degrees of peripheral neuropathy and to determine if abnormalities in these forces might contribute to the risk of plantar ulceration. RESEARCH DESIGN AND METHODS: Subjects from the following groups were included: healthy control subjects (C); diabetic control subjects (D); subjects with diabetic neuropathy (DN); subjects with previous neuropathic ulceration (DNU); and subjects with Charcot neuro-arthropathy (CH). Gait analysis was performed as subjects walked over a Kistler force plate. Peak forces were measured (as percent body weight) in the vertical and horizontal planes. Comparisons were made between all of the groups and between each diabetic group and a healthy control group matched for walking speed. RESULTS: There were 181 subjects studied. In comparison with that of the speed-matched controls, the mean peak vertical force was higher in each of the diabetic groups, especially in the most neuropathic subjects (DNU, 113 vs. 110%, P &amp;lt; 0.01). This increase was entirely due to higher forces during heel contact (DNU, 111 vs. 106%, P &amp;lt; 0.001). The single peak force occurred during heel strike (rather than during foot push-off) in 23-38% of footsteps of healthy and diabetic control subjects but in 53-73% of footsteps of neuropathic subjects. There was also a trend for higher peak medial forces (CH, 6.2 vs. 5.5%, P &amp;lt; 0.05). CONCLUSIONS: Diabetic neuropathy is associated with a change in the time pattern of the forces transmitted through the foot and an increase in the vertical forces through the heel. The magnitude of the changes is small in absolute terms, but these changes may contribute to the risk of plantar foot ulceration.
Expanding the Diabetes Arsenal
Authors: Rebecca Voelker
Journal: JAMA (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
The construction of emotional experience requires the integration of implicit and explicit emotional processes
Authors: Markus Quirin, Richard D. Lane
Journal: Behavioral and Brain Sciences (2012)

Although we agree that a constructivist approach to emotional experience makes sense, we propose that implicit (visceromotor and somatomotor) emotional processes are dissociable from explicit (attention and reflection) emotional processes, and that the conscious experience of emotion requires an integration of the two. Assessments of implicit emotion and emotional awareness can be helpful in the neuroscientific investigation of emotion.
EBUS-TBNA in the differential diagnosis of pulmonary artery sarcoma and thromboembolism: Figure 1–
Authors: David Montani, Xavier Jaïs, Olivier Sitbon, Philippe Dartevelle, Gérald Simonneau, Marc Humbert
Journal: European Respiratory Journal (2012)

EBUS-TBNA in the differential diagnosis of pulmonary artery sarcoma and thromboembolismTo the Editors:We read with interest the correspondence published by PARK et al.[1] suggesting a potential role for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to differentiate pulmonary artery sarcoma and thromboembolism.Pulmonary artery sarcoma usually has its origin in the pulmonary arterial trunk and extends towards pulmonary branches, and is indeed sometimes difficult to differentiate from chronic thromboembolic disease.However, we believe that the authors' conclusions suggesting that EBUS-TBNA is safe in this setting are premature.Indeed, such an approach could be associated with significant complications.
p38-Mediated Inactivation of Cyclin D1/Cyclin-Dependent Kinase 4 Stimulates Nucleolar Translocation of RelA and Apoptosis in Colorectal Cancer Cells
Authors: Hazel C. Thoms, Malcolm G. Dunlop, Lesley A. Stark
Journal: Cancer Research (2007)

Abstract Aberrant nuclear factor-κB (NF-κB) signaling plays a role in cancer initiation and progression; thus, it represents a potential therapeutic target. We previously identified a mechanism of repression of NF-κB transcriptional activity and induction of apoptosis in colon cancer cells involving nuclear/nucleolar translocation of the RelA (p65) component of NF-κB. This response was stimulated by cellular stress-inducing agents, including aspirin, but not by tumor necrosis factor. Here, we investigate the upstream molecular mechanisms responsible for nucleolar targeting of RelA and show that aspirin activates the p38 mitogen-activated protein kinase (MAPK) pathway in colorectal cancer cells. We also show that aspirin causes rapid, ubiquitin-dependent degradation of cyclin D1, a known p38 target. Aspirin-induced p38 activation preceded cyclin D1 degradation, which was then followed by activation of the NF-κB pathway, suggesting a causative link. Indeed, chemical p38 inhibition (PD169316) and small interfering RNA directed against p38 blocked aspirin-induced cyclin D1 degradation, nucleolar translocation of RelA, and apoptosis. Furthermore, chemical inhibition of the cyclin D1/cyclin-dependent kinase 4 (CDK4) kinase complex, used as a surrogate for cyclin D1 degradation, caused nucleolar translocation of RelA, repression of κB-driven transcription, and apoptosis, thereby reproducing the effects of aspirin. In addition, we found that aspirin and the CDK4 inhibitor induced nucleolar translocation of RelA and apoptosis through a common mechanism involving the NH2-terminal nucleolar localization signal. Collectively, these data suggest that aspirin causes inhibition of cyclin D1/CDK4 through the p38 MAPK pathway. This inhibition stimulates the NF-κB pathway to induce nucleolar translocation of RelA and apoptosis. These novel findings have considerable relevance to the rational design of novel chemotherapeutic and chemopreventative strategies. [Cancer Res 2007;67(4):1660–9]
Prognostic Impact of Immunohistochemical Expression of Ezrin in Highly Malignant Soft Tissue Sarcomas
Authors: Wen-Hui Weng, Jan Åhlén, Kristina Åström, Weng-Onn Lui, Catharina Larsson
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Ezrin is a cytoskeleton linker protein that is actively involved in regulating the growth and metastatic capacity of cancer cells. It has recently been reported to be involved in dissemination of pediatric soft tissue sarcoma (STS). Experimental Design: To further evaluate the prognostic value of ezrin in STS progression, we screened 50 primary STSs of high malignancy grade using immunohistochemistry. At the initial surgery, all patients were without local or distant metastasis. The expression was then compared with the outcome during follow-up for at least 4 years or until the patients' death. Results: Twenty-five of the 50 STSs analyzed (50%) showed ezrin immunoreactivity in the membrane and cytoplasm of the tumor cells. A significant association was shown between positive expressions of ezrin and death in disease as well as overall survival (P = 0.014 and 0.007, respectively). Similarly, ezrin expression was significantly associated with development of distant metastasis during follow-up (P = 0.031), also excluding locally recurrent disease (P = 0.049). The relative abundance of metastasis in ezrin-positive cases was observed both over time and irrespective of time. In comparison with clinical, histopathologic, and genetic characteristics of the STSs, ezrin expression was found to correlate significantly with an infiltrative growth pattern outside the tumor capsule as well as with copy number gain of chromosomal region 9cen-q22. Conclusion: Our findings suggest that ezrin immunoreactivity could be valuable as an additional prognostic marker in highly malignant STSs and support a causative role of ezrin in STS tumor dissemination.
Sites of symptomatic gas retention during intestinal lipid perfusion in healthy subjects
Authors: A C Hernando-Harder
Journal: Gut (2004)

Gas pooling within the gut may produce abdominal symptoms but the segment of the intestine responsible for gas retention is unknown. Our aim was to determine the role of the proximal and distal bowel in symptomatic gas accumulation using an experimental model of gas retention triggered by intraluminal lipids.Sixteen healthy subjects.A gas mixture (N2, O2, and CO2 in venous proportions) was infused into the intestine at12 ml/min for three hours and gas evacuation was continuously measured via an anal cannula connected to a barostat. Abdominal perception and girth changes were measured at 10 minute intervals. Lipids (1 kcal/min) were simultaneously perfused either into the duodenum (n = 8) or into the ileum (n = 8). Each subject was studied twice on separate days, with gas infused into the jejunum or ileum.Duodenal lipids produced retention of gas infused into the jejunum (646 (62) ml) but the volume retained was much smaller when gas was infused directly into the ileum (262 (90) ml; p<0.05). The effects on gas retention were even more pronounced during ileal perfusion of lipids (1546 (184) ml during jejunal gas infusion and 847 (142) ml during ileal gas infusion; p<0.05). Abdominal distension correlated with the volume of gas retained (r = 0.87; p<0.001). Healthy subjects tolerated gas retention, and significant symptoms (score 3.7 (0.8)) developed only during jejunal gas infusion plus ileal lipid perfusion when gas retention was very large.Intraluminal lipids induce intestinal gas retention, predominantly acting on the proximal small bowel.