tbuckley/cabot-search huggingface dataset:
Prognosis of Critically Ill Patients With Cancer and Acute Renal Dysfunction
Authors: Márcio Soares, Jorge I.F. Salluh, Marilia S. Carvalho, Michael Darmon, José R. Rocco, Nelson Spector
Journal: Journal of Clinical Oncology (2006)

To evaluate the outcomes of critically ill patients with cancer and acute renal dysfunction.Prospective cohort study conducted at a 10-bed oncologic medical-surgical intensive care unit (ICU) over a 56-month period.Of 975 patients, 309 (32%) had renal dysfunction and were studied. Their mean age was 60.9 +/- 15.9 years; 233 patients (75%) had solid tumors and 76 (25%) had hematologic malignancies. During the ICU stay, 98 patients (32%) received dialysis. Renal dysfunction was multifactorial in 56% of the patients, and the main associated factors were shock/ischemia (72%) and sepsis (63%). Overall hospital and 6-month mortality rates were 64% and 73%, respectively. Among patients who required dialysis, mortality rates were lower in patients who received dialysis on the first day of ICU in comparison with those who required it thereafter. In a multivariable Cox model, age more than 60 years, uncontrolled cancer, impaired performance status, and more than two associated organ failures were associated with increased 6-month mortality. Renal function was completely re-established in 82% and partially re-established in 12%, and only 6% of survivors required chronic dialysis.Acute renal dysfunction is frequent in critically ill patients with cancer. Although mortality rates are high, selected patients can benefit from ICU care and advanced organ support. When evaluating prognosis and the appropriateness of dialysis in these patients, older age, functional capacity, cancer status and the severity of associated organ failures are important variables to take into consideration.
Anaphase Catastrophe Is a Target for Cancer Therapy
Authors: Fabrizio Galimberti, Sarah L. Thompson, Saranya Ravi, Duane A. Compton, Ethan Dmitrovsky
Journal: Clinical Cancer Research (2011)

Neoplastic cells are genetically unstable. Strategies that target pathways affecting genome instability can be exploited to disrupt tumor cell growth, potentially with limited consequences to normal cells. Chromosomal instability (CIN) is one type of genome instability characterized by mitotic defects that increase the rate of chromosome mis-segregation. CIN is frequently caused by extra centrosomes that transiently disrupt normal bipolar spindle geometry needed for accurate chromosome segregation. Tumor cells survive with extra centrosomes because of biochemical pathways that cluster centrosomes and promote chromosome segregation on bipolar spindles. Recent work shows that targeted inhibition of these pathways prevents centrosome clustering and forces chromosomes to segregate to multiple daughter cells, an event triggering apoptosis that we refer to as anaphase catastrophe. Anaphase catastrophe specifically kills tumor cells with more than 2 centrosomes. This death program can occur after genetic or pharmacologic inhibition of cyclin dependent kinase 2 (Cdk2) and is augmented by combined treatment with a microtubule inhibitor. This proapoptotic effect occurs despite the presence of ras mutations in cancer cells. Anaphase catastrophe is a previously unrecognized mechanism that can be pharmacologically induced for apoptotic death of cancer cells and is, therefore, appealing to engage for cancer therapy and prevention.
Replication error phenotype in colorectal cancer Reply
Authors: J R JASS;
Journal: Gut (2000)

Editor,—The results presented in the article by Curran et al ((2000) Gut 46:200–204; [OpenUrl][1][Abstract/FREE Full Text][2]) may have been different if the authors had classified DNA microsatellite instability status as stable (MSS), low (MSI-L) or high (MSI-H), as recommended by a National Cancer Institute sponsored workshop.1 Their “RER+” group included both MSI-H and MSI-L cancers. The finding of bandshifts in two of eight dinucleotide markers is not specific for MSI-H cancers and will pick up a proportion of MSI-L cases.2 ,3 Two of the three RER+ cancers with a K-ras mutation (study Nos 52 and 129) showed bandshifts at only two loci, … Dr D T Croke. Email:dtcroke{at}rcsi.ie [1]: {openurl}?query=rft.jtitle%253DCancer%2BResearch%26rft.stitle%253DCancer%2BRes.%26rft.aulast%253DBoland%26rft.auinit1%253DC.%2BR.%26rft.volume%253D58%26rft.issue%253D22%26rft.spage%253D5248%26rft.epage%253D5257%26rft.atitle%253DA%2BNational%2BCancer%2BInstitute%2BWorkshop%2Bon%2BMicrosatellite%2BInstability%2Bfor%2BCancer%2BDetection%2Band%2BFamilial%2BPredisposition%253A%2BDevelopment%2Bof%2BInternational%2BCriteria%2Bfor%2Bthe%2BDetermination%2Bof%2BMicrosatellite%2BInstability%2Bin%2BColorectal%2BCancer%26rft_id%253Dinfo%253Apmid%252F9823339%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=canres&resid=58/22/5248&atom=%2Fgutjnl%2F47%2F4%2F597.atom
Role of diabetes.
Authors: K G Alberti
Journal: BMJ (1991)

The Health of the Nation' is ostensibly a consultative document, but in the past such documents have been taken on as established policy all too rapidly.The document is none the less to be welcomed as it shows, firstly, a welcome move from administrative and financial priorities to real health issues and, secondly, a clear indication that prevention is to be targeted rather than disease.Sixteen key areas of interest have been chosen.The sting in the tail, however, is that only a few of these will be targeted initially.The criteria for final selection are, sadly, likely to be largely financial as well as health oriented, and payment for any new ventures will inevitably be at the expense of other aspects of health care or come out of so called "cost improve- ments."Below I present the case for and against including diabetes in the final list and discuss suggested targets and the strategy needed to achieve those targets.
A <i>KRAS</i>-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk
Authors: Elena Ratner, Lingeng Lu, Marta Boeke, Rachel Barnett, Sunitha Nallur, Lena J. Chin, Cory Pelletier, Rachel Blitzblau, Renata Tassi, Trupti Paranjape, Pei Hui, Andrew K. Godwin, Herbert Yu, Harvey Risch, Thomas Rutherford, Peter Schwartz, Alessandro Santin, Ellen Matloff, Daniel Zelterman, Frank J. Slack, Joanne B. Weidhaas
Journal: Cancer Research (2010)

Ovarian cancer (OC) is the single most deadly form of women's cancer, typically presenting as an advanced disease at diagnosis in part due to a lack of known risk factors or genetic markers of risk. The KRAS oncogene and altered levels of the microRNA (miRNA) let-7 are associated with an increased risk of developing solid tumors. In this study, we investigated a hypothesized association between an increased risk of OC and a variant allele of KRAS at rs61764370, referred to as the KRAS-variant, which disrupts a let-7 miRNA binding site in this oncogene. Specimens obtained were tested for the presence of the KRAS-variant from nonselected OC patients in three independent cohorts, two independent ovarian case-control studies, and OC patients with hereditary breast and ovarian cancer syndrome (HBOC) as well as their family members. Our results indicate that the KRAS-variant is associated with more than 25% of nonselected OC cases. Further, we found that it is a marker for a significant increased risk of developing OC, as confirmed by two independent case-control analyses. Lastly, we determined that the KRAS-variant was present in 61% of HBOC patients without BRCA1 or BRCA2 mutations, previously considered uninformative, as well as in their family members with cancer. Our findings strongly support the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing OC, and they suggest that the KRAS-variant may be a new genetic marker of cancer risk for HBOC families without other known genetic abnormalities.
Screening for Prostate Cancer: Early Detection or Overdetection?
Authors: Andrew J. Vickers, Monique J. Roobol, Hans Lilja
Journal: Annual Review of Medicine (2011)

A sophisticated reading of the randomized trial evidence suggests that, although screening for prostate cancer with prostate-specific antigen (PSA) can reduce cancer-specific mortality, it does so at considerable cost in terms of the number of men who need to be screened, biopsied, and treated to prevent one death. The challenge is to design screening programs that maximize benefits (reducing prostate cancer mortality) and minimize costs (overtreatment). Recent research has suggested that this can be achieved by risk-stratifying screening and biopsy; increasing reliance on active surveillance for low-risk cancer; restricting radical prostatectomy to high-volume surgeons; and using appropriately high-dose radiotherapy. In current U.S. practice, however, many men who are screened are unlikely to benefit, most men found to have low-risk cancers are referred for unnecessary curative treatment, and much treatment is given at low-volume centers.
Clinical Predictors of Mortality from Asbestosis in the North American Insulator Cohort, 1981 to 1991
Authors: STEVEN B. MARKOWITZ, ALFREDO MORABIA, RUTH LILIS, ALBERT MILLER, WILLIAM J. NICHOLSON, STEPHEN LEVIN
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Recorded mortality from asbestosis has increased markedly in the United States in recent decades, from 0.49 to 3.06 per million persons between 1970 and 1990. Although asbestosis is generally considered to be a slowly progressive disorder, little is known about how clinical and exposure parameters among individuals with asbestosis quantitatively predict subsequent risk of death from asbestosis. We followed 2,609 insulators from the North American insulator cohort 10 yr to determine cause of death and to relate clinical findings to risk of death. This group had undergone clinical and radiologic examination between 1981 and 1983 in 19 cities in the United States. Seventy-four (11.0%) of 674 deaths during the subsequent 10 yr were due to asbestosis, according to the best clinical and radiologic evidence available at the time of death. The 10 yr risk of death (expressed as a percentage) due to asbestosis rose sharply with increasing interstitial fibrosis as identified on the baseline chest X-ray, from 0.9% to 2.4%, 10.8%, and 35.4% for International Labor Office (ILO) profusion categories 0, 1, 2, and 3, respectively. Dyspnea, a low FVC, and/or physical examination findings typical of interstitial fibrosis (rales, clubbing, or cyanosis) raised the risk of subsequent death from asbestosis by 2- to 6-fold. The effect of cigarette smoking on risk of death from asbestosis was small and disappeared after adjustment for ILO profusion score.
Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium.
Authors: C M Boulanger, F C Tanner, M L Béa, A W Hahn, A Werner, T F Lüscher
Journal: Circulation Research (1992)

Experiments were designed to examine the effect of oxidized low density lipoproteins (Ox-LDLs) on the expression and the release of endothelin from cultured endothelial cells and intact blood vessels. Ox-LDLs (30-300 micrograms/ml), but not native low density lipoproteins (200 micrograms/ml), stimulated the expression of preproendothelin mRNA in porcine and human endothelial cells, leading to a time- and concentration-dependent release of the peptide into the culture medium. The Ox-LDL-stimulated release of endothelin was mimicked by acetylated low density lipoprotein and abolished by downregulation of protein kinase C by phorbol ester. In the intact porcine aorta, Ox-LDLs, but not native low density lipoproteins, also increased the release of peptide in an endothelium- and concentration-dependent manner. The maximal effect was observed at a concentration of 100 micrograms/ml. Incubation of the intact porcine aorta with the scavenger receptor antagonist dextran sulfate decreased the formation of endothelium evoked by Ox-LDLs. The Ox-LDL-stimulated production of the peptide was further augmented in the presence of thrombin (4 units/ml) and was unaffected by nitric oxide-generating compound 3-morpholinosydnonimine (10(-5) M). These results suggest that Ox-LDL may be an endogenous mediator of the augmented release of endothelin observed in hyperlipidemia and atherosclerosis. The increased production of the peptide could contribute to vasospastic events and may promote vascular smooth muscle proliferation and progression of atherosclerotic vascular disease.
Hepatitis C virus NS5A-regulated gene expression and signaling revealed via microarray and comparative promoter analyses
Authors: Sophie Girard, Erik Vossman, David E. Misek, Philippe Podevin, Samir Hanash, Christian Bréchot, Laura Beretta
Journal: Hepatology (2004)

Most individuals exposed to hepatitis C virus (HCV) become chronically infected and are predisposed to liver disease. The mechanisms underlying viral persistence and disease progression are unknown. A role for the HCV NS5A protein in viral replication and interferon resistance has been demonstrated. To identify mechanisms affected by NS5A, we analyzed the gene expression of Huh7 cells expressing NS5A and control cells using oligonucleotide microarrays. A set of 103 genes (43 up-regulated, 60 down-regulated) whose expression was modified by at least twofold was selected. These included genes involved in cell adhesion and motility, calcium homeostasis, lipid transport and metabolism, and genes regulating immune responses. The finding of modulated expression of genes related to the TGF-β superfamily and liver fibrosis was observed. Interestingly, both the tumor necrosis factor and lymphotoxin beta receptors were down-regulated by NS5A. Similar data were obtained following expression of four NS5A mutants obtained from patients who were not responsive or were sensitive to interferon therapy. Through computational analysis, we determined that 39 of the 43 genes up-regulated by NS5A contained one or more nuclear factor κB (NF-κB) binding sites within their promoter region. Using the Gibbs sampling method, we also detected enrichment of NF-κB consensus binding sites in the upstream regions of the 43 coexpressed genes. Activation of NF-κB by NS5A was subsequently demonstrated in luciferase reporter assays. Adenovirus-mediated expression of IκBα reverted NS5A mediated up-regulation of gene expression. In conclusion , this study suggests a role of NS5A and NF-κB in HCV pathogenesis and related liver disease. Supplementary material for this article can be found on the Hepatology website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (Hepatology 2004;40:708-718.)
American Society of Clinical Oncology 2007 Clinical Practice Guideline Update on the Role of Bisphosphonates in Multiple Myeloma
Authors: Robert A. Kyle, Gary C. Yee, Mark R. Somerfield, Patrick J. Flynn, Susan Halabi, Sundar Jagannath, Robert Z. Orlowski, David G. Roodman, Patricia Twilde, Kenneth Anderson
Journal: Journal of Clinical Oncology (2007)

To update the recommendations for the use of bisphosphonates in the prevention and treatment of bone disease in multiple myeloma. The Update Committee expanded the guideline to include a discussion of osteonecrosis of the jaw (ONJ).
HLA and rheumatoid arthritis: a combined analysis of 440 British patients.
Authors: D Jaraquemada, W Ollier, J Awad, A Young, A Silman, I M Roitt, M Corbett, F Hay, J A Cosh, R N Maini
Journal: Annals of the Rheumatic Diseases (1986)

Four hundred and forty unrelated British Caucasoid patients with rheumatoid arthritis (RA) have been HLA typed for class I and class II antigens. Analyses of HLA antigen associations were performed on the overall group and in patient subsets selected according to particular disease parameters or sex, or both. The results confirm previously reported positive associations of HLA-DR4, Dw4, and DRw53 and negative associations of HLA-DR2 and DR7 with RA. Patients subsets with severe erosions, seropositivity, and features of extra-articular disease showed a stronger association, also confirming earlier reports. The link between HLA and disease severity was emphasised by a significant trend of increased Dw4 frequency with increasing severity of radiological erosions. In addition, a positive association of RA with HLA-A2 was observed and a strong negative association with DR3. The frequency of HLA-B27 was significantly increased in patients with subluxation of the spine. Differences were observed between male and female patients in relation to the HLA association. In men an increase in the frequency of the haplotype HLA/Dw4/DR4/Bw62/Cw3/A2 was observed. This showed no relationship with parameters of disease severity other than extra-articular disease. In women only class II antigens (DRw53/Dw4/DR4) showed an increased frequency. This increase was strongly associated with disease severity. A significant decrease of this class II association was observed with increasing age of disease onset; this was not seen in men.
Induction of CD4+ and CD8+ T-Cell Responses to the Human Stromal Antigen, Fibroblast Activation Protein: Implication for Cancer Immunotherapy
Authors: Martin Fassnacht, Jaewoo Lee, Caterina Milazzo, David Boczkowski, Zhen Su, Smita Nair, Eli Gilboa
Journal: Clinical Cancer Research (2005)

The propensity of tumor cells to escape immune elimination could limit, if not defeat, the long-term benefits of effective immunotherapeutic protocols. Immunologic targeting of tumor stroma could significantly reduce the ability of tumors to evade immune elimination. Murine studies have shown that inducing immunity against angiogenesis-associated products engenders potent antitumor immunity without significant pathology. It is, however, not known whether T cells corresponding to stromal products are present in humans. In this study, we describe a method to screen for human stromal products that have not triggered significant tolerance and could therefore serve as candidate antigens for cancer immunotherapy.To identify candidates for human stromal antigens, we used an in vitro-screening method to determine whether dendritic cells transfected with mRNA encoding products, which are overexpressed in the tumor stroma, are capable of stimulating cytotoxic CD8(+) (CTL) responses from human peripheral blood mononuclear cells.CTL responses could be consistently generated against fibroblast activation protein (FAP) but not against matrix metalloproteinase-9 (MMP-9) or MMP-14. To enhance the immunogenicity of the mRNA-translated FAP product, a lysosomal targeting signal derived from lysosome-associated membrane protein-1 (LAMP-1) was fused to the COOH terminus of FAP to redirect the translated product into the class II presentation pathway. Dendritic cells transfected with mRNA encoding the FAP-LAMP fusion product stimulated enhanced CD4(+) and CD8(+) T-cell responses.This study identifies FAP, a protease preferentially expressed in tumor-associated fibroblasts, as a candidate human stromal antigen to target in the setting of cancer immunotherapy, and shows that differential expression of stromal products is not a sufficient criteria to indicate its immunogenicity in a vaccination setting.
G12/13 and Gq mediate S1P2-induced inhibition of Rac and migration in vascular smooth muscle in a manner dependent on Rho but not Rho kinase
Authors: Shin-ichiro Takashima, Naotoshi Sugimoto, Noriko Takuwa, Yasuo Okamoto, Kazuaki Yoshioka, Masayuki Takamura, Shigeo Takata, Shuichi Kaneko, Yoh Takuwa
Journal: Cardiovascular Research (2008)

The lysophospholipid mediator sphingosine-1-phosphate (S1P) activates G protein-coupled receptors (GPCRs) to induce potent inhibition of platelet-derived growth factor (PDGF)-induced Rac activation and, thereby, chemotaxis in rat vascular smooth muscle cells (VSMCs). We explored the heterotrimeric G protein and the downstream mechanism that mediated S1P inhibition of Rac and cell migration in VSMCs.S1P inhibition of PDGF-induced cell migration and Rac activation in VSMCs was abolished by the selective S1P(2) receptor antagonist JTE-013. The C-terminal peptides of Galpha subunits (Galpha-CTs) act as specific inhibitors of respective G protein-GPCR coupling. Adenovirus-mediated expression of Galpha(12)-CT, Galpha(13)-CT, and Galpha(q)-CT, but not that of Galpha(s)-CT or LacZ or pertussis toxin treatment, abrogated S1P inhibition of PDGF-induced Rac activation and migration, indicating that both G(12/13) and G(q) classes are necessary for the S1P inhibition. The expression of Galpha(q)-CT as well as Galpha(12)-CT and Galpha(13)-CT also abolished S1P-induced Rho stimulation. C3 toxin, but not a Rho kinase inhibitor or a dominant negative form of Rho kinase, abolished S1P inhibition of PDGF-induced Rac activation and cell migration. The angiotensin II receptor AT(1), which robustly couples to G(q), did not mediate either Rho activation or inhibition of PDGF-induced Rac activation or migration, suggesting that activation of G(q) alone was not sufficient for Rho activation and resultant Rac inhibition. However, the AT(1) receptor fused to Galpha(12) was able to induce not only Rho stimulation but also inhibition of PDGF-induced Rac activation and migration. Phospholipase C inhibition did not affect S1P-induced Rho activation, and protein kinase C activation by a phorbol ester did not mimic S1P action, suggesting that S1P inhibition of migration or Rac was not dependent on the phospholipase C pathway.These observations together suggest that S1P(2) mediates inhibition of Rac and migration through the coordinated action of G(12/13) and G(q) for Rho activation in VSMCs.
Influence of cholecystectomy on sphincter of Oddi motility
Authors: W Luman, A J K Williams, A Pryde, G D Smith, S J Nixon, R C Heading, K R Palmer
Journal: Gut (1997)

Background —Gall bladder and sphincter of Oddi (SO) function are coordinated by hormonal and neuronal mechanisms. Nerve fibres pass between the gall bladder and the SO via the cystic duct. It is therefore possible that cholecystectomy may alter SO motility. Aim —To investigate the effect of cholecystectomy on SO function Methods —SO manometry was performed in five women (median age 52 years), a few days before and six months after laparoscopic cholecystectomy which was undertaken for uncomplicated cholelithiasis. Basal and post-cholecystokinin (CCK) SO motility were measured. Results —All patients were symptom free after laparoscopic cholecystectomy. Prior to surgery common bile duct pressure, and tonic and phasic SO motility were normal and phasic contractions were inhibited by intravenous CCK (1 Ivy Dog Unit/kg). Six months later, common bile duct pressure and baseline tonic and phasic activity were unchanged but CCK failed to suppress phasic activity. Conclusion —Cholecystectomy, at least in the short term, suppresses the normal inhibitory effect of pharmacological doses of CCK on the SO. The mechanism of this effect is unknown but it could be due to SO denervation.
Combination immunotherapy: Where do we go from here?
Authors: Abigail E. Overacre, Sema Kurtulus, Mario Sznol, Drew M. Pardoll, Ana Anderson, Dario A. A. Vignali
Journal: Journal for ImmunoTherapy of Cancer (2015)

The remarkable clinical success of cancer immunotherapies targeting the checkpoint receptors CTLA-4 and PD-1 has generated considerable excitement and emboldened efforts to build on this important foundation. Research efforts are now focused on understanding the mechanism of action of these immunotherapies, identifying new inhibitory mechanisms that could be targeted to achieve responses in patients with refractory cancers, and developing approaches that might exhibit efficacy against "immunologically inert" tumors. The outstanding challenges in moving forward are developing reliable strategies for determining which patients will respond optimally to a given immunotherapy, and what combination of immunotherapies and conventional therapies will prove beneficial against each tumor type. These issues were discussed in a one-day workshop at the SITC meeting in November 2014.