tbuckley/cabot-search huggingface dataset:
PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer
Authors: Fotios Loupakis, Luca Pollina, Irene Stasi, Annamaria Ruzzo, Mario Scartozzi, Daniele Santini, Gianluca Masi, Francesco Graziano, Chiara Cremolini, Eliana Rulli, Emanuele Canestrari, Niccola Funel, Gaia Schiavon, Iacopo Petrini, Mauro Magnani, Giuseppe Tonini, Daniela Campani, Irene Floriani, Stefano Cascinu, Alfredo Falcone
Journal: Journal of Clinical Oncology (2009)

PTEN, AKT, and KRAS are epidermal growth factor receptor (EGFR) downstream regulators. KRAS mutations confer resistance to cetuximab. This retrospective study investigated the role of PTEN loss, AKT phosphorylation, and KRAS mutations on the activity of cetuximab plus irinotecan in patients with metastatic colorectal cancer (mCRC).A cohort of patients with irinotecan-refractory mCRC who were treated with cetuximab plus irinotecan was tested for PTEN immunoreactivity (ie, immunohistochemistry; IHC), pAKT IHC, and KRAS mutations. Analyses were performed both on primary tumors and on related metastases, and the association among IHC, mutational results, and treatment outcomes was investigated.One-hundred two patients were eligible. Ninety-six primary tumors, 59 metastases, and 53 paired samples were available. Forty-nine primary tumors (58% of assessable samples) had a preserved PTEN expression (PTEN-positive), whereas 35 (40% of assessable samples) were pAKT-positive. Levels of concordance between primary tumors and metastases were 60%, 68%, and 95% for PTEN, pAKT, and KRAS, respectively. PTEN status on primary tumors and pAKT status both on primary tumors and on metastases did not predict response or progression-free survival (PFS). On metastases, 12 (36%) of 33 patients with PTEN-positive tumors were responders compared with one (5%) of 22 who had PTEN-negative tumors (P = .007). The median PFS of patients with PTEN-positive metastases was 4.7 months compared with 3.3 months for those with PTEN-negative metastases (hazard ratio [HR], 0.49; P = .005). Patients with PTEN-positive metastases and KRAS wild type had longer PFS compared with other patients (5.5 months v 3.8 months; HR, 0.42; P = .001).PTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan. The combination of PTEN IHC and KRAS mutational analyses could help to identify a subgroup of patients with mCRC who have higher chances of benefiting from EGFR inhibition.
THE EFFECTS OF SPORTS-RELATED INJURIES ON QUALITY OF LIFE AND ATHLETIC PERFORMANCE WITHIN THE KOREAN LADIES PROFESSIONAL GOLF PLAYERS
Authors: LN Kim, JH Woo, HS Yng
Journal: British Journal of Sports Medicine (2014)

Objective To evaluate the effects of sports-related injuries of Korea ladies professional golf players on their quality of life and athletic performance. Design Cross-sectional study. Statistical analysis (student T-test) was conducted to examine whether there were any differences according to existence or non-existence of injuries. Setting The survey was conducted. Participants 100 Korea ladies professional golf players. Intervention The survey was conducted among them to investigate the existence or non-existence of injuries. Main outcome measurement SF-36 questionnair was conducted to evaluate the quality of life; prize money rankings were investigated to evaluate athletic performance. Results Among the subjects, 55 players were found to have past and present experiences of injuries. The results of SF-36 analysis on the quality of life showed that physical score was 52.9±5.4; mental score was 46.7±9.6. In order to examine the effects of injuries on the players' quality of life and athletic performance, the subjects were divided into the injury group of those who experienced injuries and the group of those who did not experience injuries. According to the existence or non-existence of injuries; there were significant differences in the physical score of SF-36(non-injury group: 54.0±4.8, injury group: 51.6±5.8, P=.029), in the mental score of SF-36 (non-injury group: 49±7.7, injury group: 43.8±10.6, P=.005), and also in the prize money rankings (P=.042). Conclusions The research results showed that athletes were higher in the average reference value of physical score, an indicator of the quality of life; they were however lower in mental score than those of reference of ordinary people. In addition, injuries influenced negatively the physical and mental quality of life; therefore, in order to heighten the degree of satisfaction concerning the quality of life of individual players and to enhance their athletic performance, prevention and management of injury considered very import.
A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
Authors: Eric A. Collisson, Christy L. Trejo, Jillian M. Silva, Shenda Gu, James E. Korkola, Laura M. Heiser, Roch-Philippe Charles, Brian A. Rabinovich, Byron Hann, David Dankort, Paul T. Spellman, Wayne A. Phillips, Joe W. Gray, Martin McMahon
Journal: Cancer Discovery (2012)

KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA) but remains an intractable pharmacologic target. Consequently, defining RAS effector pathway(s) required for PDA initiation and maintenance is critical to improve treatment of this disease. Here, we show that expression of BRAF(V600E), but not PIK3CA(H1047R), in the mouse pancreas leads to pancreatic intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant expression of BRAF(V600E) and TP53(R270H) result in lethal PDA. We tested pharmacologic inhibitors of RAS effectors against multiple human PDA cell lines. Mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) inhibition was highly effective both in vivo and in vitro and was synergistic with AKT inhibition in most cell lines tested. We show that RAF→MEK→ERK signaling is central to the initiation and maintenance of PDA and to rational combination strategies in this disease. These results emphasize the value of leveraging multiple complementary experimental systems to prioritize pathways for effective intervention strategies in PDA.PDA is diffi cult to treat, in large part, due to recurrent mutations in the KRAS gene. Here, we defi ne rational treatment approaches for the disease achievable today with existing drug combinations by thorough genetic and pharmacologic dissection of the major KRAS effector pathways, RAF→MEK→ERK and phosphoinositide 3′-kinase (PI3'K)→AKT.
Lymphocyte subpopulation imbalances, bone marrow hematopoiesis and histopathology in rituximab-treated lymphoma patients with late-onset neutropenia
Authors: K Stamatopoulos, T Papadaki, C Pontikoglou, I Athanasiadou, N Stavroyianni, J Bux, I Batsis, K Pyrovolaki, G Paterakis, D Anagnostou, A Anagnostopoulos, H A Papadaki
Journal: Leukemia (2008)
Interleukin 3 and interleukin 6 synergistically promote the proliferation and differentiation of malignant plasma cell precursors in multiple myeloma.
Authors: L Bergui, M Schena, G Gaidano, M Riva, F Caligaris-Cappio
Journal: The Journal of Experimental Medicine (1989)

PBMC from 11 patients with multiple myeloma (MM) were cultured in vitro in presence of IL-3 and IL-6. After 3 d, actively proliferating immunoblast-like B cells (20-62%) were apparent. After 6 d, a population of morphologically evident plasma cells was observed (30-50%) that expressed, in each individual case, the same light and heavy chain produced by bone marrow malignant plasma cells. We conclude that in MM the malignant plasma cell precursors are circulating and their growth and terminal differentiation are under the synergistic control of IL-3 and IL-6.
Effect of endotoxin on arachidonic acid release and thromboxane B<sub>2</sub> production by human platelets
Authors: Marie J. Stuart
Journal: American Journal of Hematology (1981)

Plasma thromboxane A2, which is elevated during endotoxemia, has previously been shown to be a major factor contributing to the mortality and morbidity that occurs in endotoxin shock in the experimental animal. Using a minimal dose of Escherichia coli endotoxin (1 microgram/ml), we have demonstrated that the preincubation of human platelets with endotoxin induces changes in platelet arachidonic acid release and the subsequent conversion of the released arachidonic acid to thromboxane B2, and stable end product of thromboxane A2. In paired experiments, in the presence of endotoxin, the addition of the aggregating agent thrombin (0.5 U/ml) caused human platelets to release 29.1 +/- 3.4% of 14C-arachidonic acid from prelabeled platelet phospholipids. This value was significantly elevated (p less than 0.02) when compared with the release of 14C-arachidonic acid from platelets in the absence of endotoxin (21.9 +/- 3.6%). Similarly, comparison of the results of the conversion of the released arachidonic acid to platelet thromboxane B2 (TxB2) revealed that TxB2 production was significantly increased (P less than 0.01) when human platelets were preincubated with endotoxin prior to the addition of thrombin (6.1 +/- 0.6%) when compared with TxB2 formation observed in the absence of endotoxin (3.4 +/- 0.5%). The absolute amount of released arachidonic acid that was converted to TxB2 in the presence of endotoxin (1.8 +/- 0.3%) was also significantly higher (P less than 0.01) than the value observed in its absence (0.8 +/- 0.2%) was also significantly higher (P less than 0.01) than the value observed in its absence (0.8 +/- 0.2%). This study suggests that one of the tissue sources of the proaggregatory vasoconstrictor thromboxane A2 during endotoxemia is the platelet.
Downregulation of Hematopoietic MUC1 during Experimental Colitis Increases Tumor-Promoting Myeloid-Derived Suppressor Cells
Authors: Tze Wei Poh, Cathy S. Madsen, Jessica E. Gorman, Ronald J. Marler, Jonathan A. Leighton, Peter A. Cohen, Sandra J. Gendler
Journal: Clinical Cancer Research (2013)

MUC1 is a tumor-associated antigen that is aberrantly expressed in cancer and inflammatory bowel disease (IBD). Even though immune cells express low MUC1 levels, their modulations of MUC1 are important in tumor progression. Consistent with previous clinical data that show increased myeloid-derived suppressor cells (MDSCs) in IBD, we now show that downregulation of MUC1 on hematopoietic cells increases MDSCs in IBD, similar to our data in tumor-bearing mice. We hypothesize that MDSC expansion in IBD is critical for tumor progression.To mechanistically confirm the linkage between Muc1 downregulation and MDSC expansion, we generated chimeric mice that did not express Muc1 in the hematopoietic compartment (KO→WT). These mice were used in two models of colitis and colitis-associated cancer (CAC) and their responses were compared with wild-type (WT) chimeras (WT→WT).KO→WT mice show increased levels of MDSCs during colitis and increased protumorigenic signaling in the colon during CAC, resulting in larger colon tumors. RNA and protein analysis show increased upregulation of metalloproteinases, collagenases, defensins, complements, growth factors, cytokines, and chemokines in KO→WT mice as compared with WT→WT mice. Antibody-mediated depletion of MDSCs in mice during colitis reduced colon tumor formation during CAC.Development of CAC is a serious complication of colitis and our data highlight MDSCs as a targetable link between inflammation and cancer. In addition, the lack of MUC1 expression on MDSCs can be a novel marker for MDSCs, given that MDSCs are still not well characterized in human cancers.
Emotion and empiricism.
Authors: H Wendel
Journal: BMJ (1979)

When he finished reading the paper he tore it into small pieces and started throwing the pieces out of the window.The second man said, "What are you doing that for ?" and the first man answered, "I do it to keep down the elephants."Whereupon the second man said, "There aren't any elephants" and the first replied, "Effective, isn't it ?"
Phase II trial of preoperative chemoradiotherapy with oxaliplatin, cisplatin, and 5-FU in locally advanced esophageal and gastric cancer
Authors: M. Pera, R. Gallego, C. Montagut, M. Martín-Richard, M. Iglesias, C. Conill, A. Reig, C. Balagué, L. Pétriz, D. Momblan, J. Bellmunt, J. Maurel
Journal: Annals of Oncology (2011)
Purification and properties of M protein extracted from group A streptococci with pepsin: covalent structure of the amino terminal region of type 24 M antigen
Authors: EH Beachey, GH Stollerman, EY Chiang, TM Chiang, JM Seyer, AH Kang
Journal: The Journal of Experimental Medicine (1977)

M protein was extracted from type 24, group A streptococci with pepsin at pH 5.8 and was further purified by ammonium sulfate precipitation, ribonuclease digestion, ion-exchange chromatography, and isoelectric focusing. The purified pepsin extract of M (pep M) protein was shown to be free of nontype-specific immunoreactivity in (a) complement fixation tests with heterologous M antiserum, (b) skin tests in normal adult guinea pigs, and (c) passive hemagglutination tests for the presence of lipoteichoic acid sensitizing or antigenic activity. The pep M24 was highly immunogenic; two of three rabbits developed opsonic antibody titers of 1:256 and the third a titer of 1:32 6 wk after a single injection of 100-pg doses of pep M24 emulsified in complete Freund's adjuvant. The antisera lacked nontype-specific antibodies and produced single precipitin lines in agar gel diffusion tests against crude HC1 extracts of the homologous M protein. Thus, the type-specific antigenic determinant(s) of type 24 M protein appears to be separable from immunotoxic, cross-reactive antigens without loss of immunogenicity in rabbits. The mobility of pep M24 upon electrophoresis in 10 percent sodium dodecyl sulfate pelyacrylamide gel was consistent with an average mol wt of 33,500 daltons. Amino acid analysis demonstrated a predominance of alanine, followed by glutamic acid, lysine, leucine, and aspartic acid. Pep M24 contained an estimated six to seven methionine residues and approximately ten phenylalanine residues per molecule. No other aromatic amino acids were detected. Automatic Edman degradation of pep M24 yielded the sequence of the first 29 amino acids (the amino terminal amino acid being valine) of the amino terminal region of the molecule. The detection of only one new amino acid at each step of Edman degradation confirmed the homogeneity of the purified pep M24.
Identification of Hypoxia-Inducible Factor-1α as a Novel Target for <i>miR-17-92</i> MicroRNA Cluster
Authors: Ayumu Taguchi, Kiyoshi Yanagisawa, Masaharu Tanaka, Ke Cao, Yasushi Matsuyama, Hidemi Goto, Takashi Takahashi
Journal: Cancer Research (2008)

Abstract MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs that posttranscriptionally repress expression of target genes through imperfect base pairing with the 3′ untranslated region. We previously reported amplification and overexpression of the miR-17-92 miRNA cluster at 13q31.3 in lung cancers, as well as growth inhibition by treatment with antisense oligonucleotides against miR-17-5p and miR-20a, constituents of miR-17-92, specifically in miR-17-92–overexpressing lung cancer cell lines. Although these findings clearly suggested important roles of miR-17-92 overexpression in lung cancers, only a few targets for the miR-17-92 cluster have been identified thus far. In this study, we identified hypoxia-inducible factor (HIF)-1α as a novel direct target for miR-17-92 through global expression profiling by mass spectrometric analysis using an isobaric tagging reagent, iTRAQ, combined with bioinformatic target prediction. This is the first report to describe negative regulation of HIF-1α by miRNA, which seemed to occur without disrupting the induction of HIF-1α for cellular adaptation to hypoxia. In addition, overexpression of c-myc led to down-regulation of HIF-1α and induction of miR-17-92, the latter of which was previously reported to be a transcriptional activation activity, suggesting that the induction of miR-17-92 may play a role at least in part in c-myc–mediated repression of HIF-1α. Together with previous reports on the functional negative regulation of c-myc by HIF-1α, our findings suggest the possible existence of an intricate and finely tuned circuit involving c-myc, miR-17-92, and HIF-1α that may play a role in cancer cell proliferation under normoxia in a cellular context–dependent manner. [Cancer Res 2008;68(14):5540–5]
Methodologic issues in effectiveness research on palliative cancer care: a systematic review.
Authors: G C Rinck, G A van den Bos, J Kleijnen, H J de Haes, E Schadé, C H Veenhof
Journal: Journal of Clinical Oncology (1997)

BACKGROUND The objective of this report is to explore methodologic issues on the basis of a systematic review of the literature of effectiveness research on palliative cancer care with regard to selection and characteristics of a study population, interventions, and outcome assessment. METHODS A systematic review was performed of randomized clinical trials on comprehensive palliative care with quality assessment of the studies by three independent observers, using predefined quality criteria. RESULTS In the literature search, 11 relevant studies were identified. Without exception, methodologic problems were experienced. In two studies, the problems were so severe that no results were reported. Problems were associated with the recruitment of a study population in 10 studies, its homogeneity in six, patient attrition in four, defining and maintaining the contrast between the strategies in six, and selection of the outcome variables in four. CONCLUSION Effectiveness research in palliative care is complex and has many pitfalls. To enhance the quality of future palliative care trials and the validity of their results, we particularly stress the importance of careful case finding, strict eligibility criteria, precise documentation of the process of care, and comprehensive outcome measurement. The relation of structure, process, and outcome variables in comprehensive palliative care should be further explored. It is a challenge for future research to link patient outcomes to the quality of care, independent from the autonomous course of the disease and from personal characteristics.
Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey
Authors: Benjamin Terrier, Fabrice Carrat, Evguenia Krastinova, Isabelle Marie, David Launay, Adeline Lacraz, Pauline Belenotti, Luc de Saint Martin, Thomas Quemeneur, Antoine Huart, Fabrice Bonnet, Guillaume Le Guenno, Jean-Emmanuel Kahn, Olivier Hinschberger, Patricia Rullier, Aurelie Hummel, Elisabeth Diot, Christian Pagnoux, Estibaliz Lzaro, Frank Bridoux, Thierry Zenone, Olivier Hermine, Jean-Marc Leger, Xavier Mariette, Patricia Senet, Emmanuelle Plaisier, Patrice Cacoub
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Data on the prognosis of non-infectious mixed cryoglobulinaemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. <h3>Methods</h3> The French multicentre and retrospective CryoVas survey included 242 patients with non-infectious mixed CryoVas. Causes of death and prognostic factors of survival were assessed and a prognostic score was determined to predict survival at 5 years. <h3>Results</h3> After a median follow-up of 35 months, 42 patients (17%) died. Causes of death were mainly serious infections (50%) and vasculitis flare (19%). One-, 2-, 5- and 10-year overall survival rates were 91%, 89%, 79% and 65%, respectively. A prognostic score, the CryoVas score (CVS), for the prediction of survival at 5 years was devised. Pulmonary and gastrointestinal involvement, glomerular filtration rate &lt;60 ml/min and age &gt;65 years were independently associated with death. At 5 years the death rates were 2.6%, 13.1%, 29.6% and 38.5% for a CVS of 0, 1, 2 and ≥3, respectively. At 1 year the death rates were 0%, 3.2%, 18.5% and 30.8% for a CVS of 0, 1, 2 and ≥3, respectively. The CVS was strongly correlated with the Five Factor Score (FFS) 2009, another prognostic score validated in primary necrotising vasculitis (r=0.82; p&lt;0.0001). The area under the curve for the CVS was 0.74 compared with 0.67 for the FFS, indicating a better performance of the CVS (p=0.052). <h3>Conclusions</h3> In patients with non-infectious mixed CryoVas, the main prognostic factors are age &gt;65 years, pulmonary and gastrointestinal involvement and renal failure. A score including these variables is significantly associated with the prognosis.
Statin Therapy for Primary Prevention of Cardiovascular Disease
Authors: Fiona C. Taylor, Mark Huffman, Shah Ebrahim
Journal: JAMA (2013)

Do statins reduce rates of cardiovascular events when used for primary prevention?When used for primary prevention, statins are associated with lower rates of all-cause mortality, major vascular events, and revascularizations compared with placebo. Statin therapy is not associated with increased rates of life-threatening adverse effects such as cancer.
Association of consumption of products containing milk fat with reduced asthma risk in pre-school children: the PIAMA birth cohort study
Authors: A H Wijga
Journal: Thorax (2003)

Environment and lifestyle contribute to the development of asthma in children. Understanding the relevant factors in this relationship may provide methods of prevention. The role of diet in the development of asthma in pre-school children was investigated.Data from 2978 children participating in a prospective birth cohort study were used. Food frequency data were collected at the age of 2 years and related to asthma symptoms reported at the age of 3 years.The prevalence of recent asthma at age 3 was lower in children who consumed (at age 2) full cream milk daily (3.4%) than in those who did not (5.6%) and in those who consumed butter daily (1.5%) than in those who did not (5.1%). The prevalence of recent wheeze was lower in children who consumed milk products daily (13.7%) than in those who did not (18.4%) and in children who consumed butter daily (7.7%) than in those who did not (15.4%). These effects remained in a logistic regression model including different foods and confounders (adjusted odds ratio (CI) for recent asthma: full cream milk daily v rarely 0.59 (0.40 to 0.88), butter daily v rarely 0.28 (0.09 to 0.88)). Daily consumption of brown bread was also associated with lower rates of asthma and wheeze, whereas no associations were observed with the consumption of fruits, vegetables, margarine, and fish.In pre-school children, frequent consumption of products containing milk fat is associated with a reduced risk of asthma symptoms.
HISTORICAL ACCOUNT OF TONSILLECTOMY
Authors: E. E. V. Glover
Journal: BMJ (1918)

EXTIRPATION of the tonsils must have been commonly practised at a very earlv period.The first clear mention of it is made by (Jelsus (A.D. 10) in his De Medicina, cap.vii, sect. 12,but lhe speaks of excising the tonsils witlh such familiarity that it was evidently considered a very ordinary procedure.He writes: ToIisils which remain indurated after inflammation, if covered by a thin membrane, should be loosened by working the finger rounld them, and then torn out; but when this is not prac- ticable, they should be seized by a hook and excised with a scalpel.Aetius (A.D. 490) gives.the following account of the operation:The portion which projects-that is, about one-half of the enlarged gland-may be removed; those who extirpate the entire tonsil remove at the same time structures-which are perfectly healthy, and in this way give rise to serious haemor- rhage.