tbuckley/cabot-search huggingface dataset:
Myeloid Cell Leukemia-1 Inversely Correlates with Glycogen Synthase Kinase-3β Activity and Associates with Poor Prognosis in Human Breast Cancer
Authors: Qingqing Ding, Xianghuo He, Weiya Xia, Jung-Mao Hsu, Chun-Te Chen, Long-Yuan Li, Dung-Fang Lee, Jer-Yen Yang, Xiaoming Xie, Jaw-Ching Liu, Mien-Chie Hung
Journal: Cancer Research (2007)

Myeloid cell leukemia-1 (Mcl-1), an antiapoptotic Bcl-2 family member, is overexpressed in many types of human cancer and associates with cell immortalization, malignant transformation, and chemoresistance. Glycogen synthase kinase-3beta (GSK-3beta), a key component of the Wnt signaling pathway, is involved in multiple physiologic processes such as protein synthesis, tumorigenesis, and apoptosis. Here, we report that expression of Mcl-1 was correlated with phosphorylated GSK-3beta (p-GSK-3beta) at Ser(9) (an inactivated form of GSK-3beta) in multiple cancer cell lines and primary human cancer samples. In addition, Mcl-1 was strikingly linked with poor prognosis of human breast cancer, in which the high level of Mcl-1 was related to high tumor grade and poor survival of breast cancer patients. Furthermore, we found that activation of GSK-3beta could down-regulate Mcl-1 and was required for proteasome-mediated Mcl-1 degradation. Under some physiologic conditions, such as UV irradiation, anticancer drug treatment, and inhibition of growth factor pathways, Mcl-1 was down-regulated through activation of GSK-3beta. Our results indicate that Mcl-1 stabilization by GSK-3beta inactivation could be involved in tumorigenesis and serve as a useful prognostic marker for human breast cancer.
Obesity and Colorectal Adenomatous Polyps
Authors: Alfred I. Neugu, Won Chul Lee, Gail C. Garbowski, Jerome D. Waye, Kenneth A. Forde, Michael R. Treat, Cecilia Fenoglio-Preiser
Journal: JNCI Journal of the National Cancer Institute (1991)

Obesity has been investigated as a risk factor for various malignancies, including colon cancer. A case-control study was conducted on patients in three colonoscopy practices in New York City to determine possible risk factors for colorectal adenomatous polyps, a known precursor lesion for most cases of colorectal cancer. Among 301 case subjects with incident adenomatous polyps (174 men and 127 women) and 506 control subjects (223 men and 283 women), an increased risk was observed with increasing body mass index in women (odds ratio 2.1, 95% confidence interval 1.1–4.0; for highest versus lowest quartile, linear trend P =.02). A nonsignificant trend was observed for men. The increased risk seen in women is consistent with prior observations regarding reproductive hormonal and dietary risk factors for colorectal cancer. [J Natl Cancer Inst 83:359–361, 1991]
Can D-dimer assay, together with clinical probability predict computed tomography pulmonary angiogram (CTPA) outcomes for pulmonary embolism (PE)?
Authors: Diana Lees, Paul Griffiths, Carol Paxton, Zaroug Wahbi
Journal: European Respiratory Journal (2011)

Introduction:  Annual incidence of PE is estimated at 60-70/100 000. Current National Guidelines recommend patients presenting with suspected PE should be risk-assessed according to presenting symptoms, risk factors, clinical findings, and investigation results. Fear of missing potentially life-threatening PE likely results in over-investigation.   Aims:  To assess if we are identifying patients correctly based upon pre-imaging risk scores and whether there is a D-dimer level most consistent with the diagnosis.   Method:  A retrospective review of patients attending for CTPA in a one month period. Clinical indicators were documented and patients were divided into risk groups.   Results:  38 patients had a CTPA. 20 (52%) male. Age range 20-99years (median 62). 6 (15%) did not have a D-dimer. 22 (58%) had a major risk factor for PE, and 16 had a minor risk factor. 32 (84%) patients had a positive D-dimer (>200 ng/mL).  In the high risk group 8/22 had a positive CTPA with median D-dimer of 1552ng/mL. 14/22 were negative for PE with median D-dimer of 345ng/mL. The remaining 16 patients who were low risk were all negative for PE on CTPA, median D-dimer 570ng/mL.   Conclusion:  The results show that improvements can be made in investigating patients with suspected PE. A D-dimer level higher than that classed as positive in our hospital trust may be more appropriate from this small sample size. Further review with a larger number of patients is required.  This may reduce the financial costs but more importantly will provide patients with appropriate directed care and reduced risk from radiological exposure.
Depletion of Peripheral Macrophages and Brain Microglia Increases Brain Tumor Titers of Oncolytic Viruses
Authors: Giulia Fulci, Nina Dmitrieva, Davide Gianni, Elisabeth J. Fontana, Xiaogang Pan, Yanhui Lu, Claire S. Kaufman, Balveen Kaur, Sean E. Lawler, Robert J. Lee, Clay B. Marsh, Daniel J. Brat, Nico van Rooijen, Anat Stemmer Rachamimov, Fred H. Hochberg, Ralph Weissleder, Robert L. Martuza, E. Antonio Chiocca
Journal: Cancer Research (2007)

Abstract Clinical trials have proven oncolytic virotherapy to be safe but not effective. We have shown that oncolytic viruses (OV) injected into intracranial gliomas established in rodents are rapidly cleared, and this is associated with up-regulation of markers (CD68 and CD163) of cells of monocytic lineage (monocytes/microglia/macrophages). However, it is unclear whether these cells directly impede intratumoral persistence of OV through phagocytosis and whether they infiltrate the tumor from the blood or the brain parenchyma. To investigate this, we depleted phagocytes with clodronate liposomes (CL) in vivo through systemic delivery and ex vivo in brain slice models with gliomas. Interestingly, systemic CL depleted over 80% of peripheral CD163+ macrophages in animal spleen and peripheral blood, thereby decreasing intratumoral infiltration of these cells, but CD68+ cells were unchanged. Intratumoral viral titers increased 5-fold. In contrast, ex vivo CL depleted only CD68+ cells from brain slices, and intratumoral viral titers increased 10-fold. These data indicate that phagocytosis by both peripheral CD163+ and brain-resident CD68+ cells infiltrating tumor directly affects viral clearance from tumor. Thus, improved therapeutic efficacy may require modulation of these innate immune cells. In support of this new therapeutic paradigm, we observed intratumoral up-regulation of CD68+ and CD163+ cells following treatment with OV in a patient with glioblastoma. [Cancer Res 2007;67(19):9398–406]
GENE EXPRESSION IN TENOCYTES SUGGESTS DEGNERATIVE TENDON TEARS ATTEMPT TO HEAL
Authors: A M Fearon, J L Cook, P Smith, A Scott
Journal: British Journal of Sports Medicine (2013)

Introduction The breakdown of the extracellular matrix (ECM) is well recognised in tendinopathy and likely the cause of degenerative tendon tears. Tendinopathy and degenerative tears can be hard and expensive to treat. Understanding the cellular processes that lead to ECM breakdown will likely lead to improved treatments. With this in mind, the gene transcript profile for extracellular matrix remodelling of tendon specimens from people with greater trochanteric pain syndrome (GTPS) and associated gluteal tendon tears were compared to an age and sex matched reference group. Methods Tendon specimens were collected from six participants undergoing gluteal tendon reconstruction for long standing (mean duration=41 months) GTPS, and four participants from an age-matched reference group (REF) of hip OA patients asymptomatic for GTPS. Specimens were collected using sterile technique and were stored at −80°C. RNA was isolated via laser capture micro-dissection (LCM) of areas of tendon that typified tendon rather than para-tendon or vessels within the specimen—identified using light microscopy and H&amp;E staining. Specimens were tested using the SABiosciences array (PAHS-013). Immunohistochemistry was used to confirm the site of a subset of the expressed genes. Results We report on gene regulation changes of at least five fold that were seen in the GTPS group compared to the REF group. Genes involved in extracellular matrix modelling were both up regulated (MMP7) and down regulated (MMP3). The following cell adhesion genes were up regulated: ITGAV, NCAM1, ITGAM, while ITG3 was down regulated. The following genes involved in ECM synthesis were up regulated (LAMC1, COL1A1, COL5A1, Col6A1), while ADMATS1, LAMB3, VTN were down regulated. Conclusions This paper presents a novel method of tissue specimen selection (LCM), reducing the likelihood of RNA contamination from cells other than tenocytes. Further, these results suggest that there is increased cell activity and collagen production indicating that the tendon is continuing to actively remodel despite prolonged tissue damage. This supports the role of appropriate advice regarding tendon loading and compression, exercises to strengthen the musclo-tendinous unit, and ongoing support to patients. Recovery from tendinopathy may be possible—even in longstanding cases.
Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial
Authors: Bernard Escudier, Anna Pluzanska, Piotr Koralewski, Alain Ravaud, Sergio Bracarda, Cezary Szczylik, Christine Chevreau, Marek Filipek, Bohuslav Melichar, Emilio Bajetta, Vera Gorbunova, Jacques-Olivier Bay, Istvan Bodrogi, Agnieszka Jagiello-Gruszfeld, Nicola Moore
Journal: The Lancet (2007)
Antigen recognition by H-2-restricted cytolytic T lymphocytes is not mediated by two independent receptors.
Authors: D T Harris, H R MacDonald, J C Cerottini
Journal: The Journal of Experimental Medicine (1984)

Detergent-solubilized murine cytolytic T lymphocytes (CTL) clones were incorporated into Sendai virus-containing synthetic liposomes. When these liposomes were then fused with other CTL clones possessing a different non-cross-reacting specificity, the fusion products were observed to lyse target cells recognized by both parental CTL clones. This method was then used with two H-2-restricted CTL clones of different, non-cross-reacting specificities (anti-H-2b-H-Y or anti-H-2b Moloney leukemia virus). Once again, the fusion products were found to be lytic against both target cells recognized by the parental clones, but in no instance was there any observable lysis of target cells bearing the same nominal antigen in the context of different H-2 molecules. These results provide strong evidence that antigen recognition by H-2-restricted CTL is not mediated by two independent antigen receptors.
Fetal and Perinatal Exposure to Drugs and Chemicals: Novel Biomarkers of Risk
Authors: Fatma Etwel, Janine R. Hutson, Parvaz Madadi, Joey Gareri, Gideon Koren
Journal: The Annual Review of Pharmacology and Toxicology (2013)

Pregnant women are almost always excluded from randomized controlled clinical trials, as the risks to the fetus posed by most new chemical entities or approved drugs cannot be sufficiently ruled out. Hence, a major scientific challenge in this field is to discover and validate alternative tools that will fill the knowledge gap created by the lack of participation in gold-standard randomized trials. This review focuses on novel tools that allow estimation of fetal risks after exposure to therapeutic agents, such as placental perfusion studies, biomarkers of fetal exposure, and novel epidemiological and pharmacogenetic tools, all of which have been tested successfully in recent years.
Clinical significance of increased CD4+CD25-Foxp3+ T cells in patients with new-onset systemic lupus erythematosus
Authors: B Zhang, X Zhang, F L Tang, L P Zhu, Y Liu, P E Lipsky
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To investigate the expressions of Foxp3 and CD25 on CD4<sup>+</sup> T cells from patients with new-onset systemic lupus erythematosus (SLE) and assess their clinical significance. <h3>Methods:</h3> 10 patients with active (systemic lupus erythematosus Disease Activity Index (SLEDAI) ⩾10) and 11 with inactive (SLEDAI ⩽5) new-onset SLE as well as 11 healthy volunteers were enrolled. The expressions of CD25, Foxp3 and CD127 on CD4<sup>+</sup> T cells were analysed by flow cytometry. Proliferation assays were performed on isolated CD4<sup>+</sup>CD25<sup>+</sup> or CD4<sup>+</sup>CD25<sup>−</sup> T cells, or both. <h3>Results:</h3> There was no significant difference in the number of CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+ </sup>T cells in subjects with either active or inactive SLE compared with normal controls (p<i>&gt;</i>0.05). Moreover, the suppressive capacity of CD4<sup>+</sup>CD25<sup>+ </sup>T cells in patients with new-onset lupus was not impaired as measured by the ability to inhibit proliferation of CD4<sup>+</sup>CD25<sup>−</sup> T cells. Interestingly, CD4<sup>+</sup>CD25<sup>−</sup>Foxp3<sup>+ </sup>T cells in new-onset lupus (2.97–10.94%) were significantly more frequent than in normal controls (1.01–3.62%) (p&lt;0.01), and correlated positively with the titres of anti-dsDNA antibodies (p = 0.029). Few of these cells expressed CD127. Treatment with glucocorticoids and cyclophosphamide reduced CD4<sup>+</sup>CD25<sup>−</sup>Foxp3<sup>+</sup> T cells in 8 of 10 patients with active disease. <h3>Conclusions:</h3> There was a significant increase in CD4<sup>+</sup>CD25<sup>−</sup>Foxp3<sup>+ </sup>T cells in patients with new-onset SLE that correlated with anti-dsDNA titres, whereas no alteration in either the percentage or function of CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+ </sup>T cells was observed.
Can CAP guideline adherence improve patient outcome in internal medicine departments?
Authors: F. Blasi, I. Iori, A. Bulfoni, S. Corrao, S. Costantino, D. Legnani
Journal: European Respiratory Journal (2008)

The impact of compliance with Italian guidelines on the outcome of hospitalised community-acquired pneumonia (CAP) in internal medicine departments was evaluated. All Fine class IV or V CAP patients were included in this multicentre, interventional, before-and-after study, composed of three phases: 1) a retrospective phase (RP; 1,443 patients); 2) a guideline implementation phase; and 3) a prospective phase (PP; 1,404 patients). Antibiotic prescription according to the guidelines increased significantly in the PP. The risk of failure at the end of the firstline therapy was significantly lower in the PP versus the RP (odds ratio (OR) 0.83, 95% confidence interval (CI) 0.69-1.00), particularly in Fine class V patients (OR 0.71, 95% CI 0.51-0.98). Analysis of outcome in the overall population (2,847 patients) showed a statistically significant advantage for compliant versus noncompliant therapies in terms of failure rate (OR 0.74, 95% CI 0.60-0.90) and an advantage in terms of mortality (OR 0.77, 95% CI 0.58-1.04). Antipneumococcal cephalosporin monotherapy was associated with a low success rate (68.6%) and the highest mortality (16.2%); levofloxacin alone and the combination of cephalosporin and macrolide resulted in higher success rates (79.1 and 76.7%, respectively) and significantly lower mortalities (9.1 and 5.7%, respectively). Overall, a low compliance with guidelines in the prospective phase (44%) was obtained, indicating the need for future more aggressive and proactive approaches.
Radiographic Findings of a Ruptured Abdominal Aortic Aneurysm
Authors: Ding-Kuo Chien, Wen-Han Chang, Yu-Hang Yeh
Journal: Circulation (2010)

A 69-year-old man with a history of gastric ulcer and hypertension presented to the emergency department complaining of a sudden onset of epigastric pain and vomiting some coffee-ground fluid.The patient appeared to be in distress.His blood pressure was 82/64 mm Hg, and his heart rate was 79 bpm.On physical examination, his upper abdomen was tender with guarding, and we heard diffuse hypoactive bowel sounds.The chest radiograph was unremarkable.A supine abdominal radiograph showed a large, soft-tissue-density central mass that had peripheral calcification with loss of the right-side margin and right psoas border unvisualized (Figure 1).The overall findings indicated a ruptured abdominal aortic aneurysm.This conclusion was confirmed by contrastenhanced computed tomography showing a large aortic aneurysm (Ϸ9 cm in diameter and 12 cm in length) with a disruption over the right cephalad side that was a massive retroperitoneal hematoma (Figures 2 and3).The patient received emergent abdominal aortic grafting quickly and subsequently recovered well 2 weeks later.Although elderly patients with ruptured abdominal aortic aneurysms and hypotension might present atypical symptoms, 1 if we could search the particular abdominal radiographs carefully for a large central mass, peripheral calcifications of the mass, loss of part of the mass margin, and loss of one or both psoas outlines, the diagnosis could be correct in 90% of these patients.
Do patients with moderately impaired gastrointestinal function requiring enteral nutrition need a predigested nitrogen source? A prospective crossover controlled clinical trial.
Authors: R G Rees, W R Hare, G K Grimble, P G Frost, D B Silk
Journal: Gut (1992)

This prospective double blind randomised seven day crossover controlled clinical trial was carried out to determine whether enterally fed patients with moderately impaired gastrointestinal function require a predigested nitrogen (N) source compared with whole protein. Twelve malnourished patients with varying gastrointestinal abnormalities, who required enteral feeding, received 2.25 l of one of two isocaloric isonitrogenous enteral diets (1 kcal/ml, 4.8 g nitrogen/l) containing either predominantly medium chain peptides (tetra or higher peptides) or whole protein as the nitrogen source. Nitrogen absorption and balance were calculated from dietary intake and analysis of 24 hour total urinary and faecal nitrogen for the last five days of each study period. There was no significant difference in either stool weight (110 (SEM) (49) v 111 (32) g/d), nitrogen absorption (91 (2) v 89 (2)%) or nitrogen balance (+1.0 (1.3) v +0.6 (1.4) g nitrogen/d) between the peptide and whole protein nitrogen sources when all patients are considered. There was, however, evidence to suggest a nutritional advantage from administering an enteral diet whose nitrogen source comprises oligopeptides, rather than whole protein, to a subgroup of patients with small bowel disease.
Capecitabine and Oxaliplatin in the Preoperative Multimodality Treatment of Rectal Cancer: Surgical End Points From National Surgical Adjuvant Breast and Bowel Project Trial R-04
Authors: Michael J. O'Connell, Linda H. Colangelo, Robert W. Beart, Nicholas J. Petrelli, Carmen J. Allegra, Saima Sharif, Henry C. Pitot, Anthony F. Shields, Jerome C. Landry, David P. Ryan, David S. Parda, Mohammed Mohiuddin, Amit Arora, Lisa S. Evans, Nathan Bahary, Gamini S. Soori, Janice Eakle, John M. Robertson, Dennis F. Moore, Michael R. Mullane, Benjamin T. Marchello, Patrick J. Ward, Timothy F. Wozniak, Mark S. Roh, Greg Yothers, Norman Wolmark
Journal: Journal of Clinical Oncology (2014)

The optimal chemotherapy regimen administered concurrently with preoperative radiation therapy (RT) for patients with rectal cancer is unknown. National Surgical Adjuvant Breast and Bowel Project trial R-04 compared four chemotherapy regimens administered concomitantly with RT.Patients with clinical stage II or III rectal cancer who were undergoing preoperative RT (45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions) were randomly assigned to one of the following chemotherapy regimens: continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m(2), 5 days per week), with or without intravenous oxaliplatin (50 mg/m(2) once per week for 5 weeks) or oral capecitabine (825 mg/m(2) twice per day, 5 days per week), with or without oxaliplatin (50 mg/m(2) once per week for 5 weeks). Before random assignment, the surgeon indicated whether the patient was eligible for sphincter-sparing surgery based on clinical staging. The surgical end points were complete pathologic response (pCR), sphincter-sparing surgery, and surgical downstaging (conversion to sphincter-sparing surgery).From September 2004 to August 2010, 1,608 patients were randomly assigned. No significant differences in the rates of pCR, sphincter-sparing surgery, or surgical downstaging were identified between the CVI FU and capecitabine regimens or between the two regimens with or without oxaliplatin. Patients treated with oxaliplatin experienced significantly more grade 3 or 4 diarrhea (P < .001).Administering capecitabine with preoperative RT achieved similar rates of pCR, sphincter-sparing surgery, and surgical downstaging compared with CVI FU. Adding oxaliplatin did not improve surgical outcomes but added significant toxicity. The definitive analysis of local tumor control, disease-free survival, and overall survival will be performed when the protocol-specified number of events has occurred.
Gastric acid inhibitors may prevent/heal oxyntic lesions by reducing blood demand
Authors: Helge Lyder Waldum, Øyvind Hauso
Journal: Gut (2012)

We read with interest the paper by Demitrack and co-workers describing how inhibitors of gastric acid secretion had a beneficial effect upon gastric wound healing beyond the effect on gastric luminal acidity.1 In that context, …
Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression
Authors: Sarah Ann R. Anderson, Michael Michaelides, Parisa Zarnegar, Yanhua Ren, Pernilla Fagergren, Panayotis K. Thanos, Gene-Jack Wang, Michael Bannon, John F. Neumaier, Eva Keller, Nora D. Volkow, Yasmin L. Hurd
Journal: Journal of Clinical Investigation (2013)

Negative affect is critical for conferring vulnerability to opiate addiction as reflected by the high comorbidity of opiate abuse with major depressive disorder (MDD). Rodent models implicate amygdala prodynorphin (Pdyn) as a mediator of negative affect; however, evidence of PDYN involvement in human negative affect is limited. Here, we found reduced PDYN mRNA expression in the postmortem human amygdala nucleus of the periamygdaloid cortex (PAC) in both heroin abusers and MDD subjects. Similar to humans, rats that chronically self-administered heroin had reduced Pdyn mRNA expression in the PAC at a time point associated with a negative affective state. Using the in vivo functional imaging technology DREAMM (DREADD-assisted metabolic mapping, where DREADD indicates designer receptors exclusively activated by designer drugs), we found that selective inhibition of Pdyn-expressing neurons in the rat PAC increased metabolic activity in the extended amygdala, which is a key substrate of the extrahypothalamic brain stress system. In parallel, PAC-specific Pdyn inhibition provoked negative affect-related physiological and behavioral changes. Altogether, our translational study supports a functional role for impaired Pdyn in the PAC in opiate abuse through activation of the stress and negative affect neurocircuitry implicated in addiction vulnerability.