tbuckley/cabot-search huggingface dataset:
Transcription Factor Signal Transducer and Activator of Transcription 5 Promotes Growth of Human Prostate Cancer Cells <i>In vivo</i>
Authors: Ayush Dagvadorj, Robert A. Kirken, Benjamin Leiby, James Karras, Marja T. Nevalainen
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Signal transducer and activator of transcription 5a/b (Stat5a/b) is the key mediator of prolactin effects in prostate cancer cells via activation of Janus-activated kinase 2. Prolactin is a locally produced growth factor in human prostate cancer. Prolactin protein expression and constitutive activation of Stat5a/b are associated with high histologic grade of clinical prostate cancer. Moreover, activation of Stat5a/b in primary prostate cancer predicts early disease recurrence. Here, we inhibited Stat5a/b by several different methodologic approaches. Our goal was to establish a proof of principle that Stat5a/b is critical for prostate cancer cell viability in vitro and for prostate tumor growth in vivo. Experimental Design: We inhibited Stat5a/b protein expression by antisense oligonucleotides or RNA interference and transcriptional activity of Stat5a/b by adenoviral expression of a dominant-negative mutant of Stat5a/b in prostate cancer cells in culture. Moreover, Stat5a/b activity was suppressed in human prostate cancer xenograft tumors in nude mice. Stat5a/b regulation of Bcl-XL and cyclin D1 protein levels was shown by antisense suppression of Stat5a/b protein expression followed by Western blotting. Results and Conclusions: We show here that inhibition of Stat5a/b by antisense oligonucleotides, RNA interference, or adenoviral expression of dominant-negative Stat5a/b effectively kills prostate cancer cells. Moreover, we show that Stat5a/b is critical for human prostate cancer xenograft growth in nude mice. The effects of Stat5a/b on the viability of prostate cancer cells involve Stat5a/b regulation of Bcl-XL and cyclin D1 protein levels but not the expression or activation of Stat3. This work establishes Stat5a/b as a therapeutic target protein for prostate cancer. Pharmacologic inhibition of Stat5a/b in prostate cancer can be achieved by small-molecule inhibitors of transactivation, dimerization, or DNA binding of Stat5a/b.
MEGA6: Molecular Evolutionary Genetics Analysis Version 6.0
Authors: Koichiro Tamura, Glen Stecher, Daniel Peterson, Alan Filipski, Sudhir Kumar
Journal: Molecular Biology and Evolution (2013)

We announce the release of an advanced version of the Molecular Evolutionary Genetics Analysis (MEGA) software, which currently contains facilities for building sequence alignments, inferring phylogenetic histories, and conducting molecular evolutionary analysis. In version 6.0, MEGA now enables the inference of timetrees, as it implements the RelTime method for estimating divergence times for all branching points in a phylogeny. A new Timetree Wizard in MEGA6 facilitates this timetree inference by providing a graphical user interface (GUI) to specify the phylogeny and calibration constraints step-by-step. This version also contains enhanced algorithms to search for the optimal trees under evolutionary criteria and implements a more advanced memory management that can double the size of sequence data sets to which MEGA can be applied. Both GUI and command-line versions of MEGA6 can be downloaded from www.megasoftware.net free of charge.
Trends in Survival of Patients With Metastatic Breast Cancer
Authors: Adri C. Voogd, Kitty van Gestel, Miranda F. Ernst
Journal: Journal of Clinical Oncology (2005)

Considering the results of three French cancer centers described in the study of Andre et al, 1 remarkable progress has been made in the treatment of breast cancer patients with synchronous metastases between 1987 and 2000.The 3-year overall survival rates of the patients improved from 27% to 44%, and the median survival increased from 23 to 29 months.In the Discussion of their article, the authors attribute part of the improvement to the increased use of taxanes and aromatase inhibitors.Although they recognize the limitations of their study design to make such a causal connection, some other potential confounders remain underexposed.From the Tables and the information in the Patients and Methods section, it is not clear whether all patients with metastatic disease have been included and if all patients have been seen by medical oncologists and have received systemic treatment.Data from the Eindhoven Cancer Registry in the Netherlands and clinical experience suggest that there will always be some patients with metastatic breast cancer who refuse systemic treatment or who are not referred to a medical oncologist because of serious comorbid conditions or an extremely short life expectancy.According to the data of the Eindhoven Cancer Registry, at least 6% of the patients with primary metastatic breast cancer diagnosed in the period from 1995 to 1997, did not receive systemic treatment; some of them received no treatment at all or only locoregional treatment, and others underwent nonsystemic palliative treatment such as radiotherapy for painful bone metastases or pleurodesis for malignant pleural effusions. 2What proportion of the patients in the study of Andre et al received no systemic treatment, and did it change over time?Exclusion of such patients from the analyses would overestimate the median and overall survival rates.Another possible source of bias that was not discussed is lead-time bias.The authors state that staging procedures for primary breast cancer were similar from 1987 to 2000, including physical examination, blood tests, chest x-ray, liver ultrasound, and bone scan.However, in many countries, the growing use of mammography during the 1980s and the introduction of breast cancer screening programs in the 1990s have led to the diagnosis of breast cancer tumors in an earlier stage.An earlier detection of the primary tumor may have led to earlier detection of metastatic disease and a better overall survival.To confirm this hypothesis, one would expect a decrease in the proportion of patients with metastatic disease in the presence of a large primary tumor and/or locally advanced breast cancer.To rule out the effect of lead-time bias, it might be necessary to adjust for changes in the local and regional tumor stage.
Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction
Authors: Ming Fu, Solange Landreville, Olga A. Agapova, Luke A. Wiley, Michael Shoykhet, J. William Harbour, Robert O. Heuckeroth
Journal: Journal of Clinical Investigation (2013)

The retinoblastoma 1 (RB1) tumor suppressor is a critical regulator of cell cycle progression and development. To investigate the role of RB1 in neural crest–derived melanocytes, we bred mice with a floxed Rb1 allele with mice expressing Cre from the tyrosinase (Tyr) promoter. TyrCre+;Rb1fl/fl mice exhibited no melanocyte defects but died unexpectedly early with intestinal obstruction, striking defects in the enteric nervous system (ENS), and abnormal intestinal motility. Cre-induced DNA recombination occurred in all enteric glia and most small bowel myenteric neurons, yet phenotypic effects of Rb1 loss were cell-type specific. Enteric glia were twice as abundant in mutant mice compared with those in control animals, while myenteric neuron number was normal. Most myenteric neurons also appeared normal in size, but NO-producing myenteric neurons developed very large nuclei as a result of DNA replication without cell division (i.e., endoreplication). Parallel studies in vitro found that exogenous NO and Rb1 shRNA increased ENS precursor DNA replication and nuclear size. The large, irregularly shaped nuclei in NO-producing neurons were remarkably similar to those in progeria, an early-onset aging disorder that has been linked to RB1 dysfunction. These findings reveal a role for RB1 in the ENS.
Effect of statin therapy on colorectal cancer
Authors: M. Bardou, A. Barkun, M. Martel
Journal: Gut (2010)

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also called statins, are commonly prescribed medications that lower serum cholesterol and decrease cardiac morbidity and mortality. They also possess beneficial effects beyond their cholesterol-lowering properties. Preclinical data suggest statins exhibit pleiotropic antineoplastic effects in a variety of tumours, but clinical studies have provided conflicting data as to whether statins influence the risk of cancer. The biological underpinning of potential effects of statins in colorectal cancer and their role in its prevention or as adjuvant therapy are reviewed. Following a meta-analysis of both randomised clinical trials and epidemiological studies, it is concluded that available clinical data only support a modest, although statistically significant, protective effect of statins in colorectal cancer. Statins may impact on outcomes by decreasing the invasiveness or metastatic properties of colorectal cancer. The data supporting these hypotheses, however, are few and further studies are required to better assess these hypotheses. Statins may also exert a beneficial effect on colorectal cancer by sensitising the tumour to chemotherapeutic agents. Further research is needed to better define the role of statins in overcoming chemoresistance. The combination of statins with other drugs, such as low-dose aspirin or safer non-steroidal anti-inflammatory medications, may be useful in both the prevention and treatment of colorectal cancer.
Pulmonary endothelinergic system in experimental congestive heart failure
Authors: Delphine Lepailleur-Enouf, Giorgia Egidy, Monique Philippe, Liliane Louedec, Jean-Paul Henry, Paul Mulder, Jean-Baptiste Michel
Journal: Cardiovascular Research (2001)

Objectives: Endothelin-1 (ET-1), plays an important role in the pathophysiology of CHF and the pulmonary endothelium is an early hemodynamic target in diastolic left ventricular dysfunction. Therefore we hypothesized that the lung is a main source of humoral endothelin in CHF and that its secretion is proportional to the degree of heart failure. Methods and results: We used rats with coronary artery ligation as an experimental model of either compensated or decompensated heart failure, depending on infarct size. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that in the lung, the expression of preproET-1 mRNA was higher in decompensated HF than in control and compensated HF rats (P<0.001). Run-on assay demonstrated that ET-1 overexpression is regulated at a transcriptional level (P<0.01). In contrast, there was no change in ET-1 mRNA expression in aortae, left ventricular myocardium and skeletal muscle. The expression of endothelin-converting enzyme (ECE)-1 mRNA was not modified and the expression of ETB receptor mRNA in the congestive lung was significantly lower than in control and compensated HF rats (P<0.0001), while the expression of ETA receptor mRNA did not differ between groups. The lung and plasma ET-1 peptide levels were respectively 4.2 and 9 fold higher in the rats with decompensated HF than in control rats (P<0.05; P<0.0001). Organoculture experiments showed that the lung ET-1 peptide secretion level in rats with decompensated HF was higher than that in control rats (P<0.01). In contrast, there was no change in ET-1 peptide secretion by the left ventricular myocardium and skeletal muscle. In plasma of rats with decompensated HF, the rate of bigET-1 conversion to ET-1 was 22%. ET-1 peptide was also present in the pleural effusion of decompensated heart failure. Plasma ET-1 concentration was significantly correlated with upstream markers of left ventricular diastolic dysfunction, with the expression of preproET-1 mRNA in the lung, with lung and pleural ET-1 concentration and with the expression ratio of ET-1/ETB receptor mRNA. Conclusion: Taken together, these data suggest that overexpression of ET-1 and down-regulation of ETB receptors in the lung are determinants of circulating endothelin in CHF. As a corollary, increased plasma endothelin may provide evidence of pulmonary endothelial dysfunction in CHF.
“The anti-developmental, the anti-narrative, the anti-historical”: Mondrian as a paradigmatic artist for empirical aesthetics
Authors: Chris McManus
Journal: Behavioral and Brain Sciences (2013)

In addition to general criticisms of scientific studies on empirical aesthetics, Bullot & Reber (B&R) particularly criticise two "representative studies" that manipulated paintings by Mondrian, those studies seemingly, "fail[ing] to consider the predictions suggested by a contextualist approach to the appreciation of imbalance" (sect. 4.2, para.2). Those criticisms are unjustified, both within the approaches of empirical aesthetics and the historical context and aims of Mondrian's work.
Nutritional Modulation of Antitumor Efficacy and Diarrhea Toxicity Related to Irinotecan Chemotherapy in Rats Bearing the Ward Colon Tumor
Authors: Hongyu Xue, Michael B. Sawyer, Catherine J. Field, Levinus A. Dieleman, Vickie E. Baracos
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To evaluate and compare the influence of dietary elements on cancer progression, chemotherapy efficacy, and toxicity, particularly severe, late-onset diarrhea related to irinotecan (CPT-11) treatment. Experimental Design: We used laboratory rats fed a standardized basal diet, Ward colon tumor, and CPT-11 therapy for the study of CPT-11–induced diarrhea. Dietary interventions were selected from nutrients already established to modify other forms of colitis and which have been hypothesized to mitigate chemotherapy-induced gastrointestinal injury (glutamine, n-3 fatty acids, prebiotic oligosaccharides). Animals adapted to test diets were treated with CPT-11 at the maximum tolerated dose (125 mg/kg × 3 days) and diarrhea was followed continuously for 1 week. Results: The inclusion of n-3 fatty acids in the diet (5%, w/w of total fat) suppressed tumor growth and enhanced CPT-11's efficacy; this treatment did not affect the incidence or severity of diarrhea. By contrast, oral glutamine bolus (0.75 g/kg) administered prior to each CPT-11 treatment reduced the incidence of severe diarrhea (34.1 ± 4.7% versus 53.8 ± 4.2%, P &amp;lt; 0.005) and decreased the area under the curve of diarrhea score (16.5 ± 1.0 versus 18.8 ± 0.5, P &amp;lt; 0.05). Identical results were obtained with i.v. bolus glutamine administration. Glutamine treatment did not alter CPT-11's antitumor efficacy. The addition of prebiotic oligosaccharides to the diet (8%, w/w of diet) did not mitigate the severity of diarrhea, and it raised the activity of β-glucuronidase in cecal contents, a key bacterial enzyme mediating CPT-11–related intestinal toxicity. Conclusion: Our experiments suggest that glutamine and n-3 fatty acids might be potentially useful adjuncts to CPT-11 treatment.
Successful treatment of hairy cell leukemia with β‐ser interferon
Authors: Peter H. Wiernik, Bradford Schwartz, Janice P. Dutcher, Nancy Turman, Crestina Adinolfi
Journal: American Journal of Hematology (1990)

Twelve patients with hairy cell leukemia underwent treatment with beta-ser interferon, a type I interferon with potent antiproliferative activity. Ten of the 12 patients had had prior therapy and the median time from diagnosis to initiation of treatment was 8.5 months (range 1 month to 18 years). Bone marrow involvement ranged from 90-100% hairy cells. Beta-ser interferon was administered as an intravenous injection of 90 million units per dose, three times weekly. Dose reductions were by dose and by frequency in individual patients. Ten of 12 patients (83%) responded, including 7 complete (CR) and 3 partial (PR) responses. The median time to at least PR was 6 months and the median time to CR was 12 months. The median duration of overall response (PR + CR or PR) is 31+ months (range 26(+)-40+ months). Of the 6 patients who underwent dose reductions due to toxicity or poor tolerance, 4 CR patients reverted to PR, and 2 PR patients have increased the number of hairy cells in the marrow, while maintaining normal peripheral blood counts. One each of these has regained CR and PR status after an increase in dose.
Pleural nodules in a patient with a colonic tumour
Authors: Edson Marchiori, Rosana Souza Rodrigues, Mario Celso Martins Reis, Gláucia Zanetti, Miriam Menna Barreto
Journal: Thorax (2013)

A 58-year-old woman underwent chest CT to monitor a colonic tumour diagnosed 1 year previously. Axial and coronal CT images showed multiple well-circumscribed pleural-based nodules in the left lower hemithorax, and the absence of the spleen in the left upper quadrant (figure 1). Routine blood work demonstrated no significant laboratory abnormality. The patient also had a history of a gunshot wound that transfixed the thoracoabdominal region 40 years previously. Thoracotomy was performed and disclosed multiple reddish-purple nodules on the pleural surface (figure 2).



Figure 1 
Axial (A) and coronal (B) CT images showed multiple pleural nodules in the left hemithorax and the …
Diagnosis of Localized, Screen-Detected, Prostate Cancer--Crisis or Opportunity?
Authors: S.-L. Yao, G. L. Lu-Yao
Journal: JNCI Journal of the National Cancer Institute (2010)

Perhaps more so than with almost any other common cancer over the past one or two decades, we have witnessed an extraordinary change in the presenting characteristics of men with prostate cancer. Whereas disease was often disseminated at diagnosis 20 years ago, it is now often organ confined. Whereas disease was often evident, it is now frequently asymptomatic at diagnosis. There could be many explanations for this change over time, but prostate-specific antigen (PSA) testing is probably chief among them because many of these changes coincided so closely with the introduction and use of this test. These vast changes in the presenting population raise the possibility that previous data that were collected during the pre-PSA era may not reflect contemporary reality and may thus limit the ability of health-care providers and their patients to make the most appropriate decisions regarding the optimal management of the disease. To address this challenge, Stattin et al. (1) report the results of a study that adds to the growing list of population-based studies (2) with data on long-term outcomes for patients diagnosed with localized disease in the contemporary PSA era. Compared with previous research, this population-based study was notable in that the authors were able to incorporate PSA and Gleason score
Collaboration of histoincompatible T and B lymphocytes using cells from tetraparental bone marrow chimeras.
Authors: H von Boehmer, L Hudson, J Sprent
Journal: The Journal of Experimental Medicine (1975)

T-B collaboration has been studied in a secondary response to sheep erythrocytes using either syngeneic or allogeneic T- and B-cell combinations. T cells prepared from tetraparental bone marrow chimeras (TBMC), carrying H-2 determinants of one parental strain only, cooperated with syngeneic, as well as with allogeneic B cells carrying the alloantigens to which the T cells had been tolerized in the chimeric environment. When TBMC-derived cells of a single H-2 specificity were transferred with a mixture of TBMC-derived B cells of both H-2 types of the parental strains, no preference for syngeneic cooperation was found. The data therefore suggest that the presence of differing H-2-complex determinants on the allogeneic T- and B-cell populations of the two different strain combinations tested do not interfere with T-B collaboration when the cell populations studied are mutually tolerant.
Histomolecular Phenotypes of Adenocarcinoma of the Ampulla of Vater: More Evidence Is Required
Authors: Gerardo F. Arroyo
Journal: Journal of Clinical Oncology (2013)

The day I started my hematology/oncology fellowship in 1988, the head of the division told us that there had been only two important advances in caring for patients with cancer since the early 1950s.One was the use of combination chemotherapy instead of single agents.Emil Frei, one of the true pioneering giants of oncology, died earlier this month.The New York Times referred to his "trailblazing use of combination chemotherapy."His reasoning (and that of others) that tumors are heterogeneous is the foundation for the concept of maintenance therapy, even with cancer progression.So many of our longstanding standard approaches (eg, continued LHRH agonist therapy for progressive metastatic prostate cancer or continued trastuzumab in progressing metastatic breast cancer) and newer US Food and Drug Administration-approved indications for continuing the same drugs, even when they seem to no longer be working (eg, irinotecan and cetuximab after progression during treatment with irinotecan in metastatic colon cancer), have as their basis of success the underlying heterogeneity of cancers.Like so many other icons in medicine, our gratitude and admiration should extend not just for what Frei imagined and demonstrated but what others were subsequently able to prove based on his ideas.
Mucin (Muc) expression during pancreatic cancer progression in spontaneous mouse model: potential implications for diagnosis and therapy
Authors: Satyanarayana Rachagani, María P Torres, Sushil Kumar, Dhanya Haridas, Michael Baine, Muzafar A Macha, Sukhwinder Kaur, Moorthy P Ponnusamy, Parama Dey, Parthasarathy Seshacharyulu, Sonny L Johansson, Maneesh Jain, Kay-Uwe Wagner, Surinder K Batra
Journal: Journal of Hematology & Oncology (2012)

Abstract Background Pancreatic cancer (PC) is a lethal malignancy primarily driven by activated Kras mutations and characterized by the deregulation of several genes including mucins. Previous studies on mucins have identified their significant role in both benign and malignant human diseases including PC progression and metastasis. However, the initiation of MUC expression during PC remains unknown because of lack of early stage tumor tissues from PC patients. Methods In the present study, we have evaluated stage specific expression patterns of mucins during mouse PC progression in (Kras G12D ;Pdx1-Cre (KC)) murine PC model from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC) by immunohistochemistry and quantitative real-time PCR. Results In agreement with previous studies on human PC, we observed a progressive increase in the expression of mucins particularly Muc1, Muc4 and Muc5AC in the pancreas of KC (as early as PanIN I) mice with advancement of PanIN lesions and PDAC both at mRNA and protein levels. Additionally, mucin expression correlated with the increased expression of inflammatory cytokines IFN-γ (p &lt; 0.0062), CXCL1 (p &lt; 0.00014) and CXCL2 (p &lt; 0.08) in the pancreas of KC mice, which are known to induce mucin expression. Further, we also observed progressive increase in inflammation in pancreas of KC mice from 10 to 50 weeks of age as indicated by the increase in the macrophage infiltration. Overall, this study corroborates with previous human studies that indicated the aberrant overexpression of MUC1, MUC4 and MUC5AC mucins during the progression of PC. Conclusions Our study reinforces the potential utility of the KC murine model for determining the functional role of mucins in PC pathogenesis by crossing KC mice with corresponding mucin knockout mice and evaluating mucin based diagnostic and therapeutic approaches for lethal PC.