tbuckley/cabot-search huggingface dataset:
miR-214 Coordinates Melanoma Progression by Upregulating ALCAM through TFAP2 and miR-148b Downmodulation
Authors: Elisa Penna, Francesca Orso, Daniela Cimino, Irene Vercellino, Elena Grassi, Elena Quaglino, Emilia Turco, Daniela Taverna
Journal: Cancer Research (2013)

Malignant melanoma is one of the most aggressive human cancers, but the mechanisms governing its metastatic dissemination are not fully understood. Upregulation of miR-214 and ALCAM and the loss of TFAP2 expression have been implicated in this process, with TFAP2 a direct target of miR-214. Here, we link miR-214 and ALCAM as well as identify a core role for miR-214 in organizing melanoma metastasis. miR-214 upregulated ALCAM, acting transcriptionally through TFAP2 and also posttranscriptionally through miR-148b (itself controlled by TFAP2), both negative regulators of ALCAM. We also identified several miR-214-mediated prometastatic functions directly promoted by ALCAM. Silencing ALCAM in miR-214-overexpressing melanoma cells reduced cell migration and invasion without affecting growth or anoikis in vitro, and it also impaired extravasation and metastasis formation in vivo. Conversely, cell migration and extravasation was reduced in miR-214-overexpressing cells by upregulation of either miR-148b or TFAP2. These findings were consistent with patterns of expression of miR-214, ALCAM, and miR-148b in human melanoma specimens. Overall, our results define a pathway involving miR-214, miR-148b, TFAP2, and ALCAM that is critical for establishing distant metastases in melanoma.
Salt and cardiovascular disease
Authors: Francesco P Cappuccio
Journal: BMJ (2007)

Reducing intake improves cardiovascular outcomes but few countries have effective policies

Blood pressure is the most powerful predictor of stroke and other cardiovascular events. The importance of salt (sodium chloride) intake in determining blood pressure and the incidence of hypertension is well established. Furthermore, randomised controlled clinical trials of moderate reductions in salt intake show a dose dependent cause-effect relation and lack of a threshold effect within usual levels of salt intake in populations worldwide.1 The effect is independent of age, sex, ethnic origin, baseline blood pressure, and body mass.

Prospective studies,2 3 4 5 with one exception,6 also indicate that higher salt intake predicts the incidence of cardiovascular events. While widespread support exists for reducing salt intake to prevent cardiovascular disease, the lack of large and long randomised trials on the effects of salt reduction on clinical outcomes has encouraged some people to argue against a policy of salt reduction in populations.6

In this week's BMJ , Cook and colleagues …
Blocked Autophagy Sensitizes Resistant Carcinoma Cells to Radiation Therapy
Authors: Anja Apel, Ingrid Herr, Heinz Schwarz, H. Peter Rodemann, Andreas Mayer
Journal: Cancer Research (2008)

Abstract Autophagy or “self eating” is frequently activated in tumor cells treated with chemotherapy or irradiation. Whether autophagy represents a survival mechanism or rather contributes to cell death remains controversial. To address this issue, the role of autophagy in radiosensitive and radioresistant human cancer cell lines in response to γ-irradiation was examined. We found irradiation-induced accumulation of autophagosomes accompanied by strong mRNA induction of the autophagy-related genes beclin 1, atg3, atg4b, atg4c, atg5, and atg12 in each cell line. Transduction of specific target-siRNAs led to down-regulation of these genes for up to 8 days as shown by reverse transcription-PCR and Western blot analysis. Blockade of each autophagy-related gene was associated with strongly diminished accumulation of autophagosomes after irradiation. As shown by clonogenic survival, the majority of inhibited autophagy-related genes, each alone or combined, resulted in sensitization of resistant carcinoma cells to radiation, whereas untreated resistant cells but not sensitive cells survived better when autophagy was inhibited. Similarly, radiosensitization or the opposite was observed in different sensitive carcinoma cells and upon inhibition of different autophagy genes. Mutant p53 had no effect on accumulation of autophagosomes but slightly increased clonogenic survival, as expected, because mutated p53 protects cells by conferring resistance to apoptosis. In our system, short-time inhibition of autophagy along with radiotherapy lead to enhanced cytotoxicity of radiotherapy in resistant cancer cells. [Cancer Res 2008;68(5):1485–94]
Interference with the Microenvironmental Support Impairs the <i>De novo</i> Formation of Bone Metastases <i>In vivo</i>
Authors: Gabri van der Pluijm, Ivo Que, Bianca Sijmons, Jeroen T. Buijs, Clemens W.G.M. Löwik, Antoinette Wetterwald, George N. Thalmann, Socrates E. Papapoulos, Marco G. Cecchini
Journal: Cancer Research (2005)

Abstract Interference with the microenvironmental growth support is an attractive therapeutic strategy for repressing metastatic tumor growth. Bone is a highly dynamic tissue that is continuously remodeled by bone resorption and subsequent bone formation. Growth factors supporting bone metastatic growth are released especially during bone resorption. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates, are available for bone. In the present study, we tested the hypothesis that inhibition of bone turnover can affect development and growth progression of experimental bone metastasis. Whole-body bioluminescent reporter imaging was used for the detection, monitoring, and quantification in vivo of the growth progression of bone metastases induced by intracardiac or intraosseous injection of luciferase-transfected breast cancer cells (MDA-231-B/luc+) to nude mice. Suppression of bone turnover by bisphosphonates, before bone colonization by cancer cells, inhibited by a great extent the number of developing bone metastasis. Tumor growth in the few, but still developing, bone metastases was affected only transiently. Reduction of bone turnover had no effect on growth progression of bone metastases, which were already established when bisphosphonate treatment was initiated, despite a substantial reduction in osteolysis. Therefore, cancer cells metastatic to bone, after an initial growth phase that depends on the interaction with the local stroma, become independent of microenvironmental growth factor support and progress autonomously. Inhibition of bone turnover may represent a useful adjuvant therapy especially for cancer patients at risk to develop bone metastasis.
<i>BRAF</i> kinase domain mutations are present in a subset of chronic myelomonocytic leukemia with wild‐type <i>RAS</i>
Authors: Liping Zhang, Rajesh R. Singh, Keyur P. Patel, Francesco Stingo, Mark Routbort, M. James You, Roberto N. Miranda, Guillermo Garcia‐Manero, Hagop M. Kantarjian, L. Jeffrey Medeiros, Rajyalakshmi Luthra, Joseph D. Khoury
Journal: American Journal of Hematology (2014)

The frequency of RAS mutations in chronic myelomonocytic leukemia (CMML) suggests that activation of the MAPK pathway is important in CMML pathogenesis. Accordingly, we hypothesized that mutations in other members of the MAPK pathway might be overrepresented in RAS(wt) CMML. We performed targeted next generation sequencing analysis on 70 CMML patients with known RAS mutation status. The study group included 37 men and 33 women with a median age of 67.8 years (range, 28-86 years). Forty patients were RAS(wt) and 30 were RAS(mut) ; the latter included KRAS = 17; NRAS = 12; KRAS + NRAS = 1. Five patients (7.1% of total group; 12.5% of RAS(wt) group) with RAS(wt) had kinase domain BRAF mutations. The BRAF mutations were of missense type and involved exon 11 in one patient and exon 15 in four patients. All BRAF(mut) patients had CMML-1 with low-risk cytogenetic findings. Two (40%) of the five patients with BRAF(mut) patients transformed to acute myeloid leukemia during follow-up. In summary, we demonstrate that a subset of patients with RAS(wt) CMML harbors BRAF kinase domain mutations that are potentially capable of activating the MAPK signaling pathway.
Induction and mode of action of suppressor cells generated against human gamma globulin. I. An immunologic unresponsive state devoid of demonstrable suppressor cells.
Authors: D E Parks, M V Doyle, W O Weigle
Journal: The Journal of Experimental Medicine (1978)

A model of unresponsiveness to human gamma-globulin (HGG) which is maintained in the absence of demonstrable suppressor cells has been described. A/J mice were tolerized with deaggregated HGG purified from a variety of sources. The spleen cells from these tolerized mice were assessed for their ability to suppress the response of normal spleen cells to HGG when transferred into lethally irradiated mice. All of the HGG preparations obtained from commercial sources as Cohn fraction II of pooled, outdated plasma induced suppressor cells to HGG, although not of equal magnitude. However, suppressor cells could not be demonstrated in the spleens of mice tolerized with deaggregated HGG purified from the plasma of a healthy individual. This inability to detect suppression was independent of the method of purification of the HGG and of the time of assessment of the putative suppressor cells after tolerization. Similarly, deaggregated HGG isolated from an IgG1 lambda-myeloma protein induced unresponsiveness to HGG but did not stimulate demonstrable suppressor cells. These data suggest that suppressor T cells are not involved in the maintenance of tolerance to this antigen, although they may play a regulatory role in the immune response to HGG. Support for this concept was obtained by assessing the duration of unresponsiveness in the T and B lymphocytes of mice tolerized with the various HGG preparations. Mice tolerized with the HGG preparations that stimulated little or no suppression were among the last to recover responsiveness. Indeed, there was no consistent correlation between the level of suppressor cell activity and the degree of unresponsiveness in either the splenic T or B lymphocytes. Thus, although certain HGG preparations may provide a tool for the generation of antigen-specific suppressor T cells, the utilization of these suppressive preparations may be inappropriate for the investigation of the mechanisms of the induction and maintenance of the unresponsive state.
Principal Results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial
Authors: Henry R. Black
Journal: JAMA (2003)

Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk, but the benefit compared with other drug classes is controversial.To determine whether initial therapy with controlled-onset extended-release (COER) verapamil is equivalent to a physician's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease.Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed the study before unblinding the results.Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic, beta-blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed.First occurrence of stroke, myocardial infarction, or cardiovascular disease-related death.Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P =.77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease-related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease-related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54 [95% CI, 1.16-2.04]; P =.003). More cardiovascular disease-related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53).The CONVINCE trial did not demonstrate equivalence of a COER verapamil-based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or beta-blocker treatment.
The feasibility of biofeedback in difficult-to-wean mechanically ventilated patients: A pilot study
Authors: Yu-Ju Chen, Shiow-Li Hwang, Chu-Yi Lee
Journal: European Respiratory Journal (2013)

Background. The development of psychological trauma in mechanical ventilated patients is currently recognized, especially for those difficult-to-wean patients requiring prolonged mechanical ventilation (MV). Purpose. The main purpose of this pilot study was to develop a heart rate variability (HRV) biofeedback for difficult-to-wean MV patients and test its feasibility. Methods. This study was conducted in a medical center in Taiwan. Ten of difficult-to-wean MV patients were recruited for testing the feasibility of a 4-session RSA biofeedback within 2 days. Psychophysiological indices (fear, dyspnea, anxiety, RSBI, and HRV) will be measured before and after the biofeedback intervention. Results. The results of psychological measures (fear, dyspnea, and anxiety) were significantly different after the biofeedback training (t = 5.97, 4.31, and 6.95; p < .01), but RSBI or HRV was not (p = .098, .18). All subjects reported that this biofeedback help them to self-controlled their breathing again and decreased their fear, dyspnea, and state anxiety. However, 6 out of 10 subjects reported that they did feel anxious to gaze at the computer screen and match their breathing with the pacer at the first two sessions, and had a difficulty to match their breathing with HRV due to the big variation of HRV at 3rd and 4th sessions. According ly, the initial HRV biofeedback protocol was modified. Discussion. The preliminary results indicated that HRV biofeedback could effectively decreased psychological distress in difficult-to-wean MV subjects. HRV biofeedback is resulted by adding an introduction session and a self-directed match their breathing with HRV session from initial program.
Is It Reasonable to Treat All Calcified Stenotic Aortic Valves With a Valved Stent?
Authors: Rachid Zegdi, Vlad Ciobotaru, Miléna Noghin, Ghassan Sleilaty, Antoine Lafont, Christian Latrémouille, Alain Deloche, Jean-Noël Fabiani
Journal: Journal of the American College of Cardiology (2008)
Niche construction, biological evolution, and cultural change
Authors: Kevin N. Laland, John Odling-Smee, Marcus W. Feldman
Journal: Behavioral and Brain Sciences (2000)

We propose a conceptual model that maps the causal pathways relating biological evolution to cultural change. It builds on conventional evolutionary theory by placing emphasis on the capacity of organisms to modify sources of natural selection in their environment (niche construction) and by broadening the evolutionary dynamic to incorporate ontogenetic and cultural processes. In this model, phenotypes have a much more active role in evolution than generally conceived. This sheds light on hominid evolution, on the evolution of culture, and on altruism and cooperation. Culture amplifies the capacity of human beings to modify sources of natural selection in their environments to the point where that capacity raises some new questions about the processes of human adaptation.
Urinary Kallikrein Excretion in Normal Man
Authors: HARRY S. MARGOLIUS, DAVID HORWITZ, RONALD G. GELLER, R. WAYNE Alexander, JOHN R. GILL., JOHN J. PISANO, HARRY R. KEISER
Journal: Circulation Research (1974)

The urinary excretion of kallikrein, a renal enzyme that cleaves the potent vasodilator kinin, kallidin, from kininogen, was measured in normal volunteers by three different assays, one of which was a bioassay. When sodium intake was changed from ad libitum or 109 mEq/day to 9 mEq/day, daily kallikrein excretion increased progressively in every subject to a mean maximal value that was 271% of control by day 7; an increase in sodium intake to 259 mEq/day resulted in the return of kallikrein excretion to control values. Urinary excretion of amylase, a protein with a molecular weight similar to that of kallikrein, did not change when sodium intake was changed, but plasma renin activity and aldosterone excretion changed appropriately. In subjects on a constant-sodium (109 mEq/day), constant-potassium (100 mEq/day) diet, fludrocortisone, 0.5 mg/day for 10 days, increased kallikrein excretion to a mean maximal value that was 203% of control. In subjects on a diet containing 9 mEq sodium/day, elevated kallikrein excretion decreased during treatment with spironolactone, 400 mg/day. Rapid administration of water (1 or 2 liters in 30 minutes, orally) or rapid infusion of 2.4 liters of normal saline did not significantly alter urinary kallikrein excretion despite large changes in urine volume or sodium excretion. Thus, kallikrein excretion appears to be directly related to the effective level of circulating sodium-retaining steroid. The findings are consistent with a role for the kallikrein-kinin system in the renal response to sodium-retaining hormones.
A Mechanism for Cell Size Regulation by the Insulin and Insulin-Like Growth Factor-I Receptors
Authors: Hongzhi Sun, Xiao Tu, Renato Baserga
Journal: Cancer Research (2006)

Abstract Deletion of the type 1 insulin-like growth factor receptor (IGF-IR) or of the insulin receptor substrate-1 (IRS-1) genes in animals causes a 50% reduction in body size at birth. Decrease in body size is due to both a decreased number of cells and a decreased cell size. Deletion of the insulin receptor (InR) genes results in mice that are normal in size at birth. We have used 32D-derived myeloid cells to study the effect of IGF-IR and InR signaling on cell size. 32D cells expressing the IGF-IR and IRS-1 are almost twice as large as 32D cells expressing the InR and IRS-1. A mechanism for the difference in size is provided by the levels of the upstream binding factor 1 (UBF1), a nucleolar protein that participates in the regulation of RNA polymerase I activity and rRNA synthesis and therefore cell size. When shifted to the respective ligands, UBF1 levels decrease in cells expressing the InR and IRS-1, whereas they remain stable in cells expressing the IGF-IR and IRS-1. The expression of the IGF-IR and IRS-1 is crucial to the stability of UBF1. (Cancer Res 2006; 66(23): 11106-9)
Environmental Factors and High Risk of Esophageal Cancer Among Men in Coastal South Carolina
Authors: L. M. Brown, W. J. Blot, S. H. Schuman, V. M. Smith, A. G. Ershow, R. D. Marks, J. F. Fraumeni
Journal: JNCI Journal of the National Cancer Institute (1988)

A case-control study involving interviews of 207 men with esophageal cancer and 422 control subjects or their next of kin was conducted to identify reasons for the unusually high rates of esophageal cancer among men in coastal South Carolina. Tobacco and alcohol, including moonshine, were identified as the major determinants of esophageal cancer risk. Increased risk was also associated with low intake of fresh fruits but not with drinking of local herbal teas. The findings suggest that efforts aimed at reducing tobacco and alcohol use will help to lower the elevated rates of esophageal cancer in coastal South Carolina.
Bayesian Inference of the Demographic History of Chimpanzees
Authors: D. Wegmann, L. Excoffier
Journal: Molecular Biology and Evolution (2010)

Due to an almost complete absence of fossil record, the evolutionary history of chimpanzees has only been studied recently on the basis of genetic data. Although the general topology of the chimpanzee phylogeny is well established, uncertainties remain concerning the size of current and past populations, the occurrence of bottlenecks or population expansions, or about divergence times and migrations rates between subspecies. Here, we present a novel attempt at globally inferring the detailed evolution of the Pan genus based on approximate Bayesian computation, an approach preferentially applied to complex models where the likelihood cannot be computed analytically. Based on two microsatellite and DNA sequence data sets and adjusting simulated data for local levels of inbreeding and patterns of missing data, we find support for several new features of chimpanzee evolution as compared with previous studies based on smaller data sets and simpler evolutionary models. We find that the central chimpanzees are certainly the oldest population of all P. troglodytes subspecies and that the other two P. t. subspecies diverged from the central chimpanzees by founder events. We also find an older divergence time (1.6 million years [My]) between common chimpanzee and Bonobos than previous studies (0.9–1.3 My), but this divergence appears to have been very progressive with the maintenance of relatively high levels of gene flow between the ancestral chimpanzee population and the Bonobos. Finally, we could also confirm the existence of strong unidirectional gene flow from the western into the central chimpanzee. These results show that interesting and innovative features of chimpanzee history emerge when considering their whole evolutionary history in a single analysis, rather than relying on simpler models involving several comparisons of pairs of populations.
Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice
Authors: R A Moore, O A Moore, S Derry, P M Peloso, A R Gammaitoni, H Wang
Journal: Annals of the Rheumatic Diseases (2009)

Background: Population mean changes from clinical trials are difficult to apply to individuals in clinical practice. Responder analysis may be better, but needs validating for level of response and treatment duration. Methods: The numbers of patients with pain relief over baseline (⩾15%, ⩾30%, ⩾50%, ⩾70%) at 2, 4, 8 and 12 weeks of treatment were obtained using the WOMAC 100 mm visual analogue pain subscale score for each treatment group in seven randomised placebo-controlled trials of etoricoxib in osteoarthritis lasting ⩾6 weeks. Dropouts were assigned 0% improvement from baseline from then on. The numbers needed to treat (NNTs) were calculated at each level of response and time point. Results: 3554 patients were treated with placebo, etoricoxib 30 mg and 60 mg, celecoxib 200 mg, naproxen 1000 mg or ibuprofen 2400 mg daily. Response rates fell with increasing pain relief: 60–80% experienced minimally important pain relief (⩾15%), 50–60% moderate pain relief (⩾30%), 40–50% substantial pain relief (⩾50%) and 20–30% extensive pain relief (⩾70%). NNTs for etoricoxib, celecoxib and naproxen were stable over 2–12 weeks. Ibuprofen showed lessening of effectiveness with time. Conclusion: Responder rates and NNTs are reproducible for different levels of response over 12 weeks and have relevance for clinical practice at the individual patient level. An average 10 mm improvement in pain equates to almost one in two patients having substantial benefit.