tbuckley/cabot-search huggingface dataset:
Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice
Authors: Chong Chen, Yu Liu, Yang Liu, Pan Zheng
Journal: Journal of Clinical Investigation (2010)

The mammalian target of rapamycin (mTOR) is a signaling molecule that senses environmental cues, such as nutrient status and oxygen supply, to regulate cell growth, proliferation, and other functions. Unchecked, sustained mTOR activity results in defects in HSC function. Inflammatory conditions, such as autoimmune disease, are often associated with defective hematopoiesis. Here, we investigated whether hyperactivation of mTOR in HSCs contributes to hematopoietic defects in autoimmunity and inflammation. We found that in mice deficient in Foxp3 (scurfy mice), a model of autoimmunity, the development of autoimmune disease correlated with progressive bone marrow loss and impaired regenerative capacity of HSCs in competitive bone marrow transplantation. Similarly, LPS-mediated inflammation in C57BL/6 mice led to massive bone marrow cell death and impaired HSC function. Importantly, treatment with rapamycin in both models corrected bone marrow hypocellularity and partially restored hematopoietic activity. In cultured mouse bone marrow cells, treatment with either of the inflammatory cytokines IL-6 or TNF-α was sufficient to activate mTOR, while preventing mTOR activation in vivo required simultaneous inhibition of CCL2, IL-6, and TNF-α. These data strongly suggest that mTOR activation in HSCs by inflammatory cytokines underlies defective hematopoiesis in autoimmune disease and inflammation.
Effect of Type C Viral Expression and Cellular Karyotype on Human B-Lymphoblast Tumorigenicity in Nude Mice<xref ref-type="fn" rid="fn2">2</xref>
Authors: A F Steuer, R C Ting, P D Markham, Z Salahuddin, R C Gallo
Journal: JNCI Journal of the National Cancer Institute (1982)

Cultured human hematopoietic cells from several normal and leukemic sources, including those cells initiated after exposure to primate type C retroviruses were tested for their capacity to induce tumors in young athymic BALB/c (nu/nu) mice after sc inoculation. An attempt was made to correlate these results with virus expression and chromosome patterns. Progressively growing tumor formation was observed in 5 of 18 normal diploid B-lymphoblast lines from normal peripheral blood and in one of three diploid B-lymphoblast lines from leukemic donors established after infection with primate type C viruses (gibbon ape leukemia virus or simian sarcoma virus). In contrast, none of eight spontaneously transformed B-lymphoblast lines with normal diploid karyotypes formed progressively growing tumors, although one formed a tumor that remained the same size (0.5 cm) for several months. Progressive tumor formation occurred in four of seven previously established cell lines of different cell types that had abnormal karyotypes. Of the normal diploid B-lymphoblast cultures exposed to type C viruses, 12 were tested for the presence of viral RNA and structural proteins (p12, p30, gp70), and this information was correlated with tumorigenicity. Four of the six cultures expressing viral RNA or proteins were tumorigenic, whereas only one of six cultures that did not express virus information was positive. The results of this study suggest that expression of type C viral RNA and proteins by human B-lymphoblasts increases their tumorigenicity in nude mice. It is also apparent that caution must be used in attempts to correlate cell tumorigenicity and chromosome abnormalities in nude mice.
Castration-Resistant Prostate Cancer: Descriptive Yet Pejorative?
Authors: E. David Crawford, Daniel Petrylak
Journal: Journal of Clinical Oncology (2010)

The euphemistic term castration-resistant prostate cancer (CRPC) has slowly entered the everyday lexicon of those who study and treat prostate cancer.Ahmann and Crawford 1 utilized this term in 1987.Emanating from what used to be called hormonerefractory prostate cancer and/or androgen-independent prostate cancer, this CRPC consensus definition was first formally reintroduced at a 2005 ODAC discussion on prostate cancer trial end points.Subsequently, in 2008, it was specifically defined in a Prostate Cancer Working Group Guidelines report, published in Journal of Clinical Oncology. 2At that time, Scher et al 2 recognized that despite medical or surgical castration, prostate cancers were still sensitive to subcastrate levels of androgens, either emanating from the adrenal cortex or from prostate cancer cells themselves (with direct intracrine activation of the androgen receptor cascade).However, there have been some concerns expressed by clinicians, and more importantly by patients themselves, that the term castration implies some sort of testicular removal, which has a negative connotation for many men who have this disease.Hormone-refractory prostate cancer and androgen-independent prostate cancer did not have this perceived stigma, but in contrast, they have proven to be considerably inaccurate, as secondgeneration androgen deprivation therapy clinical trials are beginning to demonstrate. 3,4herefore, we would like to propose that a term such as endocrineresistant prostate cancer may be a better description to utilize with our colleagues and patients.It is both accurate and less emotionally charged.Seen in this fashion, it gives us in the field, as well as our patients, a clearer way to view therapeutic options (which will increase significantly in the years to come).Therapeutically, if patients knew their disease was either endocrine sensitive or endocrine resistant, potentially approvable agents like Abiraterone, MDV-3100, and even estrogenic compounds could be clearly delineated from the evolving nonhormonal options that are also coming down the pike, like immunotherapy, targeted agents, and newer chemotherapies.
Covariation Is a Poor Measure of Molecular Coevolution
Authors: David Talavera, Simon C. Lovell, Simon Whelan
Journal: Molecular Biology and Evolution (2015)

Recent developments in the analysis of amino acid covariation are leading to breakthroughs in protein structure prediction, protein design, and prediction of the interactome. It is assumed that observed patterns of covariation are caused by molecular coevolution, where substitutions at one site affect the evolutionary forces acting at neighboring sites. Our theoretical and empirical results cast doubt on this assumption. We demonstrate that the strongest coevolutionary signal is a decrease in evolutionary rate and that unfeasibly long times are required to produce coordinated substitutions. We find that covarying substitutions are mostly found on different branches of the phylogenetic tree, indicating that they are independent events that may or may not be attributable to coevolution. These observations undermine the hypothesis that molecular coevolution is the primary cause of the covariation signal. In contrast, we find that the pairs of residues with the strongest covariation signal tend to have low evolutionary rates, and that it is this low rate that gives rise to the covariation signal. Slowly evolving residue pairs are disproportionately located in the protein's core, which explains covariation methods' ability to detect pairs of residues that are close in three dimensions. These observations lead us to propose the "coevolution paradox": The strength of coevolution required to cause coordinated changes means the evolutionary rate is so low that such changes are highly unlikely to occur. As modern covariation methods may lead to breakthroughs in structural genomics, it is critical to recognize their biases and limitations.
Human Tumor-Released Microvesicles Promote the Differentiation of Myeloid Cells with Transforming Growth Factor-β–Mediated Suppressive Activity on T Lymphocytes
Authors: Roberta Valenti, Veronica Huber, Paola Filipazzi, Lorenzo Pilla, Gloria Sovena, Antonello Villa, Alessandro Corbelli, Stefano Fais, Giorgio Parmiani, Licia Rivoltini
Journal: Cancer Research (2006)

Abstract Human tumors constitutively release endosome-derived microvesicles, transporting a broad array of biologically active molecules with potential modulatory effects on different immune cells. Here, we report the first evidence that tumor-released microvesicles alter myeloid cell function by impairing monocyte differentiation into dendritic cells and promoting the generation of a myeloid immunosuppressive cell subset. CD14+ monocytes isolated from healthy donors and differentiated with interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in the presence of tumor-derived microvesicles turned into HLA-DR−/low cells, retaining CD14 expression and failing to up-regulate costimulatory molecules, such as CD80 and CD86. These phenotypic changes were paralleled by a significant release of different cytokines, including IL-6, tumor necrosis factor-α, and transforming growth factor-β (TGF-β), and a dose-dependent suppressive activity on activated T-cell–proliferation and cytolytic functions, which could be reversed by anti-TGF-β–neutralizing antibodies. Microvesicles isolated from plasma of advanced melanoma patients, but not from healthy donors, mediated comparable effects on CD14+ monocytes, skewing their differentiation toward CD14+HLA-DR−/low cells with TGF-β–mediated suppressive activity on T-cell–functions. Interestingly, a subset of TGF-β–secreting CD14+HLA-DR− cells mediating suppressive activity on T lymphocytes was found to be significantly expanded in peripheral blood of melanoma patients compared with healthy donors. These data suggest the development in cancer patients of an immunosuppressive circuit by which tumors promote the generation of suppressive myeloid cells through the release of circulating microvesicles and without the need for cell-to-cell contact. Therapeutic interventions on the crucial steps of this pathway may contribute to restore tumor/immune system interactions favoring T-cell–mediated control of tumor growth in cancer patients. (Cancer Res 2006; 66(18): 9290-8)
A case for non-intervention
Authors: D. Fowler
Journal: BMJ (1995)

In May 1994 I sent an expanded version of the following letter to friends and colleagues.

“This will be a rather personal and serious letter, so please don't start reading until you have some time and calm to reflect on it.

“On 9 January, at a peak of intellectual activity, emotional strength, and, I thought, physical wellbeing, I worke to a strange collection of sensations: I felt sick, my left eye was twitching strongly, and I smelt a strange sweet smell. This passed after a few minutes; then suddenly, some time later, I was sick. ‘Isn't the body a funny thing,' I thought and was going to leave it at that, until the same thing happened three times the next night. I went to the doctor, who sent me to a neurologist; I now take 300 mg of carbamazepine a day. I have had perhaps a dozen episodes and have been sick five times, but never since taking the tablets. These are all the symptoms I have had. The most inconvenient thing is that I am not now allowed to drive.

“I also had some tests, and computed tomography of my brain showed a tumour inaccessibly deep in my left frontal lobe. This diagnosis is imprecise since it does not reveal the nature of the tumour. I might live out a natural span, I might not. A more precise but still not entirely reliable diagnosis would be possible by doing an intrusive biopsy. But, even with perfect knowledge, the range of treatments is limited, and these treatments will give only remission from symptoms.

“We have of course discussed the situation with our GP, the consultant neurologist, and my brother—a consultant physician who is strongly concerned for his patients' quality of life. They all agree that, if we feel comfortable with …
Effectiveness of Sensor-Augmented Insulin-Pump Therapy in Type 1 Diabetes
Authors: Richard M. Bergenstal, William V. Tamborlane, Andrew Ahmann, John B. Buse, George Dailey, Stephen N. Davis, Carol Joyce, Tim Peoples, Bruce A. Perkins, John B. Welsh, Steven M. Willi, Michael A. Wood
Journal: New England Journal of Medicine (2010)

Recently developed technologies for the treatment of type 1 diabetes mellitus include a variety of pumps and pumps with glucose sensors.In this 1-year, multicenter, randomized, controlled trial, we compared the efficacy of sensor-augmented pump therapy (pump therapy) with that of a regimen of multiple daily insulin injections (injection therapy) in 485 patients (329 adults and 156 children) with inadequately controlled type 1 diabetes. Patients received recombinant insulin analogues and were supervised by expert clinical teams. The primary end point was the change from the baseline glycated hemoglobin level.At 1 year, the baseline mean glycated hemoglobin level (8.3% in the two study groups) had decreased to 7.5% in the pump-therapy group, as compared with 8.1% in the injection-therapy group (P<0.001). The proportion of patients who reached the glycated hemoglobin target (<7%) was greater in the pump-therapy group than in the injection-therapy group. The rate of severe hypoglycemia in the pump-therapy group (13.31 cases per 100 person-years) did not differ significantly from that in the injection-therapy group (13.48 per 100 person-years, P=0.58). There was no significant weight gain in either group.In both adults and children with inadequately controlled type 1 diabetes, sensor-augmented pump therapy resulted in significant improvement in glycated hemoglobin levels, as compared with injection therapy. A significantly greater proportion of both adults and children in the pump-therapy group than in the injection-therapy group reached the target glycated hemoglobin level. (Funded by Medtronic and others; ClinicalTrials.gov number, NCT00417989.)
Cannabis Abuse as a Risk Factor for Depressive Symptoms
Authors: Gregory B. Bovasso
Journal: American Journal of Psychiatry (2001)

This study sought to estimate the degree to which cannabis abuse is a risk factor for depressive symptoms rather than an effort to self-medicate depression.Participants (N=1,920) in the 1980 Baltimore Epidemiologic Catchment Area (ECA) study who were reassessed between 1994 and 1996 as part of a follow-up study provided the data. The analysis focused on two cohorts: those who reported no depressive symptoms at baseline (N=849) and those with no diagnosis of cannabis abuse at baseline (N=1,837). Symptoms of depression, cannabis abuse, and other psychiatric disorders were assessed with the Diagnostic Interview Schedule.In participants with no baseline depressive symptoms, those with a diagnosis of cannabis abuse at baseline were four times more likely than those with no cannabis abuse diagnosis to have depressive symptoms at the follow-up assessment, after adjusting for age, gender, antisocial symptoms, and other baseline covariates. In particular, these participants were more likely to have experienced suicidal ideation and anhedonia during the follow-up period. Among the participants who had no diagnosis of cannabis abuse at baseline, depressive symptoms at baseline failed to significantly predict cannabis abuse at the follow-up assessment.Further research is needed to identify characteristics of individuals who abuse cannabis that account for their higher risk of depression to estimate the degree of impairment resulting from their depression.
Individual patient data meta-analysis of randomized evidence to assess the effectiveness of laparoscopic uterosacral nerve ablation in chronic pelvic pain
Authors: J. P. Daniels, L. Middleton, T. Xiong, R. Champaneria, N. P. Johnson, E. M. Lichten, C. Sutton, P. Vercellini, R. Gray, R. K. Hills, K. D. Jones, G. Aimi, K. S. Khan
Journal: Human Reproduction Update (2010)

BACKGROUNDThere have been conflicting results in randomized trials of the effects of laparoscopic uterosacral nerve ablation (LUNA) in chronic pelvic pain. Our objective was to perform a meta-analysis using individual patient data (IPD) to provide the most comprehensive and reliable assessment of the effectiveness of LUNA.
Endoscopic mucosal biopsies are useful in distinguishing granulomatous colitis due to Crohn's disease from tuberculosis
Authors: A B Pulimood, B S Ramakrishna, G Kurian, S Peter, S Patra, V I Mathan, M M Mathan
Journal: Gut (1999)

Intestinal tuberculosis and Crohn's disease are chronic granulomatous disorders that are difficult to differentiate histologically.To characterise distinctive diagnostic features of tuberculosis and Crohn's disease in mucosal biopsy specimens obtained at colonoscopy.Selected histological parameters were evaluated retrospectively in a total of 61 biopsy sites from 20 patients with tuberculosis and 112 biopsy sites from 20 patients with Crohn's disease. The patients were chosen on the basis of clinical history, colonoscopic findings, diagnostic histology, and response to treatment.The histological parameters characteristic of tuberculosis were multiple (mean number of granulomas per section: 5.35), large (mean widest diameter: 193 microm), confluent granulomas often with caseating necrosis. Other features were ulcers lined by conglomerate epithelioid histiocytes and disproportionate submucosal inflammation. The features characteristic of Crohn's disease were infrequent (mean number of granulomas per section: 0.75), small (mean widest diameter: 95 microm) granulomas, microgranulomas (defined as poorly organised collections of epithelioid histiocytes), focally enhanced colitis, and a high prevalence of chronic inflammation, even in endoscopically normal appearing areas.The type and frequency of granulomas, presence or absence of ulcers lined by epithelioid histiocytes and microgranulomas, and the distribution of chronic inflammation have been identified as histological parameters that can be used to differentiate tuberculosis and Crohn's disease in mucosal biopsy specimens obtained at colonoscopy.
Nerves projecting from the intrinsic cardiac ganglia of the pulmonary veins modulate sinoatrial node pacemaker function
Authors: Manuel Zarzoso, Kristina Rysevaite, Michelle L. Milstein, Conrado J. Calvo, Adam C. Kean, Felipe Atienza, Dainius H. Pauza, José Jalife, Sami F. Noujaim
Journal: Cardiovascular Research (2013)

Pulmonary vein ganglia (PVG) are targets for atrial fibrillation ablation.However, the functional relevance of PVG to the normal heart rhythm remains unclear.Our aim was to investigate whether PVG can modulate sinoatrial node (SAN) function. Methods and resultsForty-nine C57BL and seven Connexin40 +/EGFP mice were studied.We used tyrosine-hydroxylase (TH) and cholineacetyltransferase immunofluorescence labelling to characterize adrenergic and cholinergic neural elements.PVG projected postganglionic nerves to the SAN, which entered the SAN as an extensive, mesh-like neural network.PVG neurones were adrenergic, cholinergic, and biphenotypic.Histochemical characterization of two human embryonic hearts showed similarities between mouse and human neuroanatomy: direct neural communications between PVG and SAN.In Langendorff perfused mouse hearts, PVG were stimulated using 200-2000 ms trains of pulses (300 ms, 400 mA, 200 Hz).PVG stimulation caused an initial heart rate (HR) slowing (36 + 9%) followed by acceleration.PVG stimulation in the presence of propranolol caused HR slowing (43 + 13%) that was sustained over 20 beats.PVG stimulation with atropine progressively increased HR.Time-course effects were enhanced with 1000 and 2000 ms trains (P , 0.05 vs. 200 ms).In optical mapping, PVG stimulation shifted the origin of SAN discharges.In five paroxysmal AF patients undergoing pulmonary vein ablation, application of radiofrequency energy to the PVG area during sinus rhythm produced a decrease in HR similar to that observed in isolated mouse hearts. ConclusionPVG have functional and anatomical biphenotypic characteristics.They can have significant effects on the electrophysiological control of the SAN.
Cultural transmission of behavior in animals: How a modern training technology uses spontaneous social imitation in cetaceans and facilitates social imitation in horses and dogs
Authors: Karen W. Pryor
Journal: Behavioral and Brain Sciences (2001)

Social learning and imitation is central to culture in cetaceans. The training technology used with cetaceans facilitates reinforcing imitation of one dolphin's behavior by another; the same technology, now widely used by pet owners, can lead to imitative learning in such unlikely species as dogs and horses. A capacity for imitation, and thus for cultural learning, may exist in many species.
Lack of Foxp3 function and expression in the thymic epithelium
Authors: Adrian Liston, Andrew G. Farr, Zhibin Chen, Christophe Benoist, Diane Mathis, Nancy R. Manley, Alexander Y. Rudensky
Journal: The Journal of Experimental Medicine (2007)

Foxp3 is essential for the commitment of differentiating thymocytes to the regulatory CD4+ T (T reg) cell lineage. In humans and mice with a genetic Foxp3 deficiency, absence of this critical T reg cell population was suggested to be responsible for the severe autoimmune lesions. Recently, it has been proposed that in addition to T reg cells, Foxp3 is also expressed in thymic epithelial cells where it is involved in regulation of early thymocyte differentiation and is required to prevent autoimmunity. Here, we used genetic tools to demonstrate that the thymic epithelium does not express Foxp3. Furthermore, we formally showed that genetic abatement of Foxp3 in the hematopoietic compartment, i.e. in T cells, is both necessary and sufficient to induce the autoimmune lesions associated with Foxp3 loss. In contrast, deletion of a conditional Foxp3 allele in thymic epithelial cells did not result in detectable changes in thymocyte differentiation or pathology. Therefore, in mice the only known role for Foxp3 remains promotion of T reg cell differentiation within the T cell lineage, whereas there is no role for Foxp3 in thymic epithelial cells.
The Hands That Guide Me
Authors: Ariela Zenilman
Journal: JAMA (2010)

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Toward optimized front-line therapeutic strategies in patients with metastatic colorectal cancer—an expert review from the International Congress on Anti-Cancer Treatment (ICACT) 2009
Authors: R. Adam, D.G. Haller, G. Poston, J.-L. Raoul, J.-P. Spano, J. Tabernero, E. Van Cutsem
Journal: Annals of Oncology (2010)