tbuckley/cabot-search huggingface dataset:
Immunotherapeutic strategies for cancer treatment: A novel protein transfer approach for cancer vaccine development
Authors: Rangaiah Shashidharamurthy, Erica N. Bozeman, Jaina Patel, Ramneet Kaur, Jeyandra Meganathan, Periasamy Selvaraj
Journal: Medicinal Research Reviews (2011)

Abstract Cancer cells have developed numerous ways to escape immune surveillance and gain unlimited proliferative capacity. Currently, several chemotherapeutic agents and radiotherapy, either alone or in combination, are being used to treat malignancies. However, both of these therapies are associated with several limitations and detrimental side effects. Therefore, recent scientific investigations suggest that immunotherapy is among the most promising new approaches in modern cancer therapy. The focus of cancer immunotherapy is to boost both acquired and innate immunity against malignancies by specifically targeting tumor cells, and leaving healthy cells and tissues unharmed. Cellular, cytokine, gene, and monoclonal antibody therapies have progressively become promising immunotherapeutic approaches that are being tested for several cancers in preclinical models as well as in the clinic. In this review, we discuss recent advances in these immunotherapeutic approaches, focusing on new strategies that allow the expression of specific immunostimulatory molecules on the surface of tumor cells to induce robust antitumor immunity.
Sodium Intake, ACE Inhibition, and Progression to ESRD
Authors: Stefan Vegter, Annalisa Perna, Maarten J. Postma, Gerjan Navis, Giuseppe Remuzzi, Piero Ruggenenti
Journal: Journal of the American Society of Nephrology (2011)

High sodium intake limits the antihypertensive and antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors in patients with CKD; however, whether dietary sodium also associates with progression to ESRD is unknown. We conducted a post hoc analysis of the first and second Ramipril Efficacy in Nephropathy trials to evaluate the association of sodium intake with proteinuria and progression to ESRD among 500 CKD patients without diabetes who were treated with ramipril (5 mg/d) and monitored with serial 24-hour urinary sodium and creatinine measurements. Urinary sodium/creatinine excretion defined low (<100 mEq/g), medium (100 to <200 mEq/g), and high (≥200 mEq/g) sodium intake. During a follow-up of >4.25 years, 92 individuals (18.4%) developed ESRD. Among those with low, medium, and high sodium intakes, the incidence of ESRD was 6.1 (95% confidence interval [95% CI], 3.8-9.7), 7.9 (95% CI, 6.1-10.2), and 18.2 (95% CI, 11.3-29.3) per 100 patient-years, respectively (P<0.001). Patients with high dietary sodium exhibited a blunted antiproteinuric effect of ACE inhibition despite similar BP among groups. Each 100-mEq/g increase in urinary sodium/creatinine excretion associated with a 1.61-fold (95% CI, 1.15-2.24) higher risk for ESRD; adjusting for baseline proteinuria attenuated this association to 1.38-fold (95% CI, 0.95-2.00). This association was independent from BP but was lost after adjusting for changes in proteinuria. In summary, among patients with CKD but without diabetes, high dietary salt (>14 g daily) seems to blunt the antiproteinuric effect of ACE inhibitor therapy and increase the risk for ESRD, independent of BP control.
Association of the oestrogen receptor gene polymorphisms with disease onset in systemic lupus erythematosus
Authors: Y J Lee
Journal: Annals of the Rheumatic Diseases (2004)

To evaluate the genetic influence of PvuII and XbaI polymorphisms of oestrogen receptor alpha (ORalpha) in patients with systemic lupus erythematosus (SLE) in Korea.Genomic DNA from 268 female controls and 137 female SLE patients (41 childhood onset and 96 adult onset) were analysed using PvuII and XbaI restriction fragment length polymorphism. Comparison of the frequencies of alleles and genotypes was made in control and patient groups and in childhood onset and adult onset SLE subgroups.Although the Pp genotype occurred more often in SLE patients than in controls (p(c) = 0.017), ORalpha genotype distributions of adult onset SLE did not differ significantly from controls. The PP, Pp, and xx genotypes occurred less often in childhood onset SLE (p(c) = 0.0045, 0.0498, and 0.0255, respectively) than in controls. Additionally, the PP genotype was less common in childhood onset than in adult onset SLE (p(c) = 0.016). SLE patients with the PP genotypes were older at disease onset than those with the other genotypes (p = 0.001). Patients with the Xx genotype had an earlier onset of SLE than those with the xx genotype (p = 0.025). The frequency of the combined ppXx genotype was greater in childhood onset SLE than in controls (p(c) = 0.0009) or adult onset SLE (p(c) = 0.027). The same trend was supported by subgroup analyses according to age at menarche and logistic multivariate analyses.ORalpha polymorphisms are significantly associated with the age at disease onset in Koreans with SLE.
Lung stem cells as a possible origin of cancer
Authors: S E A Fairbairn
Journal: Thorax (2005)

▴ Kim CFB, Jackson EL, Woolfenden AE, et al . Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell2005;121:823–35

[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4]



Epithelial stem cell populations are thought to exist in anatomically and functionally distinct locations within the lung, as suggested by earlier observations of lung injury models. This observational study looked at mouse models to support the hypotheses that stem cell populations exist in the distal lung, that these stem cells act to maintain bronchiolar Clara and alveolar cells, and that their transformation may give rise to lung adenocarcinomas. …

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Apelin Gene Transfer Into the Rostral Ventrolateral Medulla Induces Chronic Blood Pressure Elevation in Normotensive Rats
Authors: Qi Zhang, Fanrong Yao, Mohan K. Raizada, Stephen T. O'Rourke, Chengwen Sun
Journal: Circulation Research (2009)

The peripheral apelin system plays a significant role in cardiovascular homeostasis and in the pathophysiology of cardiovascular diseases. However, the central effect of this neurohormonal system in neural control of cardiovascular function remains poorly understood. Thus, this study was undertaken to evaluate the effect of apelin in the rostral ventrolateral medulla (RVLM) on blood pressure, cardiac function, and sympathetic nerve activity. Apelin mRNA and protein levels were detected with real-time RT-PCR and Western blots, respectively. Expression of apelin was significantly enhanced in the RVLM of spontaneously hypertensive rat (SHR) compared with normotensive Wistar-Kyoto (WKY) rats. To study the functional consequence of upregulated apelin expression, apelin was overexpressed by bilateral microinjection of the AAV2-apelin viral vector into the RVLM of WKY rats. Immunofluorescence staining and Western blots demonstrated that microinjection of AAV2-apelin into the RVLM resulted in a significant increase in apelin expression, which was associated with a chronic elevation in blood pressure and cardiac hypertrophy. In addition, direct microinjection of exogenous apelin-13 (200 pmol in 50 nL) into the RVLM caused a 20 mm Hg elevation in blood pressure and a 24% increase in sympathetic nerve activity. The present study is the first to show that apelin expression is enhanced in the RVLM of SHR versus WKY rats and that overexpression of this gene in the RVLM results in chronic blood pressure elevation and cardiac hypertrophy in normotensive rats. Thus, the apelin system in the RVLM may play a very important role in central blood pressure regulation and in the pathogenesis of hypertension.
Signaling Events Downstream of Mammalian Target of Rapamycin Complex 2 Are Attenuated in Cells and Tumors Deficient for the Tuberous Sclerosis Complex Tumor Suppressors
Authors: Jingxiang Huang, Shulin Wu, Chin-Lee Wu, Brendan D. Manning
Journal: Cancer Research (2009)

Abstract Mutations in the TSC1 and TSC2 tumor suppressor genes give rise to the neoplastic disorders tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis. Their gene products form a complex that is a critical negative regulator of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and cell growth. We recently found that the TSC1-TSC2 complex promotes the activity of mTOR complex 2 (mTORC2), an upstream activator of Akt, and this occurs independent of its inhibitory effects on mTORC1. Loss of mTORC2 activity in cells lacking the TSC1-TSC2 complex, coupled with mTORC1-mediated feedback mechanisms, leads to strong attenuation of the growth factor–stimulated phosphorylation of Akt on S473. In this study, we show that both phosphatidylinositol 3-kinase–dependent and phosphatidylinositol 3-kinase–independent mTORC2 substrates are affected by loss of the TSC1-TSC2 complex in cell culture models and kidney tumors from both Tsc2+/- mice (adenoma) and TSC patients (angiomyolipoma). These mTORC2 targets are all members of the AGC kinase family and include Akt, protein kinase Cα, and serum and glucocorticoid-induced protein kinase 1. We also show that the TSC1-TSC2 complex can directly stimulate the in vitro kinase activity of mTORC2. The interaction between these two complexes is mediated primarily through regions on TSC2 and a core component of mTORC2 called Rictor. Hence, loss of the TSC tumor suppressors results in elevated mTORC1 signaling and attenuated mTORC2 signaling. These findings suggest that the TSC1-TSC2 complex plays opposing roles in tumor progression, both blocking and promoting specific oncogenic pathways through its effects on mTORC1 inhibition and mTORC2 activation, respectively. [Cancer Res 2009;69(15):6107–14]
Global transcriptional responses of fission and budding yeast to changes in copper and iron levels: a comparative study
Authors: Gabriella Rustici, Harm van Bakel, Daniel H Lackner, Frank Holstege, Cisca Wijmenga, Jurg Bahler, Alvis Brazma
Journal: Genome biology (2007)

Recent studies in comparative genomics demonstrate that interspecies comparison represents a powerful tool for identifying both conserved and specialized biologic processes across large evolutionary distances. All cells must adjust to environmental fluctuations in metal levels, because levels that are too low or too high can be detrimental. Here we explore the conservation of metal homoeostasis in two distantly related yeasts. We examined genome-wide gene expression responses to changing copper and iron levels in budding and fission yeast using DNA microarrays. The comparison reveals conservation of only a small core set of genes, defining the copper and iron regulons, with a larger number of additional genes being specific for each species. Novel regulatory targets were identified in Schizosaccharomyces pombe for Cuf1p (pex7 and SPAC3G6.05) and Fep1p (srx1, sib1, sib2, rds1, isu1, SPBC27B12.03c, SPAC1F8.02c, and SPBC947.05c). We also present evidence refuting a direct role of Cuf1p in the repression of genes involved in iron uptake. Remarkable differences were detected in responses of the two yeasts to excess copper, probably reflecting evolutionary adaptation to different environments. The considerable evolutionary distance between budding and fission yeast resulted in substantial diversion in the regulation of copper and iron homeostasis. Despite these differences, the conserved regulation of a core set of genes involved in the uptake of these metals provides valuable clues to key features of metal metabolism.
Non-Communicable Diseases in Sub-Saharan Africa: The Case for Cohort Studies
Authors: Michelle D. Holmes, Shona Dalal, Jimmy Volmink, Clement A. Adebamowo, Marina Njelekela, Wafaie W. Fawzi, Walter C. Willett, Hans-Olov Adami
Journal: PLoS Medicine (2010)

The Policy Forum allows health policy makers around
Two Functional Subsets of FOXP3+ Regulatory T Cells in Human Thymus and Periphery
Authors: Tomoki Ito, Shino Hanabuchi, Yi-Hong Wang, Woong Ryeon Park, Kazuhiko Arima, Laura Bover, F. Xiao-Feng Qin, Michel Gilliet, Yong-Jun Liu
Journal: Immunity (2008)
Treatment of Metastatic Renal Cell Carcinoma With a Combination of Bevacizumab and Erlotinib
Authors: John D. Hainsworth, Jeffrey A. Sosman, David R. Spigel, Donna L. Edwards, Cara Baughman, Anthony Greco
Journal: Journal of Clinical Oncology (2005)

To evaluate the efficacy and toxicity of combined treatment with two targeted agents, an antibody against vascular endothelial growth factor (bevacizumab) and an epidermal growth factor receptor tyrosine kinase inhibitor (erlotinib), in the treatment of patients with metastatic clear-cell renal carcinoma.Sixty-three patients with metastatic clear-cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks and erlotinib 150 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients who responded continued treatment until they experienced tumor progression.Fifteen (25%) of 59 assessable patients (95% CI, 16% to 37%) had objective responses to treatment, and an additional 36 patients (61%) had stable disease after 8 weeks of treatment. Only eight patients' (14%) disease had progressed at this time point. The median and 1-year progression-free survivals were 11 months and 43%, respectively. After a median follow-up of 15 months, median survival has not been reached; survival at 18 months was 60%. Treatment was generally well tolerated; only two patients discontinued treatment because of toxicity (skin rash). Grade 1/2 skin rash and diarrhea were the most frequent treatment-related toxicities.The combination of bevacizumab and erlotinib is an effective and well-tolerated treatment for patients with advanced renal cell carcinoma. The efficacy of these two drugs in combination suggests that targeting of separate pathways critical to tumor growth and dissemination may achieve results superior to either drug as a single agent. Additional development of this and other combinations of targeted agents is warranted.
Effects of Marrow Grafting on Preleukemia Cells and Thymic Nurse Cells in C57BL/Ka Mice After a Leukemogenic Split-Dose Irradiation&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Marie-Paule Defresne, Roland Greimers, Patrick Lenaerts, Jacques Boniver
Journal: JNCI Journal of the National Cancer Institute (1986)

A split-dose regimen of whole-body irradiation (4 X 175 rad at weekly intervals) induced thymic lymphomas in C57BL/Ka mice after a latent period of 3-9 months. Meanwhile, preleukemia cells arose in the thymus and bone marrow and persisted until the onset of lymphomas. Simultaneously, thymic lymphopoiesis was impaired; thymocyte numbers were subnormal and thymic nurse cells disappeared in a progressive but irreversible fashion. The depletion of these lymphoepithelial complexes, which are normally involved in the early steps of thymic lymphopoiesis, was related to altered prothymocyte activity in bone marrow and to damaged thymic microenvironment, perhaps as a consequence of the presence of preleukemia cells. The grafting of normal bone marrow cells after irradiation prevented the development of lymphomas. However, marrow reconstitution did not inhibit the induction of preleukemia cells. They disappeared from the thymus during the second part of the latent period. At the same time, thymic lymphopoiesis was restored; thymocytes and nurse cell numbers returned to normal as a consequence of the proliferation of grafted marrow-derived cells within the thymus. The results thus demonstrated an intimate relationship between preleukemia cells and an alteration of thymic lymphopoiesis, which particularly involved the nurse cell microenvironment. Some preleukemia cells in marrow-reconstituted, irradiated mice derived from the unirradiated marrow inoculate. Thus these cells acquired neoplastic potential through a factor present in the irradiated tissues. The nature of this indirect mechanism was briefly discussed.
CD36 Expression Contributes to Age-Induced Cardiomyopathy in Mice
Authors: Debby P.Y. Koonen, Maria Febbraio, Sebastien Bonnet, Jayan Nagendran, Martin E. Young, Evangelos D. Michelakis, Jason R.B. Dyck
Journal: Circulation (2007)

Background— Cardiac remodeling and impaired cardiac performance in the elderly significantly increase the risk of developing heart disease. Although vascular abnormalities associated with aging contribute to the age-related decline in cardiac function, myocardium-specific events may also be involved. Methods and Results— We show that intramyocardial lipid accumulation, as well as a reduction in both fatty acid and glucose oxidation and a subsequent deterioration in cardiac ATP supply, also occurs in aged mice. Consistent with an energetically compromised heart, hearts from aged mice display depressed myocardial performance and cardiac hypertrophy. Associated with this is a dramatic increase in the fatty acid transport protein CD36 in aged hearts compared with young hearts, which suggests that CD36 is a mediator of these multiple metabolic, functional, and structural alterations in the aged heart. In accordance with this, hearts from aged CD36-deficient mice have lower levels of intramyocardial lipids, demonstrate improved mitochondria-derived ATP production, have significantly enhanced function compared with aged wild-type mice, and have a blunted hypertrophic response. Conclusions— These findings provide evidence that CD36 mediates an age-induced cardiomyopathy in mice and suggest that inhibition of CD36 may be an approach for the treatment of the detrimental age-related effects on cardiac performance.
Inhibition of the alveolar macrophage oxidative burst by a diffusible component from the surface of the spores of the fungus Aspergillus fumigatus.
Authors: J Slight, W J Nicholson, C G Mitchell, N Pouilly, P H Beswick, A Seaton, K Donaldson
Journal: Thorax (1996)

BACKGROUND: Aspergillus fumigatus is a fungus that grows on dead and decaying organic matter in the environment and whose spores are present ubiquitously in the air. The fungus causes a range of diseases in the human lung. A study was undertaken to demonstrate and partially characterise an inhibitor of the macrophage respiratory burst from the surface of A fumigatus spores that could be an important factor in allowing the fungus to colonise the lung. METHODS: The spore-derived inhibitor of the respiratory burst of rat alveolar macrophages, as measured by generation of superoxide anion, was demonstrated in Hank9s balanced salt solution extracts of four clinical isolates and an environmental isolate of A fumigatus. The time course of the release of the inhibitor into aqueous solution was assessed and the cytotoxic potential of the spore-derived inhibitor towards macrophages was tested using the propidium iodide method. An oxygen electrode was used to confirm the superoxide anion measurements. Molecular weight cutoff filters were used to determine the size of the inhibitor as assessed in the respiratory burst assay and also by its ability to inhibit macrophage spreading on glass. The crude diffusate from the spore surface was fractionated by reversed phase high pressure liquid chromatography (HPLC) and the fractions analysed for inhibitory activity, protein, and carbohydrate content. RESULTS: A small molecular weight (&lt; 10 kD) heat stable toxin was released from the spores of clinical and environmental isolates of A fumigatus within minutes of deposition in aqueous solution. The key effect of the toxin demonstrated here was its ability to inhibit the oxidative burst of macrophages as measured by superoxide anion release. The inhibition was not due to cell death or detectable loss of membrane integrity as measured by permeability to propidium iodide. The toxin was not a scavenger of superoxide anion. Oxygen electrode studies suggested indirectly that the inhibitor acted to inhibit the assembly of the macrophage NADPH-oxidase complex. Fractions of &lt; 10 kD also inhibited the spreading of alveolar macrophages, confirming that the toxin had an additional effect on macrophages that leads to loss of adherence or impairment of cytoskeletal function. In reversed phase HPLC fractions the inhibitory activity eluted with an associated carbohydrate, although the exact chemical nature of the toxin remains to be elucidated. CONCLUSIONS: This spore toxin may, through its ability to diffuse rapidly into lung lining fluid, diminish the macrophage respiratory burst and play a part in allowing A fumigatus to persist in the lung and manifest its well known pathogenic effects. Future research will be focused on further molecular characterisation of the toxin and elaboration of the effect of the toxin on intracellular signalling pathways involved in the activation of alveolar macrophages.
The impact of tacrolimus ointment on health-related quality of life of adult and pediatric patients with atopic dermatitis
Authors: Lynn Drake, Mary Prendergast, Rochelle Maher, Debra Breneman, Neil Korman, Yoichi Satoib, Kathleen M. Beusterien, Ira Lawrence
Journal: Journal of the American Academy of Dermatology (2001)
Pregenerative medicine: developmental paradigms in the biology of cardiovascular regeneration
Authors: B. Alexander Yi, Oliver Wernet, Kenneth R. Chien
Journal: Journal of Clinical Investigation (2010)

The ability to create new functional cardiomyocytes is the holy grail of cardiac regenerative medicine. From studies using model organisms, new insights into the fundamental pathways that drive heart muscle regeneration have begun to arise as well as a growing knowledge of the distinct families of multipotent cardiovascular progenitors that generate diverse lineages during heart development. In this Review, we highlight this intersection of the "pregenerative" biology of heart progenitor cells and heart regeneration and discuss the longer term challenges and opportunities in moving toward a therapeutic goal of regenerative cardiovascular medicine.