tbuckley/cabot-search huggingface dataset:
Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma
Authors: Liping Song, Tasnim Ara, Hong-Wei Wu, Chan-Wook Woo, C. Patrick Reynolds, Robert C. Seeger, Yves A. DeClerck, Carol J. Thiele, Richard Sposto, Leonid S. Metelitsa
Journal: Journal of Clinical Investigation (2007)

Valpha24-invariant natural killer T (NKT) cells are potentially important for antitumor immunity. We and others have previously demonstrated positive associations between NKT cell presence in primary tumors and long-term survival in distinct human cancers. However, the mechanism by which aggressive tumors avoid infiltration with NKT and other T cells remains poorly understood. Here, we report that the v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN), the hallmark of aggressive neuroblastoma, repressed expression of monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2), a chemokine required for NKT cell chemoattraction. MYCN knockdown in MYCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction. Unlike other oncogenes, MYCN repressed chemokine expression in a STAT3-independent manner, requiring an E-box element in the CCL2 promoter to mediate transcriptional repression. MYCN overexpression in neuroblastoma xenografts in NOD/SCID mice severely inhibited their ability to attract human NKT cells, T cells, and monocytes. Patients with MYCN-amplified neuroblastoma metastatic to bone marrow had 4-fold fewer NKT cells in their bone marrow than did their nonamplified counterparts, indicating that the MYCN-mediated immune escape mechanism, which we believe to be novel, is operative in metastatic cancer and should be considered in tumor immunobiology and for the development of new therapeutic strategies.
VEGF-C–dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease
Authors: Silvia D’Alessio, Carmen Correale, Carlotta Tacconi, Alessandro Gandelli, Giovanni Pietrogrande, Stefania Vetrano, Marco Genua, Vincenzo Arena, Antonino Spinelli, Laurent Peyrin-Biroulet, Claudio Fiocchi, Silvio Danese
Journal: Journal of Clinical Investigation (2014)

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology that are associated with an aberrant mucosal immune response. Neoangiogenesis and vascular injury are observed in IBD along with increased lymphangiogenesis. While the pathogenic role of angiogenesis in IBD is well characterized, it is not clear how or if increased lymphangiogenesis promotes disease. Here, we determined that enhancing lymphangiogenesis and lymphatic function reduces experimental IBD. Specifically, we demonstrated that adenoviral induction of prolymphangiogenic factor VEGF-C provides marked protection against the development of acute and chronic colitis in 2 different animal models. VEGF-C-dependent protection was observed in combination with increased inflammatory cell mobilization and bacterial antigen clearance from the inflamed colon to the draining lymph nodes. Moreover, we found that the VEGF-C/VEGFR3 pathway regulates macrophage (MΦ) plasticity and activation both in cultured MΦs and in vivo, imparting a hybrid M1-M2 phenotype. The protective function of VEGF-C was meditated by the so-called resolving MΦs during chronic experimental colitis in a STAT6-dependent manner. Together, these findings shed light on the contribution of lymphatics to the pathogenesis of gut inflammation and suggest that correction of defective lymphatic function with VEGF-C has potential as a therapeutic strategy for IBD.
Long term care for older people
Authors: I. Heath
Journal: BMJ (2002)

See also News p 1542 

Long term care is a reality for thousands of frail older people, a source of great anxiety for many more and, across the developed world, a political hot potato that shows no sign of cooling. The heat is fuelled by two factors. Firstly, current government policy in many countries is widely perceived to be unjust, with older people themselves paying an ever greater proportion of the costs of health care. Secondly, the rising percentage of older people in the population, while fuelling doom laden economic projections, is inexorably increasing the power of the older vote, producing democratic pressure for change that is gradually intensifying. This week's changes to the funding of long term care in Scotland will further intensify this pressure (p 1542).

Very shortly after winning power in May 1997, the New Labour government in the United Kingdom sought to deal with the problem by appointing a royal commission to examine the options and to recommend how the costs of care should be apportioned between public funds and individuals.1 In June 2000, after delaying a decision for more than a year, the government refused to implement the commission's most important …
Influence of heart failure on nucleocytoplasmic transport in human cardiomyocytes
Authors: R. Cortes, E. Rosello-Lleti, M. Rivera, L. Martinez-Dolz, A. Salvador, I. Azorin, M. Portoles
Journal: Cardiovascular Research (2009)

The role of the cell nucleus in the development of heart failure (HF) is unknown, so the objectives of this study were to analyse the effect of HF on nucleocytoplasmic transport and density of the nuclear pore complex (NPC).A total of 51 human heart samples from ischaemic (ICM, n = 30) and dilated (DCM, n = 16) patients undergoing heart transplantation and control donors (CNT, n = 5) were analysed by western blotting. Subcellular distribution of proteins and NPC were analysed by fluorescence and electron microscopy, respectively. When we compared nucleocytoplasmic machinery protein levels according to aetiology of HF, ICM showed higher levels of importins [(IMP-beta3) (150%, P < 0.0001), IMP-alpha2 (69%, P = 0.001)] and exportins [EXP-1 (178%, P < 0.0001), EXP-4 (81%, P = 0.006)] than those of the CNT group. Furthermore, DCM also showed significant differences for IMP-beta3 (192%, P < 0.0001), IMP-alpha2 (52%, P = 0.025), and EXP-1 (228%, P < 0.0001). RanGTPase-activating proteins (RanGAP1 and RaGAP1u) were increased in ICM (76%, P = 0.005; 51%, P = 0.012) and DCM (41%, P = 0.042; 50%, P = 0.029). Furthermore, subcellular distribution of nucleocytoplasmic machinery was not altered in pathological hearts. Finally, nucleoporin (Nup) p62 was increased in ICM (80%) and DCM (109%) (P < 0.001 and P = 0.024). Nuclear pore density was comparable in pathological and CNT hearts, and ICM showed a low diameter (P = 0.005) and different structural configuration of NPC.This study shows the effect of HF on nucleocytoplasmic trafficking machinery, evidenced by higher levels of importins, exportins, Ran regulators and Nup p62 in ischaemic and dilated human hearts than those in the controls, with NPCs acquiring a different configuration and morphology in ICM.
LEFT VENTRICULAR DYSSYNCHRONY IN ASYMPTOMATIC WOMEN PREDICTS ADVERSE CARDIOVASCULAR OUTCOME: MULTI ETHNICITY STUDY OF ATHEROSCLEROSIS (MESA)
Authors: Ravi Sharma, Volpe Gustavo, Bharath Ambale-Venkatesh, Boaz Rosen, Sirisha Donekal, Veronica Fernandes, Colin Wu, Jeffrey Carr, David Bluemke, Joao Lima
Journal: Journal of the American College of Cardiology (2014)
Respiratory Tract Carcinogenesis Induced in Hamsters by Different Dose Levels of Benzo[α]pyrene and Ferric Oxide&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Umberto Saffiotti, Ruggero Montesano, Arthur R. Sellakumar, David G. Kaufman
Journal: JNCI Journal of the National Cancer Institute (1972)

Dose-response relationships for different dosages per administration of a suspension of benzo[α]pyrene (BP) and ferric oxide given intratracheally to Syrian golden hamsters were examined for respiratory carcinogenesis. Each group received 30 weekly instillations. The amounts of BP were 2.0, 1.0, 0.5, and 0.25 mg/dose, all with an equal amount of ferric oxide. A positive correlation was demonstrated between the dose level of individual administrations and the yield of respiratory tumors. Both tumor latency and tumor multiplicity were related to the dose per administration and hence total dose. As previously noted in this animal model, squamous cell carcinomas were the predominant morphologic type, and the most frequently affected site was the bronchi, followed by the trachea.—J Natl Cancer Inst 49: 1199–1204, 1972.
Clonality and altered behavior of endothelial cells from hemangiomas
Authors: Eileen Boye, Ying Yu, Gretchen Paranya, John B. Mulliken, Bjorn R. Olsen, Joyce Bischoff
Journal: Journal of Clinical Investigation (2001)

Hemangioma, the most common tumor of infancy, is a benign vascular neoplasm of unknown etiology. We show, for the first time to our knowledge, that endothelial cells from proliferating hemangioma are clonal, and we demonstrate that these hemangioma-derived cells differ from normal endothelial cells in their rates of proliferation and migration in vitro. Furthermore, migration of hemangioma endothelial cells is stimulated by the angiogenesis inhibitor endostatin, unlike the inhibition seen with normal endothelial cells. We conclude that hemangiomas constitute clonal expansions of endothelial cells. This is consistent with the possibility that these tumors are caused by somatic mutations in one or more genes regulating endothelial cell proliferation.
Preliminary experience with a new method of endoscopic transbronchial real time ultrasound guided biopsy for diagnosis of mediastinal and hilar lesions
Authors: M Krasnik
Journal: Thorax (2003)

The aim of the present study was to gain experience with a new method of endoscopic transbronchial ultrasonography with direct, real time guided fine needle aspiration biopsy (EBUS-FNA).EBUS-FNA was performed in 11 patients. Selection of the patients for EBUS-FNA was based on computed tomographic (CT) scanning in 10 patients and on positron emission tomography in one. The ultrasonic bronchoscope used was a prototype with an outer diameter of 6.9 mm. The instrument has a small curved array transducer located in front of a 30 degrees oblique forward viewing optic lens and a biopsy channel of 2 mm. The procedures were performed under general anaesthesia. EBUS-FNA was performed by direct transducer contact with the trachea or main bronchi with a prototype 22 gauge needle.A total of 15 lesions were punctured. No complications were experienced. Four lesions were targeted in region 10L, four in region 10R, one in region 4L, three in region 4R, one in region 1, one in region 7, and one in region 2R. The size of the lesions ranged from 7 mm to 80 mm. EBUS-FNA identified malignant cells in 13 lesions and benign cells in two.EBUS-FNA is a promising technique for lymph node staging of lung cancer as well as for the primary diagnosis of solid lesions located adjacent to the trachea and main bronchi and not accessible by other methods apart from surgical intervention.
On the Estimation of the Insertion Time of LTR Retrotransposable Elements
Authors: T.E. Kijima, H. Innan
Journal: Molecular Biology and Evolution (2009)

It has been proposed that the insertion time of a long terminal repeat (LTR) retrotransposon can be estimated by the divergence between the two LTRs at the both ends because their sequences were identical at the insertion event. This method is based on the assumption that the two LTRs accumulate point mutations independently; therefore, the divergence reflects the time since the insertion event. However, if gene conversion occurs between LTRs, the nucleotide divergence will be much smaller than expected with the assumption of the independent accumulation of point mutations. To examine this assumption, we investigated the extent of gene conversion between LTRs by applying a comparative genomic approach to primates (humans and rhesus macaques) and rodents (mice and rats). We found that gene conversion plays a significant role in the molecular evolution of LTRs in primates and rodents, but the extent is quite different. In rodents, most LTRs are subject to extensive gene conversion that reduces the divergence, so that the divergence-based method results in a serious underestimation of the insertion time. In primates, this effect is limited to a small proportion of LTRs. The most likely explanation of the difference involves the minimum length of the interacting sequence (minimal efficient processing segment [MEPS]) for interlocus gene conversion. An empirical estimate of MEPS in human is 300–500 bp, which exceeds the length of most of the analyzed LTRs. In contrast, MEPS for mice should be much smaller. Thus, MEPS can be an important factor to determine the susceptibility of LTRs to gene conversion, although there are many other factors involved. It is concluded that the divergence method to estimate the insertion time should be applied with special caution because at least some LTRs undergo gene conversion.
Intestinal transport of dipeptides in man: relative importance of hydrolysis and intact absorption
Authors: Siamak A. Adibi, Emile L. Morse
Journal: Journal of Clinical Investigation (1971)

A 30 cm segment of the duodenum, jejunum, or ileum of normal human volunteers was perfused, on separate occasions, with test solutions containing either glycylglycine, free glycine, glycylleucine, or equimolar amounts of free glycine and free leucine. Luminal fluid contained no hydrolytic activity against glycylglycine and minimal activity against glycylleucine. In each intestinal segment, amino acid absorption rates were significantly greater from the test solutions containing the same amount of amino acids in dipeptide than in free form(as high as 185% increase). Perfusion of each intestinal segment with a test solution containing the equimolar mixture of free glycine and free leucine always resulted in a greater leucine than glycine absorption rate. This preferential absorption of leucine, however, was either diminished (jejunum) or almost abolished (duodenum and ileum) when the glycylleucine solution instead of the equimolar mixture was presented to the intestinal mucosa. Among the three segments, the duodenum exhibited the least potential for the disappearance of dipeptides. The jejunal and ileal dipeptide disappearance rates were either similar for glycylleucine (94% vs. 92%) or slightly different for glycylglycine (92% vs. 79%). Despite lack of a remarkable difference in the disappearance rates, absorption rates of constituent amino acids were markedly greater in the jejunum than in the ileum. This reduced amino acid absorption was brought about by a greater accumulation of free amino acids in the lumen of the ileal segment (3 to 10-fold difference). Inhibition of free glycine absorption by leucine during the perfusion of the intestine with a test solution containing glycylglycine and leucine did not result in any greater concentration of free glycine in the lumen than when the glycylglycine test solution did not contain free leucine. Similarly, inhibition of free glycine and free leucine absorption by isoleucine was not accompanied by any remarkable alteration of absorption rates of the constituent amino acids of glycylleucine. The results of these studies suggest that: (a) dipeptide disappearance in the gut lumen is principally accomplished by intact absorption and not by hydrolysis; (b) intracellular hydrolysis of dipeptides is markedly greater in the ileum than in the jejunum, while dipeptide absorption rates are either similar or only slightly different in these two segments; (c) there is no appreciable hydrolysis of glycylglycine by the membrane-bound enzymes and only a small fraction of glycylleucine is hydrolyzed by these enzymes.
Chemoprevention of Breast Cancer: A Summary of the Evidence for the U.S. Preventive Services Task Force
Authors: Linda S. Kinsinger, Russell Harris, Steven H. Woolf, Harold C. Sox, Kathleen N. Lohr
Journal: Annals of Internal Medicine (2002)

Purpose: Chemoprevention offers promise as a strategy for reducing morbidity and mortality from breast cancer in women. This review examined the evidence for the effectiveness of chemoprevention in women without a history of breast cancer. Data Sources: MEDLINE (1966 to December 2001). Study Selection: English-language, randomized, controlled trials (RCTs) of chemoprevention of breast cancer in women without a previous diagnosis of breast cancer were examined, and 4 relevant trials, 3 involving tamoxifen and 1 involving raloxifene, were selected. Trials that provided data on the harms of tamoxifen or raloxifene, studies of the costs of chemoprevention, and studies of risk assessment were also reviewed. Data Extraction: Four reviewers independently abstracted data on key variables, including study population, sample size, randomization, treatment, and outcomes. Data Synthesis: The largest of the RCTs of tamoxifen reported a 49% reduction in relative risk (0.51 [95% CI, 0.39 to 0.66]) for invasive cancer among women with an estimated 5-year breast cancer risk of at least 1.66%. The other tamoxifen trials did not observe a statistically significant benefit, but only a few women in each trial took tamoxifen during the entire study period. The raloxifene study of postmenopausal women with osteoporosis found a 76% reduction in relative risk (0.24 [CI, 0.13 to 0.44]) for invasive breast cancer. Tamoxifen and raloxifene were effective only against estrogen receptor-positive tumors. Both drugs increased risk for venous thromboembolic disease and hot flashes; tamoxifen increased risk for endometrial cancer and stroke. Conclusions: Tamoxifen and raloxifene reduce the incidence of estrogen receptor-positive breast cancer in women. The relative risk reduction seems similar across all breast cancer risk groups. The absolute risk reduction varies by risk factors for breast cancer, however, and must be balanced against the potential harms to judge the appropriateness of treatment for individual women.
Long-term Absolute Risk of Cervical Intraepithelial Neoplasia Grade 3 or Worse Following Human Papillomavirus Infection: Role of Persistence
Authors: S. K. Kjaer, K. Frederiksen, C. Munk, T. Iftner
Journal: JNCI Journal of the National Cancer Institute (2010)

Infection with high-risk human papillomavirus (HPV) is the main cause of high-grade cervical intraepithelial neoplasia (CIN) and cancer. It has been suggested that information about high-risk HPV type–specific infection might make cervical cancer screening more effective. Persistent HPV infection could also be a useful screening marker. We estimated the long-term risk of high-grade CIN after one-time detection of high-risk HPV DNA and after persistent infection with individual high-risk HPV types. A cohort of 8656 women from the general population of Denmark was examined twice, 2 years apart (first study examination: May 15, 1991, to January 31, 1993; second study examination: October 1, 1993, to January 31, 1995). The women underwent a gynecological examination and cervical cytology and had swabs taken for HPV DNA analysis by the Hybrid Capture 2 and line probe assays. The women were followed up through the nationwide Danish Pathology Data Bank for cervical neoplasia for up to 13.4 years. The absolute risk of developing cervical lesions before a given time was estimated as a function of time. For women with normal cytological findings who were concurrently HPV16 DNA positive at the second examination, the estimated probability of developing CIN grade 3 (CIN3) or worse within 12 years of follow-up was 26.7% (95% confidence interval [CI] = 21.1% to 31.8%). The corresponding risks among those infected with HPV18 was 19.1% (95% CI = 10.4% to 27.3%), with HPV31 was 14.3% (95% CI = 9.1% to 19.4%), and with HPV33 was 14.9% (95% CI = 7.9% to 21.1%). The absolute risk of CIN3 or worse after infection with high-risk HPV types other than HPV16, HPV18, HPV31, or HPV33 was 6.0% (95% CI = 3.8% to 8.3%). The estimated absolute risk for CIN3 or cancer within 12 years of the second examination among women who were HPV16 DNA positive at both examinations was 47.4% (95% CI = 34.9% to 57.5%); by contrast, the risk of CIN3 or worse following a negative Hybrid Capture 2 test was 3.0% (95% CI = 2.5% to 3.5%). HPV16, HPV18, HPV31, and HPV33 infection and especially HPV16 persistence were associated with high absolute risks for progression to high-grade cervical lesions. The results indicate the potential value of genotyping in cervical cancer screening. Given that HPV DNA–negative women retained their low risk of CIN3 or worse for many years, frequent screening of these women may be unnecessary.
Delivery of Survivorship Care by Primary Care Physicians: The Perspective of Breast Cancer Patients
Authors: Jun J. Mao, Marjorie A. Bowman, Carrie T. Stricker, Angela DeMichele, Linda Jacobs, Dingyun Chan, Katrina Armstrong
Journal: Journal of Clinical Oncology (2009)

Most of the 182,460 women diagnosed with breast cancer in the United States this year will become long-term survivors. Helping these women transition from active treatment to survivorship is a challenge that involves both oncologists and primary care physicians (PCPs). This study aims to describe postmenopausal breast cancer survivors' (BCS) perceptions of PCP-related survivorship care.We conducted a cross-sectional survey of 300 BCSs seen in an outpatient breast oncology clinic at a large university hospital. The primary outcome measure was a seven-item self-reported measure on perceived survivorship care (Cronbach's alpha = .89). Multivariate regression analyses were used to identify factors associated with perceived care delivery.Overall, BCSs rated PCP-related survivorship care as 65 out of 100 (standard deviation = 17). The areas of PCP-related care most strongly endorsed were general care (78%), psychosocial support (73%), and health promotion (73%). Fewer BCSs perceived their PCPs as knowledgeable about cancer follow-up (50%), late effects of cancer therapies (59%), or treating symptoms related to cancer or cancer therapies (41%). Only 28% felt that their PCPs and oncologists communicated well. In a multivariate regression analysis, nonwhite race and level of trust in the PCP were significantly associated with higher perceived level of PCP-related survivorship care (P = .001 for both).Although BCSs perceived high quality of general care provided by their PCPs, they were not as confident with their PCPs' ability to deliver cancer-specific survivorship care. Interventions need to be tested to improve oncology-primary care communication and PCP knowledge of cancer-specific survivorship care.
CYTOLOGICAL AND PHARMACOLOGICAL OBSERVATIONS ON THE RELEASE OF HISTAMINE BY MAST CELLS
Authors: Don W. Fawcett
Journal: The Journal of Experimental Medicine (1954)

Experimental solutions known to affect mast cells or to cause liberation of histamine from the tissue were introduced into the peritoneal cavity of rats. Samples of the peritoneal fluid were withdrawn at intervals afterward and assayed for histamine and the condition of the mast cells was subsequently ascertained by microscopic examination of stained spreads of the mesenteries. Intraperitoneal injection of distilled water caused osmotic disruption of the mast cells and the appearance of an appreciable amount of histamine in the peritoneal fluid. Injection of Tyrode solution alone was not particularly damaging to the mast cells and little or no histamine was released. Injection of Tyrode solution containing compound 48/80 resulted in extensive release of granules from mast cells and the appearance of large amounts of histamine in the fluid. Solution of 48/80 failed however to cause histamine release when injected into rats whose subserosal mast cells had previously been destroyed. A series of increasing doses of compound 48/80 had a graded morphological effect upon mast cells and resulted in a graded increase in the amount of histamine that appeared in the peritoneal fluid. It is unlikely therefore that this compound acts by simply lysing the plasma membrane. It is concluded that mast cells in the rat are extraordinarily rich in histamine which is liberated under conditions which cause mast cells to release their granules. The histamine set free by the potent histamine liberator, compound 48/80, appears to come principally from the tissue mast cells.