tbuckley/cabot-search huggingface dataset:
Suppression of tumor formation in lymph nodes by L-selectin–mediated natural killer cell recruitment
Authors: Shihao Chen, Hiroto Kawashima, John B. Lowe, Lewis L. Lanier, Minoru Fukuda
Journal: The Journal of Experimental Medicine (2005)

Natural killer (NK) cells are known to reject certain tumors in vivo; however, the ability of NK cells to prevent metastasis of tumors into secondary lymphoid organs has not been addressed. Here, we report that in tumor-bearing hosts, NK cells are recruited to regional lymph nodes in wild-type mice, but not in mice deficient for L-selectin or L-selectin ligands. By adoptive transfer and complete Freund's adjuvant stimulation experiments, we demonstrated that L-selectin on NK cells and L-selectin ligands on endothelial cells are essential for NK cell recruitment to lymph nodes. Furthermore, freshly isolated resident lymph node NK cells lysed tumors efficiently, and metastasis of B16 melanoma cells to draining lymph nodes was suppressed in wild-type or Rag-1–deficient mice, but not when NK cells were depleted. Although L-selectin–deficient NK cells efficiently lysed tumor cells in vitro, NK cell–dependent suppression of tumor metastasis was diminished in mice deficient for L-selectin or L-selectin ligands because of insufficient NK cell recruitment to lymph nodes. Moreover, tumor metastasis was substantially inhibited in L-selectin–deficient mice reconstituted with wild-type NK cells. These findings indicate that L-selectin–mediated NK cell recruitment plays a crucial role in the control of tumor metastasis into secondary lymphoid organs.
e Antigen in Hepatitis B Virus Infected Dialysis Patients: Assessment of Its Prognostic Value
Authors: BARBARA G. WERNER
Journal: Annals of Internal Medicine (1978)

Many investigators consider the presence of e antigen (HBeAg) valuable in predicting which patients with acute hepatitis B are at risk of remaining infected and developing chronic liver disease. We tested this hypothesis in a retrospective study of serial samples from patients undergoing long-term hemodialysis. We found HBeAg in the early phase of all hepatitis B virus (HBV) infections. There was no significant difference between transiently and persistently hepatitis B surface antigen (HBsAg)-positive persons with regard to the frequency of HBeAg during the first 3 months of HBs antigenemia. Thus during the early period of viral activity, the presence of HBeAg is of no prognostic value in determining chronicity of HBV infection. We believe the disagreement on the prognostic value of HBeAg is a reflection of variations in time and frequency of sampling. The HBeAg remains, however, a useful indicator of potential infectivity of HBsAg(+) persons.
Epiphenomenon of telomere lengths: lessons from ulcerative colitis
Authors: Ramesh Arasaradnam, Chuka U Nwokolo
Journal: Gut (2012)

We read with great interest the article by Jones et al detailing TERC polymorphisms, longer telomeres and increased risk of colorectal cancer (CRC).1 Indeed, it is accepted that shorter telomere lengths (measured from peripheral leucocytes) have been shown in senescent somatic cells and also to predispose to cancer. The biological rationale is that telomeres which form a protective cap at the end of chromosomes can be disrupted to undergo double strand breaks, inefficient repair and eventually chromosomal instability. The latter is a well-established precursor to cancer development. Thus, the authors' finding of longer telomeres associated with risk of CRC is particularly intriguing.
Biologic Challenges in the Detection of Circulating Tumor Cells
Authors: Simon A. Joosse, Klaus Pantel
Journal: Cancer Research (2012)

Carcinoma cells found in the blood of cancer patients are predictors of metastatic progression and may guide treatment decisions. Most of the current strategies for detecting circulating tumor cells (CTC) are based on the epithelial markers epithelial cell adhesion molecule and keratin; however, evidence is accumulating that in certain tumor types, these epithelial markers are downregulated during tumor cell dissemination, hampering the detection of CTCs. This short review discusses the implications of the cellular changes of tumor cells during the metastatic cascade on CTC diagnostics.
Abnormalities in the duodenal transit and motility in duodenal ulcer patients: studies with a new isotopic technique.
Authors: M G Quon, I Mena, J E Valenzuela
Journal: Gut (1989)

Abnormalities of duodenal motility have been described in patients with duodenal ulcer and in experimental ulcers in rats and it has been postulated that they could be pathogenic in peptic ulcer disease. We have investigated with an isotopic technique whether duodenal bulb clearance or duodenal transit are abnormal in duodenal ulcer. Six patients with inactive and six with active duodenal ulcers, all men, and six healthy male controls were studied. Motility of the duodenum was simultaneously monitored. A bolus of 99mTcDTPA was injected into the duodenum while water or acid were perfused on different occasions. Duodenal bulb clearance and transit to the ligament of Treitz were calculated. Duodenal transit in duodenal ulcer patients 108.8 (23) sec was faster than in controls, 194.9 (5.1) sec (p less than 0.05) during the quiescent period of the motility cycle. The frequency of duodenal bulb contractions during acid perfusion was higher in duodenal ulcer patients 1.7 (0.4) cont/min, than in controls 0.8 (0.1) cont/min (p less than 0.05). No other significant differences were observed between ulcer patients and controls. These data suggest that patients with duodenal ulcers do not have major abnormalities of duodenal bulb clearance, nor of duodenal transit and that duodenal motility does not play a primary role in the pathogenesis of the ulcer.
microRNA Regulatory Network Inference Identifies miR-34a as a Novel Regulator of TGF-β Signaling in Glioblastoma
Authors: Giannicola Genovese, Ayla Ergun, Sachet A. Shukla, Benito Campos, Jason Hanna, Papia Ghosh, Steven N. Quayle, Kunal Rai, Simona Colla, Haoqiang Ying, Chang-Jiun Wu, Sharmistha Sarkar, Yonghong Xiao, Jianhua Zhang, Hailei Zhang, Lawrence Kwong, Katherine Dunn, Wolf Ruprecht Wiedemeyer, Cameron Brennan, Hongwu Zheng, David L. Rimm, James J. Collins, Lynda Chin
Journal: Cancer Discovery (2012)

Abstract Leveraging The Cancer Genome Atlas (TCGA) multidimensional data in glioblastoma, we inferred the putative regulatory network between microRNA and mRNA using the Context Likelihood of Relatedness modeling algorithm. Interrogation of the network in context of defined molecular subtypes identified 8 microRNAs with a strong discriminatory potential between proneural and mesenchymal subtypes. Integrative in silico analyses, a functional genetic screen, and experimental validation identified miR-34a as a tumor suppressor in proneural subtype glioblastoma. Mechanistically, in addition to its direct regulation of platelet-derived growth factor receptor-alpha (PDGFRA), promoter enrichment analysis of context likelihood of relatedness–inferred mRNA nodes established miR-34a as a novel regulator of a SMAD4 transcriptional network. Clinically, miR-34a expression level is shown to be prognostic, where miR-34a low-expressing glioblastomas exhibited better overall survival. This work illustrates the potential of comprehensive multidimensional cancer genomic data combined with computational and experimental models in enabling mechanistic exploration of relationships among different genetic elements across the genome space in cancer. Significance: We illustrate here that network modeling of complex multidimensional cancer genomic data can generate a framework in which to explore the biology of cancers, leading to discovery of new pathogenetic insights as well as potential prognostic biomarkers. Specifically in glioblastoma, within the context of the global network, promoter enrichment analysis of network edges uncovered a novel regulation of TGF-β signaling via a Smad4 transcriptomic network by miR-34a. Cancer Discov; 2(8); 736–49. ©2012 AACR. Read the Commentary on this article by Babic et al., p. 676. This article is highlighted in the In This Issue feature, p. 653.
Serum and r32kd induced cytokine levels and expression in tuberculosis patients and contacts
Authors: Lavanya Joshi, P.S. Raju, Vijayalakshmi Valluri, Suman latha Gaddam
Journal: European Respiratory Journal (2012)

Tuberculosis is a disease caused by Mycobacterium tuberculosis(MTB) whose interaction with the host may lead to a cell-mediated protective immune response. Several cytokines, including IL-6, IFN-g and TNF-a, play important roles in mediating resistance against MTB. The aim was to investigate the candidate cytokines in active pulmonary tuberculosis patients of younger age (15 to 25yrs), their Household Contacts and controls. Levels were estimated by ELISAin pg/ml in serum(n=30) and PBMCs stimulated with r32-kd antigen of M.bovis BCG (n=30). Expression by qRT-PCR in 5 individuals from each group in culture supernatants were studied. In serum IFN-g and TNF-a concentrations were elevated in patients compared with their contacts and controls(24.51±10.60, 20.45±4.93, 14.14±8.22 at p
Oncogenic Potential of the Nuclear Receptor Coregulator Proline-, Glutamic Acid–, Leucine-Rich Protein 1/Modulator of the Nongenomic Actions of the Estrogen Receptor
Authors: Rajib Rajhans, Sujit Nair, Alan H. Holden, Rakesh Kumar, Rajeshwar Rao Tekmal, Ratna K. Vadlamudi
Journal: Cancer Research (2007)

Proline-, glutamic acid-, leucine-rich protein 1 (PELP1), a novel nuclear receptor coactivator, and its expression is deregulated in hormone-dependent cancers, including those of the breast, endometrium, and ovary. PELP1 interacts with estrogen receptor and modulates its genomic and nongenomic functions. In this study, we examined whether PELP1 functions as an oncogene. The overexpression of PELP1 in fibroblasts and epithelial model cells resulted in cellular transformation. PELP1 also enhanced the transformation potential of c-Src kinase in focus formation assays, and PELP1 overexpression potentiated estradiol-mediated cell migratory potential and anchorage-independent growth. Using PELP1-small interfering RNA, we provided evidence that endogenous PELP1 plays an essential role in E2-mediated anchorage-independent growth, cell migration, and cytoskeletal changes. When compared with control vector transfectants, breast cancer cells stably overexpressing PELP1 showed a rapid tumor growth in xenograft studies. Immunohistochemical analysis of PELP1 expression using a tumor progression array of 252 breast carcinomas and normal breast tissue specimens revealed that PELP1 expression is deregulated to a greater degree in higher grade node-positive invasive tumors than in normal breast tissue or ductal carcinoma in situ. Our data suggest that PELP1 is a potential oncogene, that its expression is deregulated during cancer progression, and that PELP1 may play a role in oncogenesis.
Low socioeconomic status is associated with worse lung function in the Danish cystic fibrosis population
Authors: David C. Taylor-Robinson, Karsten Thielen, Tania Pressler, Hanne V. Olesen, Finn Diderichsen, Peter J. Diggle, Rosalind Smyth, Margaret Whitehead
Journal: European Respiratory Journal (2014)

To the Editor: 

Low socioeconomic status is associated with worse lung function and greater risk of death in people with cystic fibrosis (CF) in the UK and USA, but there are no population level studies from other countries [1–4]. A feature of previous analyses of inequalities in lung function in CF by socioeconomic status has been the identification of a lung function deficit in more disadvantaged children, which is evident as soon as spirometry can be routinely undertaken at ∼5–6 years of age [1, 3]. The finding of a fixed lung function deficit in the most deprived children in the early years of life has important policy implications, and suggests that deprivation has a detrimental effect on lung health in the early years of a child’s life [5].

We questioned whether similar patterns were evident in other CF populations, so assessed the effect of socioeconomic status on lung function trajectory measured by forced expiratory volume in 1 s (FEV1) % predicted in the Danish population. Therefore, we undertook a retrospective, longitudinal, cohort study of all children and adults with CF who had contributed lung function measures to the Danish CF registry between 1969 and 2010 who could be linked to the national level administrative registers.

Patients attending the two Danish CF centres (Copenhagen and Aarhus) were routinely seen every month in the outpatient clinic for evaluation of clinical status, pulmonary function and microbiology of lower respiratory tract secretions. It is estimated that coverage of CF patients resident in Denmark is almost complete from 1990, when CF care was centralised. This coverage and the unparalleled frequency of measurement make this a unique dataset for epidemiological research [6].

The primary outcome for the analysis was FEV1 % predicted. Pulmonary …
Jet-Lag and Shift Work: (2) Therapeutic Use of Melatonin
Authors: Josephine Arendt
Journal: Journal of the Royal Society of Medicine (1999)

The preceding article1 has laid the foundations for understanding the difficulties of jet-lag and shiftworker's malaise and for appreciating the various countermeasures other than chronobiotics (drugs that alter rhythms). Several approaches have met with some success. One of the major difficulties in this area is the uncontrollable nature of field studies on jet-lag and our inability to simulate timezone change in the laboratory in a way that takes account of all the factors that may arise in the field.
Dose escalation of leflunomide (LEF) to 40 mg once daily in patients with rheumatoid arthritis and insufficient response to standard dose LEF
Authors: C Fiehn
Journal: Annals of the Rheumatic Diseases (2004)

Figure 1 Active genital ulcer of the left labium majus together with genital scars.(A) Before the first infusion with infliximab; (B) 2 weeks after the first infusion; (C) 4 weeks after the second infusion.744 www.annrheumdis.com
Hepatic silicosis, cirrhosis, and liver tumors in mice and hamsters: Studies of transforming growth factor ? expression
Authors: A O Williams, A D Knapton
Journal: Hepatology (1996)

Hepatic silicosis, cirrhosis, liver cell adenoma, and carcinomas developed in nude mice (NCr-Nu) given quartz by the subcutaneous and intraperitoneal routes. Syrian golden hamsters (15:16 EHS:cr) given quartz by both routes developed extensive fibrosis and cirrhosis and had higher morbidity and mortality rates after 3 months. Crystalline silica (quartz) induces fibrosis, adenomas, and carcinomas in the lungs of Fisher 344 rats, but certain strains of mice and hamsters are resistant to quartz-induced pulmonary carcinogenesis. Pulmonary fibrosis, however, is minimal in mice and absent in hamsters who received quartz intratracheally. To determine whether species differences are due to organ-specific rather than species-specific factors, susceptibility of the liver to quartz toxicity was investigated in nude mice and hamsters. The present study shows that the differential manifestations of quartz toxicity by these rodent species are dependent on factors that are organ-specific rather than host-specific. At 3 months, hepatocytes in mice were immunostained with intracellular transforming growth factor (TGF) beta 1 (LC 1-30) but not with TGF-beta 1 latency-associated peptide (LAP) protein (266-278); at 12 months, hepatocytes were immunostained with TGF-beta 1 LAP (266-278) but not with TGF-beta 1 (LC1-30). The hepatocytes of hamsters at 3 months showed immunoreactivities to TGF-beta 1 LAP (266-278) and TGF-beta 1 (LC1-30); immunostaining to TGF-beta 1 (LC1-30) was detected in nonparenchymal cells. Extracellular TGF-beta 1 (CC1-30) was detected in the silicotic granulomas and fibrous tissue in livers of both species. Quartz-induced liver carcinoma did not express TGF-beta 1 LAP (266-278) and LC (1-30) proteins, but these were detected in the cells of the adenoma in the same liver. Control animals showed no hepatic lesions nor immunoreactivity to TGF-beta 1. The spatial and temporal patterns of expression of TGF-beta 1, TGF-beta 2, TGF-beta receptor type II messenger RNAs (mRNAs), and TGF-beta 1 proteins in the different hepatic lesions suggests that TGF-beta isoforms may play a role in the pathogenesis of quartz-induced fibrosis, cirrhosis, liver cell adenoma, and carcinoma.
Initial Combination of Empagliflozin and Linagliptin in Subjects With Type 2 Diabetes
Authors: Andrew Lewin, Ralph A. DeFronzo, Sanjay Patel, Dacheng Liu, Renee Kaste, Hans J. Woerle, Uli C. Broedl
Journal: Diabetes Care (2015)

To evaluate the efficacy and safety of empagliflozin/linagliptin in subjects with type 2 diabetes.Subjects not receiving antidiabetes therapy for ≥12 weeks were randomized to empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 135), empagliflozin 10 mg (n = 134), or linagliptin 5 mg (n = 135) for 52 weeks. The primary end point was change from baseline in HbA1c at week 24.Mean HbA1c at baseline was 7.99-8.05% (64 mmol/mol). At week 24, adjusted mean (SE) changes from baseline in HbA1c with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg were -1.08 (0.06)% (-11.8 [0.7] mmol/mol), -1.24 (0.06)% (-13.6 [0.7] mmol/mol), -0.95 (0.06)% (-10.4 [0.7] mmol/mol), -0.83 (0.06)% (-9.1 [0.7] mmol/mol), and -0.67 (0.06)% (-7.3 [0.7] mmol/mol), respectively. Reductions in HbA1c were significantly greater for empagliflozin 25 mg/linagliptin 5 mg compared with linagliptin 5 mg (P < 0.001) but not compared with empagliflozin 25 mg and were significantly greater for empagliflozin 10 mg/linagliptin 5 mg compared with the individual components (P < 0.001 for both). At week 24, 55.4%, 62.3%, 41.5%, 38.8%, and 32.3% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) reached HbA1c <7% with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg, respectively. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across groups (68.9-81.5%), with no confirmed hypoglycemic AEs.Reductions from baseline in HbA1c with empagliflozin/linagliptin were significantly different versus linagliptin and empagliflozin 10 mg but not versus empagliflozin 25 mg. Empagliflozin/linagliptin was well tolerated.
Absence of a Correlation between the Presence of a Single Nucleotide Polymorphism in the Matrix Metalloproteinase 1 Promoter and Outcome in Patients of Chondrosarcoma
Authors: Yi-Chin Fong, Charyl M. Dutton, Stephen S. Cha, Nandor Garamszegi, Franklin H. Sim, Sean P. Scully
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Increased levels of matrix metalloproteinase 1 (MMP-1) expression have been associated with poor outcome in chondrosarcoma. The existence of a single nucleotide polymorphism creating an Ets-binding site in the MMP-1 promoter may be one mechanism for elevated MMP-1 transcription. The aim of our study was to identify the prevalence of this single nucleotide polymorphism (SNP) in chondrosarcoma patients, to determine its correlation with disease outcome, and to discern whether it could serve as a prognostic marker in patients with chondrosarcoma. Experimental Design: Sixty-seven chondrosarcoma specimens were selected sequentially from an established tumor bank with a median duration of 47 months follow-up (range, 24 to 179 months). DNA was extracted, amplified with PCR, and sequenced to determine presence (GG) or absence of the Ets-binding site created by the SNP. Results: Eighteen (27%) samples were homozygous for the absence of the Ets site, 34 (51%) were heterozygous for the SNP, and 15 (22%) were homozygous for the SNP. The 5-year overall survival rate for patients was 78, 80, and 84%, respectively (P = 0.5527). The disease-free survival rate was 16, 63, and 76%, respectively (P = 0.0801). The 5-year disease-free survival rate for patients with the homozygous G/G genotype was 16%, compared with 71% for patients who were either homozygous or heterozygous for the GG allele (P = 0.0444). Conclusions: Despite a statistical correlation between MMP-1 gene expression and outcome in chondrosarcoma, this study demonstrates an absence of a correlation between the presence of the SNP and prognosis in patients with chondrosarcoma.
Point: Pulmonary Inhalation of Insulin: Another “Brick in the Wall”
Authors: William T. Cefalu
Journal: Diabetes Care (2007)

The latest innovation for advancing diabetes care is not a new pharmacologic class; it represents a new “twist” on one of the oldest pharmacologic agents known for treatment of diabetes. After >80 years of clinical use and after many years of research for alternative means of delivery (including dermal, nasal, and oral approaches), insulin delivered by pulmonary inhalation is finally a clinical reality. The availability of inhaled insulin could not have come at a better time. At a time when the prevalence of diabetes is increasing at alarming rates worldwide and when the majority of individuals with diabetes have not achieved the recommended glycemic goal, new insights into the disease itself are being revealed at a rapid pace and are allowing for the development of novel approaches to better manage the disease. As such, inhaled insulin now joins the glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase-IV inhibitors, and synthetic analogs of amylin as the latest tools available to the clinician. However, it is somewhat surprising that despite the promise that inhaled insulin could contribute to a paradigm shift in the clinical management of diabetes, considerable concern is openly expressed regarding its routine use.

There is no question about the need for insulin therapy in an individual with type 1 diabetes. The use of insulin in type 2 diabetes and, in particular, earlier in the course of management is supported by the natural history of the disease, which is characterized by progressive β-cell dysfunction. However, as a medical community, we need to do a much better job in advancing therapy in order to achieve glycemic control. Data from the National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999–2000 suggested, if anything, a decrease in the percentage of individuals achieving glycemic targets (1). At the same time, the percentage of …