Miracle-dz/UniFAR-FTUs huggingface dataset:
CpG island methylation profiling in human melanoma cell lines

A better understanding of key molecular changes during the pathogenesis of melanoma could impact strategies to reduce mortality from this cancer. Two epigenetic events involved in the pathogenesis of cancer are hypermethylation of tumor-suppressor gene promoters associated with transcriptional repression and hypomethylation associated with gene reexpression and genomic instability. We analyzed 16 melanoma cell lines for aberrant hypermethylation of 15 cancer-linked genes (ER&agr;, MGMT, RAR&bgr;2, RIL, RASSF1A, PAX7, PGR&bgr;, PAX2, NKX2-3, OLIG2, HAND1, ECAD, CDH13, MLH1, and p16) and hypomethylation of two genes (MAGEA1, maspin) and two repetitive sequences (LINE-1 and Alu) using pyrosequencing. We observed hypermethylation of ER&agr; in 50% of the cell lines, MGMT (50%), RAR&bgr;2 (44%), RIL (88%), RASSF1A (69%), PAX7 (31%), PGR&bgr; (56%), PAX2 (38%), NKX2-3 (63%), OLIG2 (63%), HAND1 (63%), ECAD (88%), CDH13 (44%), MLH1 (0%), and p16 (6%). In human melanoma cell lines, hypomethylation of MAGEA1 (44%), maspin (25%), LINE-1 (75%), and Alu (13%) is frequently observed. We analyzed a panel of cell lines for BRAF V600E and NRAS codon 61 mutations. In melanoma cell lines, the BRAF and NRAS mutations had no association with aberrant methylation. We found that the cumulative aberrant hypermethylation of the gene promoters was correlated with the level of global DNA methylation. We conclude that aberrant hypermethylation, is frequent in melanoma cell lines, directly correlated with global DNA methylation, and independent of BRAF and NRAS mutations.
Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis

While dietary folate deficiency is associated with increased risk for birth defects and other diseases, evidence suggests that supplementation with folic acid can contribute to predisposition to some diseases, including immune dysfunction and cancer. Herein, we show that diets supplemented with folic acid both below and above the recommended levels led to significantly altered metabolism in multiple tissues in mice. Surprisingly, both low and excessive dietary folate induced similar metabolic changes, which were particularly evident for nucleotide biosynthetic pathways in B-progenitor cells. Diet-induced metabolic changes in these cells partially phenocopied those observed in mice treated with anti-folate drugs, suggesting that both deficiency and excessive levels of dietary folic acid compromise folate-dependent biosynthetic pathways. Both folate deficiency and excessive dietary folate levels compromise hematopoiesis, resulting in defective cell cycle progression, persistent DNA damage, and impaired production of lymphocytes. These defects reduce the reconstitution potential in transplantation settings and increase radiation-induced mortality. We conclude that excessive folic acid supplementation can metabolically mimic dietary folate insufficiency, leading to similar functional impairment of hematopoiesis.
Improvement in cardiac sympathetic nerve activity in responders to resynchronization therapy.

AIMS To assess changes in cardiac adrenergic activity with cardiac resynchronization therapy (CRT), and to investigate whether these changes are related to improvement in left ventricular ejection fraction (LVEF). METHODS AND RESULTS Sixteen patients (13 males, age 66 +/- 7 years) were studied at baseline and after > or =6 months of CRT (mean follow-up 9.2 +/- 3.2 months). LVEF was assessed by nuclear angiography. Responders were defined as patients showing > or =5% absolute increase in LVEF + improvement in > or =1 NYHA class + absence of heart failure hospitalization. Cardiac sympathetic nerve activity was studied by (123)I-metaiodobenzyl-guanidine ((123)I-MIBG) scintigraphy. Responders (n = 8) showed lower (123)I-MIBG washout at follow-up when compared with non-responders (P = 0.002), indicating lower cardiac sympathetic nerve activity. The decrease in (123)I-MIBG washout at follow-up when compared with baseline was only seen in the responder group (P = 0.036). There was a moderate correlation between increase in LVEF and decrease in (123)I-MIBG washout (r = 0.52, P = 0.04). CONCLUSION CRT induces a reduction in cardiac sympathetic nerve activity in responders, that parallels an improvement in LVEF, whereas non-responders do not show any significant changes.
Thermal status of wet-suited divers using closed circuit O2 apparatus in sea water of 17-18.5 degrees C.

A wet suit may not provide adequate thermal protection when diving in moderately cold water (17-18 degrees C), and any resultant mild hypothermia may impair performance during prolonged diving. We studied heat exchange during a dive to a depth of 5 m in sea water (17-18.5 degrees C) in divers wearing a full wet suit and using closed-circuit oxygen breathing apparatus. Eight fin swimmers dived for 3.1 h and six underwater scooter (UWS) divers propelled themselves through the water for 3.7 h. The measurements taken throughout the dive were the oxygen pressure in the cylinder and skin and rectal temperatures (Tre). Each subject also completed a cold score questionnaire. The Tre decreased continuously in all subjects. Oxygen consumption in the fin divers (1.40 l.min-1) was higher than that of the UWS divers (1.05 l.min-1). The mean total insulation was 0.087 degree C.m2. W-1 in both groups. Mean body insulation was 37% of the total insulation (suit insulation was 63%). The reduction in Tre over the 1st hour was related to subcutaneous fat thickness. There was a correlation between cold score and Tre at the end of 1 h, but not after that. A full wet suit does not appear to provide adequate thermal protection when diving in moderately cold water.
IMC growth in solid-liquid interdifussion bonds

3D ICs is a promising new technology that has many advantages over traditional planar packages. To take advantage of this technology, new bonding techniques have to be developed to satisfy the need for high density micro interconnects. Solid liquid inter-diffusion bonding in which the bond is established by placing a low melting temperature material between high temperature melting substrate and applying heat and pressure, is a new technology that may resolve issues with other type of bonding. This manuscript presents a 1D analytical phase lag model to estimate the complete bonding time (complete transformation to IMCs) for bonds with different thicknesses. The time for complete transformation of the bond to IMC is estimated using this technique for bonds with range of thicknesses of 10 microns to 200 microns. An experiment is conducted to produce bonds with variety of thicknesses. Bonding was carried out at 260°C and process parameters were varied to produce bonds with thicknesses varying between 15 microns and 250 microns. The SEM and EDS imaging is used to determine the extent of copper diffusion in the bonds and different IMC compounds. This analysis show that 45 minutes is long enough to transform all bonds with variety of thicknesses to η phase of IMC. Traces of ε phase of IMC were also found in all the cases and were more significant in the case of 15 micron thickness.
Primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma: temporary remission by oral doxycycline.

IMPORTANCE In the recent World Health Organization-European Organisation for Research and Treatment of Cancer classification, primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma is listed as a provisional entity that is histopathologically characterized by pleomorphic CD3+/CD4+/CD8-/CD30- T lymphocytes. Clinically, it is characterized by solitary tumors mostly affecting the head and neck area and by an indolent clinical course with an estimated 5-year survival of about 60% to 80%. Currently, therapeutic options include topical or systemic treatment with glucocorticoids, local excision of solitary lesions, radiotherapy, and chemotherapy (e.g., cyclophosphamide) in cases of aggressive clinical behavior or systemic disease. OBSERVATIONS We present the case of a 21-year-old female patient with a 5-year history of a solitary, slowly growing tumor of the right cheek. Histopathologic findings revealed a primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma with an admixture of numerous CD20+ B cells representing almost half of the infiltrate. In this patient we achieved a temporary (13 months) complete remission of the lymphoma by oral treatment with doxycycline monohydrate, 200 mg per day. CONCLUSIONS AND RELEVANCE Doxycycline is a relatively nontoxic and well-tolerated oral agent and should be considered as a therapeutic option in primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma, especially in cases with a high percentage of B lymphocytes and no signs of systemic disease.
Influence of forest machine function on operator exposure to whole-body vibration in a cut-to-length timber harvester

The influence of machine function (tree felling and processing, and machine movement over the terrain) on operator exposure to whole-body vibration in a cut-to-length (CTL) timber harvester was evaluated. Vibrations were measured on the seat and the cabin chassis in three orthogonal (x, y, z) axes for the tree felling and processing, and during motion on a test track. It was found that the level of vibration transmitted to the operator during felling and processing was mainly affected by the tree size (diameter). For tree diameter at breast height (dbh) range of 0.25 – 0.35 m that was investigated, the vertical (z-axis) vibration component during processing increased by up to 300%, and increased by 50% during felling. However, the associated vibration levels were not sufficient to pose any serious health risks to the operator for an exposure limit of 8 h. Vibration at the operator seat and cabin chassis was predominant in the lateral (y-axis) and vertical (z-axis) respectively, during vehicle motion over the standard test track. Vibration peaks of approximately 0.20 and 0.17 ms−2 occurred at 5 and 3.2 Hz respectively.
Cyclic AMP-Related and Cation-Affected Human Platelet Chloride Transport Regulation

Cystic fibrosis has been characterized as a defect in the regulation of cyclic AMP-dependent transepithelial chloride transport. The activation of cyclic AMP-dependent protein kinase A by cyclic AMP occurs normally in cystic fibrosis cells, but they fail to transport chloride ions in response to protein kinase A stimulation. Defective chloride secretion and abnormal electrolyte transport occurs in several organs including the lung, sweat glands, intestine and pancreas. The present work was aimed at exploring whether the same or similar regulatory systems are functional in platelets, and if they are altered or deficient in individuals with cystic fibrosis. Chloride transport in platelets from normal subjects and from cystic fibrosis patients was measured by cell sizing techniques where chloride permeability is the limiting factor. In platelets from healthy volunteers, the chloride channel blocker, 5-nitro-2-(3-phenylpropylamino) benzoic acid, inhibits the transport in a dose-dependent manner. The preservation of chloride transport capability is shown to be dependent upon the presence of either Ca2+ or two divalent cation substitutes, Cd2+ or Cu2+. It is also shown that in normal subjects 0.1 mumol/l prostaglandin E1, which elevates cyclic AMP 6 times and abolishes platelet aggregation, significantly enhances the rate constant of the transport. Furthermore, in five out of nine cystic fibrosis patients studied, platelet chloride transport did not respond to stimulation by prostaglandin E1.
Dietary protein modulates intrarenal distribution of renin and its mRNA during development.

To determine whether high protein feeding throughout development affects renal growth, renal hemodynamics, and the intrarenal distribution of renin and its mRNA in the adult animal, male Wistar rats were fed diets containing either 20% protein [normal (NP), n = 12] or 40% protein [high (HP), n = 12] from weaning until studied at 6 or 12 wk of age. Kidney weight, kidney weight-to-body weight ratio, cortical DNA content, and cortical protein-to-DNA ratio were higher in HP- than in NP-fed rats at 6 and 12 wk of age. Somatic and kidney growth response to HP was blunted by angiotensin II type 1 receptor antagonist Dup 753. Glomerular filtration rate and renal plasma flow were higher in HP- than in NP-fed rats at 6 and 12 wk of age. The intrarenal distribution of renin and renin mRNA, assessed by immunocytochemistry and in situ hybridization, respectively, were markedly different between the two groups. In NP-fed rats, renin and renin mRNA were confined to a juxtaglomerular location. In HP-fed rats, renin and its mRNA extended proximally along the afferent arterioles. The percentage of visible afferent arteriolar length containing renin or renin mRNA was higher in HP-fed rats (60 +/- 3.2 and 61 +/- 3.9%, respectively) than in NP-fed rats (39 +/- 2.5 and 33 +/- 0.6%; P less than 0.05). Also, the percentage of juxtaglomerular apparatuses (JGAs) containing renin or renin mRNA was higher in HP-fed rats (80 +/- 1.6 and 72 +/- 2%, respectively), than in NP-fed rats (46 +/- 2.2 and 40 +/- 4%; P less than 0.05). (ABSTRACT TRUNCATED AT 250 WORDS)
Associations of GAD65- and IA-2-Autoantibodies With Genetic Risk Markers in New-Onset IDDM Patients and Their Siblings. The Belgian Diabetes Registry

OBJECTIVE To investigate the association of GAD (65-kDa) autoantibodies (GAD65-Abs) and IA-2 autoantibodies (IA-2-Abs) with human leukocyte antigen (HLA)-DQ and insulin gene (INS) risk markers in patients with recent-onset IDDM and their siblings. RESEARCH DESIGN AND METHODS Blood was sampled from 608 recent-onset IDDM patients and 480 siblings, aged 0–39 years and consecutively recruited by the Belgian Diabetes Registry, to determine GAD65- and IA-2-Ab (radiobinding assay), HLA-DQ- (allele-specific oligonucleotyping), and INS-genotypes (restriction fragment length polymorphism analysis; siblings, n = 439). RESULTS At the onset of IDDM, GAD65-Abs were preferentially associated with two populations at genetic risk but only in the 20- to 39-year age-group: 1) their prevalence was higher in carriers of DQA1*0301-DQB1*0302 (88 vs. 73% in non[DQA1*0301-DQB1*0302], P = 0.001), and 2) an association was found in patients lacking this haplotype but carrying DQA1*0501-DQB1*0201, together with INS I/I (87 vs. 54% vs. non[INS I/I], P = 0.003). Siblings of IDDM patients also presented the association of GAD65-Abs with DQA1*0301-DQB1*0302 (13 vs. 2% non[DQA1*0301-DQB1*0302], P < 0.001), while associations with the second genetic risk group could not yet be assessed. At the onset of IDDM, IA-2-Ab prevalence was higher in carriers of DQA1*0301-DQB1*0302 (69 vs. 39% non[DQA1*0301-DQB1*0302], P < 0.001) but not of DQA1*0501-DQB1*0201 or INS I/I. This association was present in both the 0- to 19- and the 20- to 39-year age-groups. It was also found in siblings of IDDM patients (4 vs. 0% non[DQA1*0301-DQB1*0302], P < 0.001). CONCLUSIONS Both GAD65- and IA-2-Abs exhibit higher prevalences in presence of HLA-DQ- and/or INS-genetic risk markers. Their respective associations differ with age at clinical onset, suggesting a possible usefulness in the identification of subgroups in this heterogeneous disease.
Kininogens Coordinate Adaptive Immunity through the Proteolytic Release of Bradykinin, an Endogenous Danger Signal Driving Dendritic Cell Maturation

Strategically positioned in peripheral tissues, immune sentinel cells sense microbes and/or their shed products through different types of pattern‐recognition receptors. Upon secretion, pre‐formed pro‐inflammatory mediators activate the microvasculature, inducing endothelium/neutrophil adherence and impairing endothelium barrier function. As plasma proteins enter into peripheral tissues, short‐lived proinflammatory peptides are rapidly generated by limited proteolysis of complement components and the kininogens (i.e. kinin‐precursor proteins). While much emphasis has been placed on the studies of the vascular functions of kinins, their innate effector roles remain virtually unknown. A few years ago, we reported that exogenous bradykinin (BK) potently induces dendritic cell (DC) maturation, driving IL‐12‐dependent Th1 responses through the activation of G‐protein‐coupled BK B2 receptors (B2R). The premise that immature DC might sense kinin‐releasing pathogens through B2R was demonstrated in the subcutaneous mouse model of Trypanosoma cruzi infection. Analysis of the dynamics of parasite‐evoked inflammation revealed that activation of TLR2/neutrophils drives the influx of plasma proteins, including kininogens, into peripheral tissues. Once associated to cell surfaces and/or extracellular matrices, the surface‐bound kininogens are cleaved by T. cruzi cysteine proteases. Acting as short‐lived ‘danger’ signals, kinins activate DC via B2R, converting them into Th1 inducers. Fine tuned control of the extravascular levels of these natural peptide adjuvants is exerted by kinin‐degrading metallopeptidases, e.g. Angiotensin converting enzyme (ACE/CD143). In summary, the studies in the subcutaneous model of T. cruzi infection revealed that the peripheral levels of BK, a DC maturation signal, are controlled by TLR2/neutrophils and ACE, respectively characterized as positive and negative modulators of innate/adaptive immunity.
Canalith repositioning maneuver for benign paroxysmal positional vertigo: randomized controlled trial in family practice.

OBJECTIVE To determine whether the canalith repositioning maneuver (CRM) is effective for treating benign paroxysmal positional vertigo when it is used by family physicians in primary care settings. DESIGN Randomized, prospective, double-blind, sham-controlled trial. SETTING An academic family practice in Hamilton, Ont. PARTICIPANTS Eighty-one patients 18 years or older whose dizziness was confirmed by the Dix-Hallpike (DH) vertigo-triggering maneuver and who had no contraindications to the CRM. INTERVENTIONS At the first visit, the intervention group received the CRM and the control group received a sham maneuver. Both groups received the CRM at the second and third visits 1 and 2 weeks later. MAIN OUTCOME MEASURES Negative results of the DH test or self-reported resolution of vertigo after the initial treatment. RESULTS Eighty-one patients were randomized and received the first treatment. After the first treatment, 34.2% of patients in the intervention group and 14.6% of patients in the control group had negative DH test results (relative risk 2.3, 95% confidence interval 1.03 to 5.2, P = .04); and 31.6% of patients in the intervention group and 24.4% of patients in the control group reported resolution of dizziness (relative risk 1.2, 95% confidence interval 0.7 to 1.9, P = .48). One week later, patients in both intervention and control groups received the CRM, and 61.8% and 57.1% of them, respectively, had negative DH test results (P = .81). By week 3, approximately 75% of patients in both groups had improved. CONCLUSION A statistically significant proportion of patients in the CRM group returned to a negative response to the DH maneuver immediately after the first treatment. Family physicians can use the CRM to treat benign paroxysmal positional vertigo and potentially avoid delays in treatment and unnecessary referrals. TRIAL REGISTRATION NUMBER NCT00182273 (ClinicalTrials.gov).
Patterns and predictors of hypertension incidence among Hispanics and non‐Hispanic Whites: the San Luis Valley Diabetes Study

Objectives: To determine whether Hispanics are at lower risk for the development of hypertension than non-Hispanic Whites. We also examined selected predictors of hypertension incidence and explored the role of markers of insulin resistance in the development of hypertension. Design A cohort study of a geographically-based sample of Hispanic and non-Hispanic white southern Colorado residents who were re-examined an average of 4 years after their baseline examination. Methods: These analyses included 664 participants who were normotensive and confirmed nondiabetic by an oral glucose tolerance test at their baseline examination. Hypertension was defined as systolic blood pressure ± 140 mmHg or diastolic blood pressure ± 90 mmHg or use of antihypertensive medication. Results: Hispanics and non-Hispanic Whites had similar hypertension incidence rates. The strongest predictors of hypertension incidence were baseline blood pressure and age. Higher baseline heart rates and higher body mass index also predicted hypertension. Increased fasting insulin levels were associated with hypertension incidence among lean participants, though the association disappeared once baseline blood pressure levels were added to the models. Models investigating change in systolic or diastolic blood pressure levels found higher baseline levels of insulin area under the glucose tolerance curve predicted greater increases in systolic blood pressure in non-Hispanic Whites only. Conclusions: Hypertension incidence rates were similar in Hispanics and non-Hispanic Whites. Higher levels of insulin area were associated with larger increases in systolic blood pressure among non-Hispanic Whites only.
No difference between prednisolone and dexamethasone treatment in bone mineral density and growth in long term survivors of childhood acute lymphoblastic leukemia

Dexamethasone is known to have both more potent leukemic activity and is associated with a higher incidence of side effects than prednisolone. In this study, we compared the long‐term effects of dexamethasone and prednisolone on bone mineral density (BMD), body composition and growth in long‐term survivors of ALL in first complete remission.
Possible missed opportunities for diagnosing colorectal cancer in Dutch primary care: a multimethods approach.

BACKGROUND Early detection of colorectal cancer (CRC) is important to achieve better survival. Discriminating symptoms suggestive of CRC from benign conditions is a challenge for GPs because most known 'alarm symptoms' have low predictive values. AIM To further understand the diagnostic process of CRC in general practice in terms of healthcare use and by analysing factors related to diagnostic intervals. DESIGN AND SETTING A multimethod approach comprising a historical, prospective registry study and qualitative content analysis. METHOD Healthcare use in the year before referral for colonoscopy was compared between patients diagnosed with CRC and an age-, sex,- and GP-matched control population. Qualitative content analysis was performed on free texts in electronic patient records from a purposive sample of patients with CRC. RESULTS Patients with CRC (n = 287) had 41% (25-59%) more face-to-face contacts and 21% (7-37%) more medication prescriptions than controls (n = 828). Forty-six per cent of patients with CRC had two or more contacts for digestive reasons, compared with 12.2% of controls, more often for symptoms than diagnoses. From qualitative analysis two themes emerged: 'possible missed diagnostic opportunities' and 'improvements in diagnostic process unlikely'. Possible missed diagnostic opportunities were related to patients waiting before presenting symptoms, doctors attributing symptoms to comorbid conditions or medication use, or doctors sticking to an initial diagnosis. CONCLUSION Fewer missed diagnostic opportunities might occur if GPs are aware of pitfalls in diagnosing CRC: the assumption that symptoms are caused by comorbid conditions or medication, or relating complaints to pre-existing medical conditions. GPs also need to be aware that repeated digestive complaints warrant rethinking an earlier diagnosis.