Miracle-dz/UniFAR-FTUs huggingface dataset:
Analysis of gene expression in gemcitabine resistant cells derived from human pancreatic cancer cell

To analyze the expression of genes involved in gemcitabine-resistant cells derived from human pancreatic cancer cell, we established several cell lines with different acquired resistance to gemcitabine from pancreatic cancer cell line MIA-PaCa2, and analyzed the expression of the genes that are considered to be associated with the resistance to gemcitabine using PCR and real-time PCR. We found that in these gemcitabine-resistant cell lines, the expression of human equilibrative nucleoside transporter 2 (hENT2) and deoxycytidine deaminase (DCTD) was lower than that of the parental cell line MIA-PaCa2 in the earlier stage of the cells incubated with 300nM gemcitabine; and, in the later stage, the expression of hENT2 recovered, but the expression levels of ribonucletide reductase subunit M1 (RRM1) and M2 (RRM2) were increased. These findings suggest that the decreased accumulation of gemcitabine and the increased expression of RRM1 and RRM2 are involved in gemcitabine-resistance formation in MIA-PaCa2.
Optimizing adherence to antiretroviral therapy

HIV has now become a manageable chronic disease. However, the treatment outcomes may get hampered by suboptimal adherence to ART. Adherence optimization is a concrete reality in the wake of ‘universal access’ and it is imperative to learn lessons from various studies and programmes. This review examines current literature on ART scale up, treatment outcomes of the large scale programmes and the role of adherence therein. Social, behavioural, biological and programme related factors arise in the context of ART adherence optimization. While emphasis is laid on adherence, retention of patients under the care umbrella emerges as a major challenge. An in-depth understanding of patients’ health seeking behaviour and health care delivery system may be useful in improving adherence and retention of patients in care continuum and programme. A theoretical framework to address the barriers and facilitators has been articulated to identify problematic areas in order to intervene with specific strategies. Empirically tested objective adherence measurement tools and approaches to assess adherence in clinical/ programme settings are required. Strengthening of ART programmes would include appropriate policies for manpower and task sharing, integrating traditional health sector, innovations in counselling and community support. Implications for the use of theoretical model to guide research, clinical practice, community involvement and policy as part of a human rights approach to HIV disease is suggested.
CXCR4 Expression and Treatment with SDF-1α or Plerixafor Modulate Proliferation and Chemosensitivity of Colon Cancer Cells.

BACKGROUND Signaling through stromal cell-derived factor-1α (SDF-1α), strongly secreted by bone marrow stromal cells and the CXC chemokine receptor 4 (CXCR4) exposed on tumor cells has pivotal roles in proliferation, metastasis, and tumor cell "dormancy. " Dormancy is associated with cytostatic drug resistance and is probably a property of tumor stem cells and minimal residual disease. Thus, hampering the SDF-1α/CXCR4 cross talk by a CXCR4 antagonist like Plerixafor (AMD3100) should overcome tumor cell dormancy bymobilization of tumor cells from "sanctuary" niches. Our aim was to elucidate the direct effects exerted by SDF-1α and Plerixafor on proliferation, chemosensitivity, and apoptosis of CXCR4-expressing tumor cells. METHODS The ability of SDF-1α and Plerixafor to regulate intracellular signaling, proliferation, and invasion was investigated using two colon cancer cell lines (HT-29 and SW480) with either high endogenous or lentiviral expression of CXCR4 compared to their respective low CXCR4-expressing counterparts as a model system. Efficacy of Plerixafor on sensitivity of these cell lines against 5-fluorouracil, irinotecan, or oxaliplatin was determined in a cell viability assay as well as stroma-dependent cytotoxicity and apoptosis assays. RESULTS SDF-1α increased proliferation, invasion, and ERK signaling of endogenously and lentivirally CXCR4-expressing cells. Exposure to Plerixafor reduced proliferation, invasion, and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Combination of chemotherapy with Plerixafor showed an additive effect on chemosensitivity and apoptosis in CXCR4-overexpressing cells. An SDF-1-secreting feeder layer provideda"protective niche" for CXCR4-overexpressing cells resulting in decreased chemosensitivity. CONCLUSION CXCR4-antagonistic therapy mobilizes and additionally sensitizes tumor cells toward cytoreductive chemotherapy.
Long-term Metabolic Effects of Laparoscopic Sleeve Gastrectomy.

IMPORTANCE The prevalence of laparoscopic sleeve gastrectomy (LSG) is increasing, but data on its long-term effect on obesity-related comorbidities are scarce. Because the population of bariatric patients is young, long-term results of those comorbidities are highly relevant. OBJECTIVE To investigate the long-term effects of LSG on weight loss, diabetes mellitus, hypertension, dyslipidemia, and hyperuricemia. DESIGN, SETTING, AND PARTICIPANTS Cohort study using a retrospective analysis of a prospective cohort at a university hospital. Data were collected from all patients undergoing LSGs performed by the same team between April 1, 2006, and February 28, 2013, including demographic details, weight follow-up, blood test results, and information on medications and comorbidities. MAIN OUTCOMES AND MEASURES Excess weight loss, obesity-related comorbidities, and partial and complete remission at 1, 3, and 5 years of follow-up. RESULTS A total of 443 LSGs were performed. Complete data were available for 241 of the 443 patients (54.4%) at the 1-year follow-up, for 128 of 259 patients (49.4%) at the 3-year follow-up, and for 39 of 56 patients (69.6%) at the 5-year follow-up. The percentage of excess weight loss was 76.8%, 69.7%, and 56.1%, respectively. Complete remission of diabetes was maintained in 50.7%, 38.2%, and 20.0%, respectively, and remission of hypertension was maintained in 46.3%, 48.0%, and 45.5%, respectively. Changes in high-density lipoprotein cholesterol level (mean [SD] level preoperatively and at 1, 3, and 5 years, 46.7 [15.8], 52.8 [13.6], 56.8 [16.0], and 52.4 [13.8] mg/dL, respectively) and triglyceride level (mean [SD] level preoperatively and at 1, 3, and 5 years, 155.2 [86.1], 106.3 [45.3], 107.2 [53.4], and 126.4 [59.7] mg/dL, respectively) were significant compared with preoperative and postoperative measurements (P < .001). The decrease of low-density lipoprotein cholesterol level was significant only at 1 year (P = .04) and 3 years (P = .04) (mean [SD] level preoperatively and at 1, 3, and 5 years, 115.8 [33.2], 110.8 [32.0], 105.7 [25.9], and 110.6 [28.3] mg/dL, respectively). The changes in total cholesterol level did not reach statistical significance (mean [SD] level preoperatively and at 1, 3, and 5 years, 189.5 [38.2], 184.0 [35.4], 183.4 [31.2], and 188.1 [35.7] mg/dL, respectively). No changes in comorbidity status correlated with preoperative excess weight. Hypertriglyceridemia was the only comorbidity whose remission rates at 1 year of follow-up (partial/complete, 80.6%; complete, 72.2%) correlated with percentage of excess weight loss (76.8%) (P = .005). CONCLUSIONS AND RELEVANCE Undergoing LSG induced efficient weight loss and a major improvement in obesity-related comorbidities, with mostly no correlation to percentage of excess weight loss. There was a significant weight regain and a decrease in remission rates of diabetes and, to a lesser extent, other comorbidities over time.
Cytomegalovirus increases collagen synthesis in chronic rejection in the rat.

BACKGROUND We have demonstrated previously that cytomegalovirus (CMV) infection enhances chronic renal allograft rejection in a rat model. Interstitial fibrosis, a characteristic finding for chronic rejection, was also more prominent in CMV-infected grafts. The effect of CMV on the development of fibrosis in this model was investigated here at the molecular level. The collagen/DNA ratio, gene expression of type I and III collagen mRNAs and the presence of myofibroblasts were examined. METHODS Transplantations were performed under triple drug immunosuppression in a rat strain combination of DA(RT1(a)) and BN(RT1(n)). One group of animals was infected with rat CMV and the other was left uninfected. The grafts were harvested at different time points post-transplantation. Graft histology was evaluated according to the Banff criteria and quantified by the chronic allograft damage index (CADI). Total collagen was measured and DNA and RNA were extracted from the grafts. Type I and III collagen mRNAs were determined by slot blot and in situ hybridizations. Myofibroblasts were demonstrated by immunohistochemistry. RESULTS The time-related increase of the collagen/DNA ratio in the CMV-infected grafts was higher than in the uninfected animals, correlating with the development of fibrosis at the histology. The expression of type I and III collagen mRNAs peaked shortly after transplantation, together with the presence of myofibroblasts, with significantly higher peaks in the CMV-infected grafts compared with the non-infected ones. CONCLUSIONS CMV increases the expression of both type I and III collagens and the accumulation of myofibroblasts, and enhances total collagen synthesis in the development of interstitial fibrosis in chronic renal allograft rejection.
Comprehensive Analysis of NKG2D Ligand Expression and Release in Leukemia: Implications for NKG2D-Mediated NK Cell Responses

Ligands of the prototypical activating NK receptor NKG2D render cancer cells susceptible to NK cell-mediated cytolysis if expressed at sufficiently high levels. However, malignant cells employ mechanisms to evade NKG2D-mediated immunosurveillance, such as NKG2D ligand (NKG2DL) shedding resulting in reduced surface expression levels. In addition, systemic downregulation of NKG2D on NK cells of cancer patients has been observed in many studies and was attributed to soluble NKG2DL (sNKG2DL), although there also are conflicting data. Likewise, relevant expression of NKG2DL in leukemia has been reported by some, but not all studies. Hence, we comprehensively studied expression, release, and function of the NKG2D ligands MHC class I chain-related molecules A and B and UL16-binding proteins 1–3 in 205 leukemia patients. Leukemia cells of most patients (75%) expressed at least one NKG2DL at the surface, and all investigated patient sera contained elevated sNKG2DL levels. Besides correlating NKG2DL levels with clinical data and outcome, we demonstrate that sNKG2DL in patient sera reduce NKG2D expression on NK cells, resulting in impaired antileukemia reactivity, which also critically depends on number and levels of surface-expressed NKG2DL. Together, we provide comprehensive data on the relevance of NKG2D/NKG2DL expression, release, and function for NK reactivity in leukemia, which exemplifies the mechanisms underlying NKG2D-mediated tumor immunosurveillance and escape.
Folic Acid Metabolism and Malaria

Folate is essential for DNA synthesis and the survival and growth of the malaria parasite. Folate sufficiency may be associated with an increased risk of malaria. Antifolate antimalarial drugs are of major importance in the prophylaxis and treatment of malaria. Folic acid reverses the inhibition by antifolate drugs of plasmodial growth or survival in vitro, and folic acid supplements given to children with malaria may increase the failure rate of treatment with antimalarials. There is no convincing evidence of a significant prevalence of folate deficiency in children in malarious areas, nor of a beneficial effect of folic acid supplementation on malarial anemia. In areas where Plasmodium falciparum malaria is holoendemic, universal supplementation of children with iron and folic acid may increase the incidence of severe morbidity and mortality. These regions should be excluded from the World Health Organization recommendation of universal folic acid supplementation of children in areas of high prevalence of anemia. This does not apply to supplementation of pregnant women with folic acid.
Tear Osmolarity and Tear Film Parameters in Patients With Ocular Rosacea.

OBJECTIVES The aim of this study was to evaluate tear osmolarity and tear film parameters in patients with ocular rosacea. METHODS In a single center, 25 eyes of 25 patients with ocular rosacea (group 1), 25 eyes of 25 patients with rosacea without ocular involvement (group 2), and 20 eyes of 20 healthy individuals (group 3) were evaluated using the Ocular Surface Disease Index (OSDI) questionnaire, Schirmer I test, tear film break-up time (TBUT), scoring of ocular surface fluorescein staining using modified Oxford scale, and tear osmolarity. RESULTS Tear osmolarity values, OSDI and Oxford scale scores were significantly higher in group 1 than in groups 2 and 3 (P<0.001 for all). Schirmer I test and TBUT in group 1 were significantly lower than in groups 2 and 3 (P<0.001 for all). There were no significant differences in OSDI, Schirmer I test, TBUT, Oxford scores, or tear osmolarity between groups 2 and 3 (P=0.629, P=0.175, P=0.713, P=865, and P=0.388, respectively). CONCLUSIONS This study showed that ocular rosacea is associated with tear hyperosmolarity and tear film dysfunction.
Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition

Background Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women. Methods Using patient data from two routine therapeutic drug monitoring (TDM) services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women’s own baseline (non-pregnant) values, using a linear mixed model. Findings Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only), we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (–51%; 95% confidence interval [CI], –66%, –30%; p<0.001), fluvoxamine (–56%; CI, –75%, –23%; p = 0.004) and citalopram (–24%; CI, –38%, –7%; p = 0,007), and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001). For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly. Conclusions For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.
Workplace Bullying Experienced by Massachusetts Registered Nurses and the Relationship to Intention to Leave the Organization

This descriptive study examines bullying behavior among nurses and tests the relationship between bullying and a nurse's intention to leave their organization. Data were collected from 511 randomly selected newly licensed registered nurses by using the Revised Negative Acts Questionnaire, an instrument that measures perceived exposure to bullying at work. Results found that 31% of respondents reported being bullied and that bullying is a significant determinant in predicting intent to leave the organization (B = 3.1, P < .0005). Data suggest that effective interventions are needed to stop workplace bullying that contributes to high rates of nurse turnover.
Hepatorenal syndrome

Introduction: Renal failure in cirrhosis is a common complication that is associated with poor survival. A rapid diagnosis of the cause of renal failure is mandatory because it is associated with prognosis. Areas covered: This review covers the differential diagnosis between hepatorenal syndrome (HRS) and other causes of renal failure, as well as the difficulty in making a correct diagnosis, caused by the differentiation between hepatorenal syndrome and acute tubular necrosis. This review also discusses the multifactorial mechanisms involved in the pathogenesis of HRS. The paper provides diagnostic algorithms to use in clinical practice, emphasized by the fact that some patients may have HRS superimposed on pre-existent renal failure. Expert opinion: The correct diagnosis of renal failure is essential to initiate the correct treatment of this complication. In patients with HRS type 1, treatment with vasopressin and albumin is the treatment of choice; however, 50% of patients do not respond to this treatment.
Febrile seizures in the predisposed brain: A new model of temporal lobe epilepsy

The atypical febrile seizure has important clinical implications because of its association with the mesial temporal lobe epilepsy syndrome, which is the most common of the intractable epilepsies. However, whether a causal relation exists between these conditions is currently unknown. We have previously shown that a focal cortical lesion induced in the neonatal rat predisposes to the development of atypical hyperthermic seizures. We show here that 86% of the lesion plus hyperthermia group experience development of spontaneous recurrent seizures recorded from the amygdala ipsilateral to the lesion. Control rats did not have spontaneous recurrent behavioral or electrographic seizures. Lesioned rats with hyperthermic seizures also showed an impaired performance on the Morris water maze when compared with naive control rats, suggesting mild deficits in learning and memory. These findings support a link between the atypical febrile seizure and mesial temporal lobe epilepsy, and at the same time establish a new model for this condition through which new preventative and therapeutic strategies can be tested. Ann Neurol 2005
Mitochondrial COI sequences of brachiopods: genetic code shared with protostomes and limits of utility for phylogenetic reconstruction.

A 1230-bp region of the cytochrome c oxidase subunit I (COI) gene of mitochondrial DNA of each of 16 brachiopod species, representing all five living orders, was amplified by polymerase chain reaction and sequenced. Pairwise comparisons of sequence differences plotted against divergence times estimated from the brachiopod fossil record revealed that, although there are considerable variations in the expected substitution rate among different lineages, amino acid substitutions of the COI sequences may largely become saturated in 100 Ma, due mostly to multiple substitutions at the same site. Coinciding with this result, phylogenetic analysis indicated low bootstrap values for nodes corresponding to divergence events that occurred before 100 Ma, suggesting that COI sequences are suitable only for inference of phylogenetic events subsequent to the Mesozoic. Examination of brachiopod codons corresponding to invariant amino acids in the COI of various other animals suggest the nonuniversal codon relationships UGA = Trp, AUA = Met, AAA/G = Lys, and AGA/G = Ser. These are identical to those in mollusks, annelids, and arthropods, consistent with the conclusion that brachiopods are protostomes, as indicated by previous molecular analyses.
Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high-fat meal.

CONTEXT Much has been written about the potential role of antioxidants in the prevention of atherosclerosis. OBJECTIVE To assess the short-term effect of a single high-fat meal with and without pretreatment with antioxidant vitamins on endothelial function in healthy, normocholesterolemic subjects. DESIGN Observer-blinded randomized trial. SETTING University hospital. PARTICIPANTS Twenty healthy, normocholesterolemic (total and low-density lipoprotein cholesterol <5.2 mmol/L and <3.4 mmol/L [<200 mg/dL and <130 mg/ dL], respectively), male (7) and female (13) hospital employee volunteers, aged 24 to 54 years. INTERVENTION Three randomly administered breakfasts: (1) a high-fat meal (3766 J [900 calories], 50 g of fat); (2) a low-fat meal (3766 J [900 calories], 0 g of fat); and (3) a high-fat meal and pretreatment with oral administration of vitamins C (1 g) and E (800 IU) (high-fat meal with vitamins). A subgroup of 10 subjects also ate the low-fat meal with the same vitamin pretreatment (low-fat meal with vitamins). MAIN OUTCOME MEASURE High-resolution ultrasound assessed flow-mediated (endothelium-dependent) brachial artery vasodilation measured as percent diameter change before and hourly for 6 hours following each meal. RESULTS Flow-mediated vasodilation fell from a mean+/-SD of 20%+/-8% before to 12%+/-6%, 10%+/-6%, and 8%+/-9% at 2, 3, and 4 hours, respectively, after the high-fat meal (P<.001). No significant changes in flow-mediated vasodilation occurred after the low-fat meal, high-fat meal with vitamins, or low-fat meal with vitamins. The change in flow-mediated vasodilation after the low-fat and high-fat meals correlated inversely with the 2-hour postprandial change in triglyceride levels (r=-0.54; P<.001). CONCLUSION A single high-fat meal transiently reduces endothelial function for up to 4 hours in healthy, normocholesterolemic subjects, probably through the accumulation of triglyceride-rich lipoproteins. This decrease is blocked by pretreatment with antioxidant vitamins C and E, suggesting an oxidative mechanism.
Transcription of the E6 and E7 genes of human papillomavirus type 6 in anogenital condylomata is restricted to undifferentiated cell layers of the epithelium

The E6 and E7 genes of human genital papillomaviruses (HPVs) appear to transform cells by different mechanisms. They seem to act synergistically but are not equally important when tested under diverse experimental conditions. We were therefore tempted to investigate the E6- and E7-specific transcription pattern in HPV6-infected condylomas separately, by in situ hybridization. Recent studies have identified three promoters within the E6-E7 region of HPV6 and HPV11 by applying S1, exonuclease VII, and cDNA analyses. On the basis of these data, we cloned subgenomic fragments of HPV6 into plasmid pBS to obtain riboprobes that differentiated between transcripts starting upstream of the E6 and E7 open reading frames, respectively. These different species of mRNAs were analyzed in serial thin sections of eight HPV6-positive anogenital condylomas. The E6 probe (nucleotides 7862 to 241) led to weak signals within the basal layer. In three cases, rather strong signals were confined to a few basal cells. The E7 probe (nucleotides 242 to 534) gave rise to a more pronounced labeling of all cells within the two to three lowest epidermal layers. In situ hybridization with a riboprobe for human c-fos revealed an expression pattern similar to that observed with the E7 probe. In contrast to the preferential expression of the transforming E6 and E7 genes in the lower epithelium, the major transcriptional activity of the virus was detected in the middle and upper third by probes colinear with the 3' moiety of the early region.