Miracle-dz/UniFAR-FTUs huggingface dataset:
Therapeutic approaches to the modulation of apoptosis.

The appreciation of the role of apoptosis in the vast majority of diseases affecting humans has revolutionized the discovery and development of drugs targeting inflammation and oncology. Novel therapeutic approaches to modulate disease by regulating apoptosis are currently being tested in preclinical and clinical settings. Enthusiasm for some of these therapies is reflected in the fact that they have received U.S. Food and Drug Administration approval in record time. Approaches include the traditional use of small molecules to target specific players in the apoptosis cascade. They also include radical new approaches such as using antisense molecules to inhibit production of the Bcl-2 protein or antibodies that ligate either death receptors, such as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), or the MHC (HLA-DR), resulting in the initiation of apoptosis of target cells. Antibodies targeting cell-specific antigens are being used in conjunction with radioactive isotopes to deliver a more specific chemotherapy, particularly in the case of B-cell lymphomas. Other therapies target mitochondria, a key organelle in the apoptosis cascade. This diverse range of therapies includes photodynamic therapy, retinoic acid and arsenic trioxide, all of which induce apoptosis by generating reactive oxygen species. As our understanding of apoptosis increases, further opportunities will arise for tailor-made therapies that will result in improved clinical outcome without the devastating side effects of current interventions.
Prognostic model for relapse after high-dose chemotherapy with autologous stem-cell transplantation for stage IV oligometastatic breast cancer.

PURPOSE To study prognostic factors after high-dose chemotherapy (HDC) for patients with stage IV oligometastatic breast cancer. PATIENTS AND METHODS Sixty patients with minimal metastatic disease amenable to local therapy enrolled onto a prospective HDC trial were analyzed for potential prognostic factors. Tumor blocks were retrospectively collected from referring institutions. RESULTS Median follow-up was 62 months (range, 4 to 120 months). Median relapse-free survival (RFS) and overall survival (OS) times were 52 and 80 months, respectively. Five-year RFS and OS rates were 52% (95% confidence interval [CI], 39% to 64%) and 62% (95% CI, 49% to 74%), respectively. HER-2 expression, number of tumor sites, primary axillary nodal ratio (number of positive nodes divided by number of sampled nodes), number of positive axillary nodes, and delivery or omission of radiotherapy to metastases correlated with RFS. HER-2 overexpression and more than one site were independent adverse risk factors for RFS. HER-2 and the axillary nodal ratio were independent predictors of OS. The following prognostic categories for RFS were established (RFS rate, median RFS): good risk, no factors (77%, 80 months); intermediate risk, one factor (41%, 28 months); and poor risk, both factors (10%, 10 months). CONCLUSION Long-term results in patients with oligometastatic breast cancer are encouraging but need validation in prospective randomized studies. HER-2 expression, number of sites, and primary nodal ratio are independent outcome predictors. Confirmation of these observations in this selected population would imply the need for reevaluation of the current tenet that early detection of metastatic breast cancer recurrence is of no benefit.
Identification of CD133+/nestin+ putative cancer stem cells in non-small cell lung cancer.

AIMS No effective treatment for lung cancer exists currently. One reason for this, is the development of drug resistance, assumed to be associated with cancer stem cell (CSCs) emergence within the tumour. This pilot study aimed to identify CSCs in 121 non-small cell lung cancer (NSCLC) patient samples via detection of the expression of stem cell markers - CD133 and nestin. MATERIAL AND METHODS Archived paraffin blocks of 121 patient samples were prepared as Tissue Microarrays (TMA). Indirect immunohistochemical staining was used to determine the level of expression of CD133 and nestin. Double immunofluorescence staining was used to investigate the co-expression of these two markers. To determine the correlation between expression of nestin and CD133 with the length of asymptomatic period and overall patient survival we used the Kaplan-Meyer analysis. RESULTS CD133 expression was detected in 22 (19%), nestin in the epithelium in 74 (66%) and vasculature in 78 (70%) of patients. Co-expression of these two markers was found in 21 (17%) patients in less than 1% of positive cells without impact on disease free or overall survival. CONCLUSIONS We identified CD133(+)/nestin(+) cells as novel potential markers of lung cancer CSCs.
Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins.

OBJECTIVE The authors previously reported that in monozygotic twins discordant for schizophrenia the affected twin almost invariably had a smaller anterior pes hippocampus, measured with magnetic resonance imaging (MRI), and invariably had less regional cerebral blood flow (rCBF) in the dorsolateral prefrontal cortex during performance of the Wisconsin Card Sorting Test. The present study was an investigation of the relationship between hippocampal pathology and prefrontal hypofunction in the same twin pairs. METHOD Nine pairs of monozygotic twins discordant for schizophrenia underwent MRI scanning for determination of anterior hippocampal volume and xenon-inhalation rCBF testing for determination of prefrontal physiological activation associated with the Wisconsin Card Sorting Test. RESULTS The differences within twin pairs on the MRI and rCBF measures were strongly and selectively correlated. Specifically, the more an affected twin differed from the unaffected twin in left hippocampal volume, the more they differed in prefrontal physiological activation during the Wisconsin Card Sorting Test. In the affected twins as a group, prefrontal activation was strongly related to both left and right hippocampal volume. These relationships were not found in the group of unaffected twins. CONCLUSIONS This finding is consistent with the notion that schizophrenia involves pathology of and dysfunction within a widely distributed neocortical-limbic neural network that has been implicated in, among other activities, the performance of cognitive tasks requiring working memory.
Basophil leukocytes and mast cells in the nose.

The aim of the present study has been to examine the pathophysiology of allergic rhinitis, and the number, distribution and antigen-reactivity of basophilic cells. Blown nasal secretions, nasal washings, scrapings and excised specimens of nasal mucosa were collected and examined cytologically and histologically in both light and electron microscopes. Antigen-induced histamine release was also studied in these specimens. The results indicate that migration of basophilic cells (mainly basophil leukocytes in the nasal secretion and predominantly mast cells in the epithelium) to the mucosal surface is characteristic for allergy and that the total number and the histamine content of these cells are sufficient to produce the nasal manifestation of allergy. In conclusion, this study provides evidence supporting our concept of the mechanism of nasal allergy, i.e., that allergic reaction to inhaled allergens is initiated on the mucosal surface, and not in the lamina propria.
Fiscal rules in the European Union

S . vi TABLES AND FIGURES . viii ABBREVIATIONS . ix THESIS PROPOSAL . ix INTRODUCTION . 1 PART I – THE EMU AND THE STABILITY AND GROWTH PACT . 2
Low-grade Endometrial Adenocarcinoma: A Diagnostic Algorithm for Distinguishing Atypical Endometrial Hyperplasia and Other Benign (and Malignant) Mimics

The distinction between endometrial hyperplasia and well-differentiated adenocarcinoma of the endometrium continues to be a difficult differential diagnosis in surgical pathology. Evidence-based diagnostic criteria for well-differentiated endometrial adenocarcinoma focus on histologic features that predict myoinvasion in the hysterectomy specimen. Only 2 diagnostic criteria with significant power aid in this distinction: complex glandular architectural patterns (glandular confluence, intraglandular complexity, and hierarchical papillary architecture) and marked cytologic atypia beyond that typically defined as atypical hyperplasia (ie, prominent macronucleoli visible at low power and marked nuclear pleomorphism). Application of these 2 criteria in problematic endometrial proliferations allows stratification of patients into 3 risk categories: very low risk (<0.05% risk of myoinvasion at hysterectomy)=complex atypical hyperplasia; intermediate risk (5.5% risk of myoinvasion at hysterectomy)=complex atypical hyperplasia, cannot exclude well-differentiated adenocarcinoma (borderline); and high risk (20% risk of myoinvasion at hysterectomy)=well-differentiated adenocarcinoma. In order to optimize the use of these diagnostic criteria, a variety of gland forming lesions that may mimic well-differentiated endometrioid adenocarcinoma must first be excluded. In addition, unusual morphologic patterns of low-grade endometrioid adenocarcinoma should be recognized, as they may cause confusion with other, higher grade (and therefore, more clinically aggressive) endometrial processes.
Assessment of soil properties and earthworms in organic and conventional farming systems after seven years of dairy farm conversions in New Zealand

ABSTRACT Environmental degradation and consumer awareness are raising concerns about the sustainability of conventional farming while increasing interest in organic farming as an alternative food and fiber production. Well-replicated studies during the transition are necessary for testing the causes of observed changes. To test soil property changes following conversion, we collected data from 18 dairy farms (nine converting and nine that remained under conventional methods) in the Waikato, Taranaki, and Manawatu regions of New Zealand. Soil properties on the converting group were compared with matched farms that continued with conventional methods. Converting to organic did not result in increased total carbon or nitrogen, but phosphorus decreased by 42%. Bulk density decreased by 3.5% in converted farms but increased by 9.8% in conventional farms. Earthworm densities were higher in organic farms but there was no significant change in soil microbial parameters. Total nitrogen was lower where microbial respiration was higher but there was no evidence of a link between earthworms and soil nutrient levels. This observation challenges whether the observed changes in studies of farms that have already converted are indeed caused by organic farming methods themselves. Long-term studies are needed before the broader implications of conversion can be fully assessed.
Cell Cycle and Hormonal Control of Nuclear-Cytoplasmic Localization of the Serum- and Glucocorticoid-inducible Protein Kinase, Sgk, in Mammary Tumor Cells

The serum- and glucocorticoid-inducible kinase (sgk) is a novel serine/threonine protein kinase that is transcriptionally regulated in rat mammary tumor cells by serum under proliferative conditions or by glucocorticoids that induce a G1 cell cycle arrest. Our results establish that the subcellular distribution of Sgk is under stringent cell cycle and hormonal control. Sgk is localized to the perinuclear or cytoplasmic compartment as a 50-kDa hypophosphorylated protein in cells arrested in G1 by treatment with the synthetic glucocorticoid dexamethasone. In serum-stimulated cells, Sgk was transiently hyperphosphorylated and resided in the nucleus. Laser scanning cytometry, which monitors Sgk localization and DNA content in individual mammary tumor cells of an asynchronously growing population, revealed that Sgk actively shuttles between the nucleus (in S andG 2/M) and the cytoplasm (in G1) in synchrony with the cell cycle. In cells synchronously released from the G1/S boundary, Sgk localized to the nucleus during progression through S phase. The forced retention of exogenous Sgk in either the cytoplasmic compartment, using a wild type sgkgene, or the nucleus, using a nuclear localization signal-containingsgk gene (NLS-Sgk), suppressed the growth and DNA synthesis of serum-stimulated cells. Thus, our study implicates the nuclear-cytoplasmic shuttling of sgk as a requirement for cell cycle progression and represents a novel convergence point of anti-proliferative and proliferative signaling in mammary tumor cells.
Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors.

PURPOSE To evaluate whether hormonal receptor (HR) status can influence the prognostic significance of pathologic complete response (pCR). PATIENTS AND METHODS This retrospective analysis included 1,731 patients with stage I to III noninflammatory breast cancer treated between 1988 and 2005 with primary chemotherapy (PC). Ninety-one percent of patients received anthracycline-based PC, and 66% received additional taxane therapy. pCR was defined as no evidence of invasive tumor in the breast and axillary lymph nodes. RESULTS Median age was 49 years (range, 19 to 83 years). Sixty-seven percent of patients (n = 1,163) had HR-positive tumors. A pCR was observed in 225 (13%) of 1,731 patients; pCR rates were 24% in HR-negative tumors and 8% in HR-positive tumors (P < .001). A significant survival benefit for patients who achieved pCR compared with no pCR was observed regardless of HR status. In the HR-positive group, 5-year overall survival (OS) rates were 96.4% v 84.5% (P = .04) and 5-year progression-free survival (PFS) rates were 91.1% v 65.3% (P < .0001) for patients with and without pCR, respectively. For the HR-negative group, 5-year OS rates were 83.9% v 67.4% (P = .003) and 5-year PFS rates were 83.4% v 50.0% (P < .0001) for patients with and without pCR, respectively. After adjustment for adjuvant hormonal treatment, HR status, clinical stage, and nuclear grade, patients who achieved a pCR had 0.36 times the risk of death. CONCLUSION pCR is associated with better outcome regardless of HR status in breast cancer patients who receive PC.
The effects of neural crest deletions on the development of sensory innervation patterns in embryonic chick hind limb.

Selected lumbosacral dorsal root ganglia (d.r.g.s) were eliminated from chick embryos by removing the parent neural crest, and the dermatomes and axonal projection patterns established in the hind limb by the remaining intact d.r. g.s were studied physiologically and/or anatomically. Dermatomes of intact d.r. g.s expanded into denervated skin regions, partially but never completely replacing the lost innervation; some skin regions consistently remained without apparent innervation. Dermatome expansion was detected in young embryos, soon after skin innervation was established, suggesting that skin sensory axons in operated embryos ignored their usual dermatome borders. The axonal pathways (nerve trunks) normally supplied by axons from the deleted d.r. g.s were missing, and axons from intact d.r. g.s were only rarely found in aberrant pathways. In contrast, the relative distribution of axons from intact d.r. g.s within their usual complement of pathways was altered, with axonal projections shifting toward, but not into the deleted pathways. Shifts in axonal projection patterns were observed in embryos prior to the onset of sensory cell death. Thus, d.r. g. deletions appeared to affect the initial growth of axons into the limb. Together these results suggest that during normal development competitive interactions among axons from neighbouring d.r. g.s play an important role in establishing the borders between dermatomes and in determining the distribution of axons within projection pathways in the limb.
Systematic review comparing the safety and efficacy of conventional and drug‐eluting bead transarterial chemoembolization for inoperable hepatocellular carcinoma

Conventional transarterial chemoembolization (cTACE) is widely used for treating patients with inoperable hepatocellular carcinoma (HCC). A variation on the technique based on drug‐eluting beads (DEB‐TACE) has recently entered the clinic, but trials of its safety and efficacy have given conflicting results. This systematic review aimed to gain a current, comprehensive picture of how DEB‐TACE compares with cTACE.
Surface Modification and Characterization of Chitosan Film Blended with Poly-L-Lysine

Biodegradable nerve guidance conduits (NGCs) represent a promising alternative to current clinical nerve repair procedures. Chitosan, a natural polysaccharide that has excellent biocompatibility and biodegradability, can be used as a nerve conduit material. The purpose of this work was to study the nerve cell affinity of chitosan modified by blending with different content of poly-L-lysine. PC12 cells culture was used to evaluate the nerve cell affinity of the chitosan-poly-L-lysine composite materials. The results showed that composite materials had significantly improved nerve cell affinity compared to chitosan as indicated by increased attachment, differentiation, and growth of nerve cells. The improved nerve cell affinity might be due to both the increased surface charge and hydrophilicity of composite materials. Composite material with 3 wt% poly-L-lysine content (PL-3) is an even better material in nerve cell affinity than collagen, suggesting that poly-L-lysine-blended chitosan is a promising candidate material for nerve regeneration.
The Stochastic Implications of Permanent Income Hypothesis for US Speculative Traders: Implications for Consumption-Based Asset Pricing

This paper examines the stochastic implications of permanent income hypothesis for speculative prices from a sample of economic data from 1967 to 2017 in the United States. One of the standard assumptions of the Consumption-Based Capital Asset Pricing Model (CCAPM)—the time separability of utility—is relaxed in the model specification of Mankiw and Shapiro (1985) and finds that the expected change in earnings has no obvious connection with stock price changes for monthly and yearly data. This finding, while accepting the excess sensitivity of consumption to income, suggests that the past consumption—unconstrained by expected change in income of that period—influences the utility of future consumption. Disposable income and consumption expenditure are highly autoregressive and non-stationary for monthly, quarterly, and yearly time series. The hypothesis that disposable income follows a random walk is clearly rejected for three-time horizons and the consumption is excessively sensitive to income for monthly and yearly data. The rejection of income follows a random walk due to liquidity constraint for quarterly data. The results of impulse response functions question the OLS/AR type of (univariate) regressions used to test the randomness of disposable income and the excess sensitivity. Equity price changes are, however, found to be completely independent from disposable income for frequent observations of income, which suggests that the use of consumption as a variable in capital asset pricing is a subjective assessment. Furthermore, the empirical evidence shows that the equity price changes cannot be effectively forecasted by the predictable change in disposable income.
Molecular bases of the fetal liver–placenta–maternal liver excretory pathway for cholephilic compounds

Potentially toxic endogenous compounds, such as bile acids (BAs) and biliary pigments, as well as many xenobiotics, such as drugs and food components, are biotransformed and eliminated by the hepatobiliary system with the collaboration of the kidney. However, the situation is very different during pregnancy because the fetal liver produces biliary compounds despite the fact that this organ, owing to its immaturity, is not able to eliminate them into bile. Moreover, the excretory ability of the fetal kidneys is also very limited. Thus, during the intra‐uterine life, the major route to eliminate fetal BAs and biliary pigments is their transfer to the mother across the placenta. The maternal liver and, to a lesser extent, the maternal kidney, are then in charge of their biotransformation and elimination into faeces and urine respectively. This review describes current knowledge of the machinery responsible for the detoxification and excretion of cholephilic compounds through the pathway formed by the fetal liver–placenta–maternal liver trio.
Predicting concentrations of the cytostatic drugs cyclophosphamide, carboplatin, 5‐fluorouracil, and capecitabine throughout the sewage effluents and surface waters of europe

The present study evaluated the potential environmental concentrations of 4 cytostatic (also known as cytotoxic) drugs in rivers. The antimetabolite 5‐fluorouracil (5FU) and its pro‐drug capecitabine were examined based on their very high use rates, cyclophosphamide (CP) for its persistence, and carboplatin for its association with the metal element platinum. The study combined drug consumption information across European countries, excretion, national water use, and sewage removal rates to derive sewage effluent values across the continent. Results showed considerable variation in the popularity of individual cytostatic drugs across Europe, including a 28‐fold difference in 5FU use and 15‐fold difference in CP use. Such variations could have a major effect on the detection of these compounds in effluent or river water. Overall, capecitabine and CP had higher predicted levels in effluent than 5FU or carboplatin. Predicted effluent values were compared with measurements in the literature, and many non‐detects could be explained by insufficient limits of detection. Linking the geographic based water resources model GWAVA with this information allowed water concentrations throughout 1.2 million km of European rivers to be predicted. The 90th percentile (worst case) prediction indicated that, with the exception of capecitabine, more than 99% of Europe's rivers (by length) would have concentrations below 1 ng/L for these cytostatic drugs. For capecitabine, 2.2% of river length could exceed 1 ng/L. Environ Toxicol Chem 2013;32:1954–1961. © 2013 SETAC
Zoonotic Potential and Molecular Epidemiology of Giardia Species and Giardiasis

SUMMARY Molecular diagnostic tools have been used recently in assessing the taxonomy, zoonotic potential, and transmission of Giardia species and giardiasis in humans and animals. The results of these studies have firmly established giardiasis as a zoonotic disease, although host adaptation at the genotype and subtype levels has reduced the likelihood of zoonotic transmission. These studies have also identified variations in the distribution of Giardia duodenalis genotypes among geographic areas and between domestic and wild ruminants and differences in clinical manifestations and outbreak potentials of assemblages A and B. Nevertheless, our efforts in characterizing the molecular epidemiology of giardiasis and the roles of various animals in the transmission of human giardiasis are compromised by the lack of case-control and longitudinal cohort studies and the sampling and testing of humans and animals living in the same community, the frequent occurrence of infections with mixed genotypes and subtypes, and the apparent heterozygosity at some genetic loci for some G. duodenalis genotypes. With the increased usage of multilocus genotyping tools, the development of next-generation subtyping tools, the integration of molecular analysis in epidemiological studies, and an improved understanding of the population genetics of G. duodenalis in humans and animals, we should soon have a better appreciation of the molecular epidemiology of giardiasis, the disease burden of zoonotic transmission, the taxonomy status and virulences of various G. duodenalis genotypes, and the ecology of environmental contamination.