Miracle-dz/UniFAR-FTUs huggingface dataset:
Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells

Objective Nearly 20%–29% of patients with colorectal cancer (CRC) succumb to liver or lung metastasis and there is a dire need for novel targets to improve the survival of patients with metastasis. The long isoform of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1-L or CC1-L) is a key regulator of immune surveillance in primary CRC, but its role in metastasis remains largely unexplored. We have examined how CC1-L expression impacts on colon cancer liver metastasis. Design Murine MC38 transfected with CC1-L were evaluated in vitro for proliferation, migration and invasion, and for in vivo experimental liver metastasis. Using shRNA silencing or pharmacological inhibition, we delineated the role in liver metastasis of Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) downstream of CC1-L. We further assessed the clinical relevance of these findings in a cohort of patients with CRC. Results MC38-CC1-L-expressing cells exhibited significantly reduced in vivo liver metastasis and displayed decreased CCL2 chemokine secretion and reduced STAT3 activity. Down-modulation of CCL2 expression and pharmacological inhibition of STAT3 activity in MC38 cells led to reduced cell invasion capacity and decreased liver metastasis. The clinical relevance of our findings is illustrated by the fact that high CC1 expression in patients with CRC combined with some inflammation-regulated and STAT3-regulated genes correlate with improved 10-year survival. Conclusions CC1-L regulates inflammation and STAT3 signalling and contributes to the maintenance of a less-invasive CRC metastatic phenotype of poorly differentiated carcinomas.
Molecular pathways to prostate cancer.

PURPOSE Prostate cancer continues to be a prevalent disease in the United States and western countries. Advances in the fields of molecular biology and genetics coupled with new developments in biotechnology have increased our understanding of events associated with the initiation and progression of prostate cancer. We reviewed recent scientific discoveries relating to genetic predisposition, somatic alterations and epigenetic phenomena involved in the pathogenesis of prostate cancer. MATERIALS AND METHODS Reports published in the scientific literature with relevance to the molecular biology, genetics and epigenetics of prostate cancer were identified using the MEDLINE data base. Particular emphasis was placed on articles that investigated the contribution of somatic alterations to prostate cancer. RESULTS A multitude of genes have recently been identified that are believed to be relevant to prostate carcinogenesis. A contemporary model for prostate cancer progression should include the potential contribution of inflammation to the development of preneoplastic or neoplastic lesions. Abnormal methylation of important growth regulatory or caretaker genes represents an alternative pathway to cancer in addition to aneuploidy, loss of heterozygosity and gene mutations. CONCLUSIONS The identification of molecular markers specific to early and late events in prostate cancer progression is critical for the development of improved detection and prognostication strategies. While there is evidence to support the association between inflammation and prostate cancer, the exact mechanisms by which these processes occur are not well defined. The significant contribution of somatic and epigenetic defects to prostate carcinogenesis underscores the need to develop therapeutic approaches that specifically target these molecular alterations.
Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration

Background: Mutations in the progranulin gene (PGRN) were identified as the causal mechanism underlying frontotemporal lobar degeneration (FTLD). Most of these mutations are predicted to create null alleles leading to a 50% loss of progranulin transcript. Methods: Patients underwent clinical and neurologic examination at the Memory Clinic of the IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy. We enrolled affected (n = 6) and unaffected at risk members (n = 73) of families carrying the FTLD associated progranulin Leu271LeufsX10 mutation; additionally, we included subjects affected by sporadic/familial FTLD (n = 65), controls (n = 75), and a family carrying the tau P301L mutation. The presence of mutations in PGRN and MAPT genes was investigated by direct sequencing of exonic and flanking intronic regions. Progranulin plasma and CSF levels were measured using ELISA. Results: We demonstrated that progranulin protein is strongly reduced (up to 3.93-fold) both in plasma and CSF of affected and unaffected subjects carrying mutations in progranulin gene (PGRN Leu271LeufsX10 and Q341X). We established a plasma progranulin protein cutoff level of 74.4 ng/mL that identifies, with specificity and sensitivity of 100%, mutation carriers among unaffected subjects. In FTLD, values ≤110.9 ng/mL give a specificity of 92.8% and a sensitivity of 100% for PGRN mutations. Conclusions: We propose the dosage of plasma progranulin as a useful tool for a quick and inexpensive large-scale screening of carriers of progranulin mutations and for monitoring future treatments that might boost the level of this protein. GLOSSARY: FTD = frontotemporal dementia; FTLD = frontotemporal lobar degeneration; PPA = primary nonfluent aphasia.
Lifetime dose-response relationships for mammary tumor induction by a single administration of N-methyl-N-nitrosourea.

Dose-response relationships for the induction of mammary tumors by a single i.v. injection of N-methyl-N-nitrosourea (MNU) were studied. At 50 days of age, groups of 20 virgin female Sprague-Dawley rats received single doses of 50, 45, 40, 35, 30, 25, 20, 15, or 10 mg MNU per kg body weight; a group of 10 control rats received 0.85% NaCl solution only. Animals were observed for the appearance of mammary tumors over their life span or until 600 days after carcinogen administration. Both malignant and benign mammary tumors appeared in all groups; however, malignant tumors appeared earlier and at a faster rate than did benign tumors. Incidence of cancer and number of cancers per animal increased with increasing MNU dose; the latent period for cancer increased with decreasing dose. The number of benign tumors induced as a percentage of total tumors increased with decreasing dose, ranging from approximately 10% in groups receiving more than 30 mg MNU per kg to 58% in the group receiving 10 mg/kg. Foci of metastatic mammary carcinoma were found in lungs of animals in several MNU dose groups. Data from the present study indicate that a single i.v. administration of MNU induces mammary cancer in a dose-related fashion, with little toxicity and a short latent period; induced cancers metastasize to distant sites. The single-dose MNU model thus appears to be superior to both the 7,12-dimethylbenz(a)anthracene and multiple-dose MNU models, particularly for use in studies of modification of mammary carcinogenesis.
Risky Business: Proposed Reform of the Antitrust Laws As Applied to Health Care Provider Networks

Because the health care industry comprises over thirteen percent of the American economy, law enforcers increasingly apply antitrust law to all aspects of health care delivery and financing. Through antitrust enforcement, consumers receive the benefits of lower health care costs and improved health care services. To achieve further cost savings, health care providers are forming, as well as joining, many different types of provider network joint ventures. Providers form networks, expect ing “them to generate efficiencies, reduce excess capacity, improve utilization, permit greater specialization and enhance quality. ” However, because they organize competing physicians and enable them to collaborate on prices and set fee schedules, provider networks raise serious antitrust concerns. Consequently, the federal government and courts are increasingly focusing their antitrust enforcement efforts on the formation and anticompetitive activities of provider networks. In Part I, this Note addresses the degree to which network providers must be economically and financially integrated to legally collaborate and set prices. Part II briefly explains the procedures one may use to enforce the federal antitrust laws. Following this explanation of antitrust enforcement procedures, Part III discusses the relevant statutory and case law applicable to health care provider networks.
Perinatal outcome among the offspring of employees and people living around a Swedish smelter.

OBJECTIVE The purpose of this study was to determine if emissions from a smelter affect the birthweight of offspring and increase the risk of prenatal death. METHODS A historical cohort was formed from registers of birth and employees from 1961 to 1991. Comparisons of birthweight and perinatal deaths between children born to smelter employees or children born to women living around the smelter and those of a reference population were performed. To study reproductive effects before 1961, a case-referent study was performed with cases of stillbirths from 1937-1961 in one parish. RESULTS No differences in birthweight were found between the children born to employees or to people living near the smelter and those in the reference group. An increased risk of perinatal death among children born to women in the exposed group was seen during the period 1966-1970. However, for the rest of the observation period, 1961-1990, this higher risk was not apparent. CONCLUSIONS For the last 20 years emissions from the smelter had not affected the birthweight and the risk of perinatal death among the offspring of parents living near the smelter or those employed at the smelter.
N-methyl-D-aspartate receptor subunit NR3A in the retina: developmental expression, cellular localization, and functional aspects.

PURPOSE Recently, a novel N-methyl-D-aspartate receptor (NMDAR) subunit, NR3A, has been discovered in the brain and shown to decrease NMDAR activity by modulating the calcium permeability of the receptor channel. The insertion of NR3A within the NMDAR complex may thus alter NMDAR properties and play a crucial role during processes of neuronal development and degeneration. The present study is the first to investigate the expression and cellular localization of NR3A on the protein level in the retina and to elucidate its putative functional roles within the retinal circuitry. METHODS The expression of NR3A in the retina was analyzed by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blot analysis. Functional aspects of NR3A in the retina were addressed by measuring the NMDA-induced increase in intracellular calcium, [Ca(2+)](i), in retinal cells prepared from wild-type (NR3A(+/+)) and NR3A knockout (NR3A(+/-), and NR3A(-/-)) mice. RESULTS NR3A protein expression was initially observed in the first postnatal week and was predominantly localized to cell bodies in the ganglion cell layer. In older animals, two bands of NR3A immunoreactivity were additionally observed in the inner plexiform layer. NMDA-evoked [Ca(2+)](i) responses were found to be significantly greater in retinal cells in NR3A(-/-) mice than in wild-type retinas. CONCLUSIONS The data indicate that NR3A is specifically expressed in the inner retina and may modulate NMDAR-mediated calcium influx and thus [Ca(2+)](i) levels in retinal ganglion cells and amacrine cells.
Cognitive Impairment after Small-dose Ketamine Isomers in Comparison to Equianalgesic Racemic Ketamine in Human Volunteers

Background Ketamine is increasingly used in pain therapy but may impair brain functions. Mood and cognitive capacities were compared after equianalgesic small-dose S (+)-, R (−)-, and racemic ketamine in healthy volunteers. Methods Twenty-four subjects received intravenous 0.5 mg/kg racemic, 0.25 mg/kg S (+)-, and 1.0 mg/kg R (−)-ketamine in a prospective, randomized, double-blind, crossover study. Hemodynamic variables, mood, and cognitive capacities were assessed for 60 min. Results Transient increases in blood pressure, heart rate, and catecholamines were similar after administration of all drugs. At 20 min after injection, subjects felt less decline in concentration and were more brave after S (+)- than racemic ketamine. They reported being less lethargic but more out-of-control after R (−)- than racemic ketamine. Ketamine isomers induced less drowsiness, less lethargy, and less impairment in clustered subjective cognitive capacity than racemic ketamine for the 60-min study. Objective concentration capacity [test time, S (+): 25.4 ± 15.2 s, R (−): 34.8 ± 18.4 s, racemic ketamine: 40.8 ± 20.8 s, mean ± SD] and retention in primary memory [test time, S (+): 4.6 ± 1.2 s, R (−): 4.2 ± 1.4 s, racemic ketamine: 4.0 ± 1.4 s, mean ± SD] declined less after S (+)- than either R (−)- or racemic ketamine at 1 min. At 5 min, immediate recall, anterograde amnesia, retention in primary memory, short-term storage capacity, and intelligence quotient were less reduced after the isomers than racemic ketamine. Speed reading and central information flow decreased less after S (+)- than racemic ketamine. Conclusions Early after injection, ketamine isomers induce less tiredness and cognitive impairment than equianalgesic small-dose racemic ketamine. In addition, S (+)-ketamine causes less decline in concentration capacity and primary memory. The differences in drug effects cannot be explained by stereoselective action on one given receptor.
Measurement of Human Immunodeficiency Virus Type 1 Preintegration Transcription by Using Rev-Dependent Rev-CEM Cells Reveals a Sizable Transcribing DNA Population Comparable to That from Proviral Templates

ABSTRACT Preintegration transcription is an early process in human immunodeficiency virus type 1 infection and has been suggested to occur at a low level. The templates have also been suggested to represent a small population of nonintegrated viral DNA, particularly the two-long-terminal-repeat (2-LTR) circles. However, these determinations were made by either using PCR amplification of viral transcripts in bulk cell populations or utilizing the LTR-driving reporter cells that measure the synthesis of Tat. The intrinsic leakiness of LTR often makes the measurement of low-level viral transcription inaccurate. Since preintegration transcription also generates Rev, to eliminate the nonspecificity associated with the use of LTR alone we have developed a novel Rev-dependent indicator cell, Rev-CEM, to measure preintegration transcription based on the amount of Rev generated. In this report, using Rev-CEM cells, we demonstrate that preintegration transcription occurs on a much larger scale than expected. The transcribing population derived from nonintegrated viral DNA was comparable (at approximately 70%) to that derived from provirus in a productive viral replication cycle. Nevertheless, each nonintegrated viral DNA template exhibited a significant reduction in the level of transcriptional activity in the absence of integration. We also performed flow cytometry sorting of infected cells to identify viral templates. Surprisingly, our results suggest that the majority of 2-LTR circles are not active in directing transcription. It is likely that the nonintegrated templates are from the predominant DNA species, such as the full-length, linear DNA. Our results also suggest that a nonintegrating lentiviral vector can be as effective as an integrating vector in directing gene expression in nondividing cells, with the proper choice of an internal promoter.
Estimation of model parameters of the Japanese quail growth curve using Gompertz model

This study was conducted to describe the growth pattern of Japanese quails with the Gompertz growth model using body weight measurements from an unselected, random bred quail population. The coefficient of determination (R2) was high for both male and female (0.98) indicating that the growth curves of the observed data were adequately described by the Gompertz model. However, male and female Japanese quails did not have identical growth patterns. Generally, females appeared to be heavier than males at all ages and this difference increased with age. Both male and female Japanese quail were 4 % mature at hatch but reached 98 and 96 % respectively, of their mature weights at 12 weeks of age. Thus, males matured faster than females though the latter had higher weights. Asymptotic weight (A) was higher (p<0.05) in females (168.83 g) than males (132.71 g) as was the case with integration constant (B). In contrast, maturity rate (k) was higher (p<0.05) in males (0.3765) compared to females (0.3262). Thus, a strong and negative relationship (–0.7981 and –0.8498 for male and female respectively) between maturation rate and asymptotic weight was observed. Age, weight and maximum gain at point of inflection for male and female Japanese quails were 2.48 vs. 2.91 weeks, 48.82 vs. 62.11 g and, 18.38 vs. 20.26 g res-pectively. Males reached the inflection point at a significantly (p<0.05) earlier age than females. Similarly, they had lower inflection weight and gain than female quail. And it explains difference between males and females Japanese quail in Nigeria.
TGF-beta family signal transduction in Drosophila development: from Mad to Smads.

The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of soluble extracellular proteins that are potent regulators of development in both vertebrates and invertebrates. Drosophila TGF-beta family members include three proteins with homology to vertebrate bone morphogenetic proteins (BMPs): Decapentaplegic (Dpp), Screw, and Glass bottom boat-60A. Genetic studies of Dpp signaling led to the identification of Smad proteins as central mediators of signal transduction by TGF-beta family members. Work in mammalian tissue culture has elucidated a biochemical model for signal transduction, in which activation of receptor serine-threonine kinase activity leads to phosphorylation of specific Smad proteins and translocation of heteromeric Smad protein complexes to the nucleus. Once in the nucleus Smad proteins interact with other DNA binding proteins to regulate transcription of specific target genes. Dissection of Dpp-response elements from genes expressed during embryonic mesoderm patterning and midgut morphogenesis provides important insights into the contributions of Smad proteins and tissue-specific transcription factors to spatial regulation of gene expression. Genetic studies in Drosophila are now expanding to include multiple BMP ligands and receptors and have uncovered activities not explained by the current signal transduction model. Identification of more ligand sequences and demonstration of a functional Drosophila activin-like signal transduction pathway suggest that all TGF-beta signal transduction pathways are present in flies.
Cyclophilin A and calcineurin functions investigated by gene inactivation, cyclosporin A inhibition and cDNA arrays approaches in the phytopathogenic fungus Botrytis cinerea

Calcineurin phosphatase and cyclophilin A are cellular components involved in fungal morphogenesis and virulence. Their roles were investigated in the phytopathogenic fungus Botrytis cinerea using gene inactivation, drug inhibition and cDNA macroarrays approaches. First, the BCP1 gene coding for cyclophilin A was identified and inactivated by homologous recombination. The bcp1Δ null mutant obtained was still able to develop infection structures but was altered in symptom development on bean and tomato leaves. Opposite to this, calcineurin inhibition using cyclosporin A (CsA) modified hyphal morphology and prevented infection structure formation. CsA drug pattern signature on macroarrays allowed the identification of 18 calcineurin‐dependent (CND) genes among 2839 B. cinerea genes. Among the co‐regulated CND genes, three were shown to be organized as a physical cluster that could be involved in secondary metabolism. The signature of BCP1 inactivation on macroarrays allowed the identification of only three BCP1 cyclophilin‐dependent (CPD) genes that were different from CND genes. Finally, no CsA drug pattern signature was observed in the bcp1Δ null mutant which provided a molecular target validation of the drug.
MMS19 as a potential predictive marker of adjuvant chemotherapy benefit in resected non-small cell lung cancer.

BACKGROUND Resectable non-small cell lung cancer (NSCLC) treatment options most often consist of surgical resection along with adjuvant chemotherapy (ACT). The benefit of ACT however is modest and is accompanied by important side effects. OBJECTIVE One central quest in the field is therefore the identification of a predictive marker of the response to ACT. METHODS We applied an unbiased approach based on high content analysis of expression data generated from a discovery patient cohort. RESULTS We identified MMS19, a component of the cytoplasmic Iron-Sulfur Assembly (CIA) machinery important for the Nucleotide Excision Repair (NER) pathway as a pivotal gene for cisplatin toxicity. We then confirmed the association between MMS19 expression and the response to Cisplatin treatment in a panel of NSCLC cell lines. Finally we validated these pre-clinical data in a subgroup of JBR.10 trial patients through a hypothesis-driven analysis, and showed that MMS19 levels associated with ACT benefit. CONCLUSIONS We therefore propose the expression level of MMS19 as a candidate predictive marker of ACT benefit in resected NSCLC patients.
National survey of antimetabolite use in glaucoma surgery in the United Kingdom

Aims: To assess the pattern of use of antimetabolites in trabeculectomy surgery by all consultant ophthalmologists in the United Kingdom. Methods: A postal questionnaire of 12 questions regarding antimetabolite use in trabeculectomy surgery was sent to all 749 consultant ophthalmologists in the United Kingdom. The consultants were asked to estimate the number of trabeculectomies they performed per year, how often they used 5-fluorouracil (5-FU) in primary and redo surgery, their usual method of administration of 5-FU, how often they used mitomycin (MMC) in primary and redo surgery, and their usual dosage regimen of MMC. Factors that influenced the decision to use or not use antimetabolites were also assessed. Results: The response rate of consultants returning the questionnaire was 82% (615 out of 749); 87% (533) of these consultants perform trabeculectomy surgery. Of these 533 consultants, 98 (18%) never use an antimetabolite. Most consultants (82%) use antimetabolites, but use them infrequently (only 9% using antimetabolites in more than half their cases). The preferred antimetabolite is 5-FU rather than MMC. Of the 435 consultants performing trabeculectomy surgery and using antimetabolites, 402 (93%) use 5-FU and 179 (41%) use MMC. Various factors influenced the decision to use or not use an antimetabolite, but experience of complications associated with their use was a factor for 34% of consultants. Conclusion: The use of antimetabolites, particularly MMC, in the United Kingdom is much less than in America or Japan, where trabeculectomy with MMC is the surgical procedure preferred by glaucoma specialists.