Miracle-dz/UniFAR-FTUs huggingface dataset:
The lower oesophageal sphincter

Abstract The lower oesophageal sphincter (LOS) is a specialized segment of the circular muscle layer of the distal oesophagus, accounting for approximately 90% of the basal pressure at the oesophago‐gastric junction. Together with the crural diaphragm, it functions as an antireflux barrier protecting the oesophagus from the caustic gastric content. During swallowing or belching, the LOS muscle must relax briefly in order to allow passage of food or intragastric air. These swallow‐induced and prolonged transient lower oesophageal sphincter relaxations (TLOSRs) respectively result from activation of the inhibitory motor innervation of the sphincter. Both in man and animals, the main neurotransmitter released by the inhibitory neurones is nitric oxide. The two typical examples of dysfunction of the LOS are achalasia and gastro‐oesophageal reflux disease (GORD). Achalasia is characterized by reduction or even absence of the inhibitory innervation to the LOS, leading to impaired LOS relaxation with dysphagia and stasis of food in the oesophagus. On the contrary, GORD results from failure of the antireflux barrier, with increased exposure of the oesophagus to gastric acid. This leads to symptoms such as heartburn and regurgitation, and in more severe cases to oesophagitis, Barrett's oesophagus and even carcinoma. To date, TLOSRs are recognized as the main underlying mechanism, and may represent an important target for treatment. More insight in the pathogenesis of both diseases will undoubtedly lead to new treatments in the near future.
Characteristics of canine nasal discharge related to intranasal diseases: a  retrospective study of 105 cases.

OBJECTIVES To compare characteristics of nasal discharge caused by different intranasal aetiologies in dogs. METHODS Medical records of 105 dogs with nasal discharge due to intranasal disease were retrospectively reviewed with special focus on composition, severity, duration and localisation of discharge. On the basis of diagnostic findings, cases were classified into different disease groups and characteristics of discharge were compared between groups. RESULTS Cases were classified as having non-specific rhinitis (n=42), nasal neoplasia (n=23), foreign bodies (n=21), nasal mycosis (n=7) and miscellaneous disorders (n=13). Dogs with foreign bodies or nasal mycosis were significantly younger. Mucous components of discharge occurred more often in non-specific rhinitis and nasal neoplasia, although haemorrhagic components predominated in nasal neoplasia when discharge lasted ê14 days. Pure or mixed haemorrhagic discharge was significantly more common with nasal neoplasia, foreign bodies and nasal mycosis. Purulent components were associated with longer duration of discharge and predominantly seen in non-specific rhinitis and foreign bodies. Dogs with foreign bodies were presented earlier and sneezing was more frequent. Nasal stridor was significantly more often observed in dogs with nasal neoplasia. CLINICAL SIGNIFICANCE Characteristics of nasal discharge and associated clinical signs might aid in planning the diagnostic approach, but a combination of diagnostic techniques is still required to confirm a diagnosis.
Highly Tolerated Amino Acid Substitutions Increase the Fidelity of Escherichia coli DNA Polymerase I*

Fidelity of DNA synthesis, catalyzed by DNA polymerases, is critical for the maintenance of the integrity of the genome. Mutant polymerases with elevated accuracy (antimutators) have been observed, but these mainly involve increased exonuclease proofreading or large decreases in polymerase activity. We have determined the tolerance of DNA polymerase for amino acid substitutions in the active site and in different segments of E. coli DNA polymerase I and have determined the effects of these substitutions on the fidelity of DNA synthesis. We established a DNA polymerase I mutant library, with random substitutions throughout the polymerase domain. This random library was first selected for activity. The essentiality of DNA polymerases and their sequence and structural conservation suggests that few amino acid substitutions would be tolerated. However, we report that two-thirds of single base substitutions were tolerated without loss of activity, and plasticity often occurs at evolutionarily conserved regions. We screened 408 members of the active library for alterations in fidelity of DNA synthesis in Escherichia coli expressing the mutant polymerases and carrying a second plasmid containing a β-lactamase reporter. Mutation frequencies varied from 1/1000- to 1000-fold greater compared with wild type. Mutations that produced an antimutator phenotype were distributed throughout the polymerase domain, with 12% clustered in the M-helix. We confirmed that a single mutation in this segment results in increased base discrimination. Thus, this work identifies the M-helix as a determinant of fidelity and suggests that polymerases can tolerate many substitutions that alter fidelity without incurring major changes in activity.
[Real-time PCR array for simultaneous detection of 37 kinds of fusion genes in leukemia].

OBJECTIVE To develop a real-time PCR array for simultaneous quantitative detection of translocations/chromosomal aberrations in patients with leukemia, and to investigate the feasibility and utility thereof. METHODS By construction and optimization a set of specific primes (totally 82 primers), an array containing 66 parallel PCR reactions was developed. That array was used on the specimens of bone marrow or peripheral blood from 31 patients with leukemia to detect simultaneously 37 fusion genes and 4 proto-oncogene activations often occurring in patients with leukemia. Eva Green fluorescent dye method was chosen in the protocol. Relative quantification was performed by Ct analysis and the result was expressed as the ratio of the target gene versus the internal control gene (ABL). Six patients with chronic myelocytic leukemia (CML) among the 31 cases underwent prior to and after treatment so as to study the expression changes of fusion genes and/or proto-oncogene. RESULTS The established PCR array showed high efficiency of amplification and good sensibility (232 copies/microl) in the fusion gene detected. The standard curve had a satisfying linear range (10(2) approximately 10(8) copies/microl), showing a good reproducibility. Fourteen fusion genes, including PML/RARalpha, PLZF/RARalpha, BCR/ABL, MLL/AF1, MLL/AF6, MLL/AF10, AML/Eto, CBFbeta/MYH11, TLS/ERG, TEL/AML1, MOZ/CBP, MLL/hCDCrel, LAF4/MLLT2, and FIP1L1/PDGFRalpha, and activation of all 4 proto-oncogenes were found in the 31 samples. In one patient, 5 fusion genes and activation of 2 proto-oncogenes were observed. Such results were compared with those of RT-nested PCR in 28 samples. The comparison showed that this array was a bit less sensitive than RT-nested PCR, however, without significant difference between them (P = 0.009). The expression of BCR/ABL fusion gene, WT1 gene, and EVI1 gene decreased after treatment in the 6 CML patients, which was in accordance with the clinical features. CONCLUSION The PCR array newly-established successfully detects various leukemia related fusion genes and proto-oncogene activation. It is useful in molecule diagnosis and monitoring minimal residual disease in leukemia, and therapeutic effect monitoring.
Preparing and Motivating Behavior Outside of Awareness

The mere activation of the idea of a behavioral act moves the human body without the person consciously deciding to take action. In an experiment, we showed that people subliminally primed with the concept of exertion were faster to squeeze a hand grip forcefully but expended more effort when the subliminal primes were directly accompanied by consciously visible positive stimuli. These findings demonstrate the human capacity to rely on mental processes in preparing and motivating behavior outside of awareness.
Cell kinetics in acute leukemia. A critical reevaluation based on new data

The current study was undertaken to compare biopsy and aspiration sampling techniques for reliable cell kinetic analysis in acute leukemia and to reevaluate the clinical significance of cell kinetic data in this disease. Ad 1: One hundred forty‐three paired simultaneously taken marrow aspirates and Jamshidi biopsies from 61 patients with acute nonlymphocytic leukemia (ANLL) were compared by means of flow cytometry (FCM) for cellular DNA and RNA measurements, autoradiography for 3H‐TdR labeling index and liquid scintillation counting of 3H‐TdR uptake. Aspirates were found unreliable for pretreatment evaluation and for monitoring of drug induced cell kinetic perturbations due to contamination with peripheral blood. Aspiration should, therefore, be replaced by marrow biopsy which provides reliable sampling of bone marrow for cell kinetic studies. Ad 2: FCM S‐phase index determined from biopsy material was not found predictive for therapeutic response in 43 patients with ANLL treated with two different induction regimens. In one of the two protocols, changes in FCM S‐phase index after 48 hours continuous infusion of cytosine arabinoside correlated significantly with clinical response and nonresponse, respectively.
[Randomized multicenter trial of sequential methotrexate and 5-fluorouracil versus 5-fluorouracil alone in advanced gastric cancer].

In a recent phase II trial we have shown a favorable response rate for sequential methotrexate-5-fluorouracil (MF) in advanced gastric and colorectal cancer. We determined the therapeutic effect of sequential MF in patients with advanced gastric cancer by comparing it to 5-fluorouracil alone (F) in a randomized multicenter trial. Since February 1987 to July 1988, 133 patients with advanced gastric cancer have been prospectively randomized to receive either MF (methotrexate 100 mg/m2 i.v. push, 5-fluorouracil 600 mg/m2 i.v. drip over 15 minutes one hour after methotrexate and leucovorin 15 mg p.o. q 6 hrs x 2 beginning 24 hrs after methotrexate) of F (the same 5-fluorouracil as described for MF). Each treatment was repeated weekly x 5, then q 2 weeks. The two treatment arms were balanced for 17 clinical characteristics. The response rate was 17.9% (10 of 56 patients) in the MF arm and 1.9% (one of 53 patients) in the F arm (p less than 0.01). Median duration of response was 6.8 weeks (MF) and 6 weeks (F), respectively. Median survival time was 7.9 months (MF) and 7.3 months (F) on interim findings. Leukocytopenia and GI toxicity were significantly more common in patients receiving MF, but the degree was similar for both arms. Other side effects were minimal and no different. This schedule of MF is more effective than F in inducing remission for patients with advanced gastric cancer.
Activity of chimeric U small nuclear RNA (snRNA)/mRNA genes in transfected protoplasts of Nicotiana plumbaginifolia: U snRNA 3'-end formation and transcription initiation can occur independently in plants

Formation of the 3' ends of RNA polymerase II (Pol II)-specific U small nuclear RNAs (U snRNAs) in vertebrate cells is dependent upon transcription initiation from the U snRNA gene promoter. Moreover, U snRNA promoters are unable to direct the synthesis of functional polyadenylated mRNAs. In this work, we have investigated whether U snRNA 3'-end formation and transcription initiation are also coupled in plants. We have first characterized the requirements for 3'-end formation of an Arabidopsis U2 snRNA expressed in transfected protoplasts of Nicotiana plumbaginifolia. We found that the 3'-end-adjacent sequence CA (N)3-10AGTNNAA, conserved in plant Pol II-specific U snRNA genes, is essential for the 3'-end formation of U2 transcripts and, similar to the vertebrate 3' box, is highly tolerant to mutation. The 3'-flanking regions of an Arabidopsis U5 and a maize U2 snRNA gene can effectively substitute for the Arabidopsis U2 3'-end formation signal, indicating that these signals are functionally equivalent among different Pol II-transcribed snRNA genes. The plant U snRNA 3'-end formation signal can be recognized irrespective of whether transcription initiation occurs at U snRNA or mRNA gene promoters, although efficiency of 3' box utilization is higher when transcription initiation occurs at the U snRNA promoter. Moreover, transcripts initiated from the U2 gene promoter can be spliced and polyadenylated. Transcription from a Pol III-specific plant U snRNA gene promoter is not compatible with polyadenylation. Finally, we reveal that initiation at a Pol II-specific plant U snRNA gene promoter can occur in the absence of the snRNA coding region and a functional snRNA 3'-end formation signal, demonstrating that these sequences play no role in determining the RNA polymerase specificity of plant U snRNA genes.
Effect of Aerobic Exercise Interventions on Mobility among Stroke Patients: A Systematic Review

ObjectiveThe purpose of this systematic review was to examine studies that examined the effectiveness of aerobic exercise interventions on mobility in long-term stroke survivors. DesignThe authors searched electronic databases for randomized control trials between January 1995 and December 2014 investigating aerobic exercise interventions and mobility in stroke survivors after the subacute phase (>6 mos). Mobility was measured using objective functional fitness tests: 6-minute walk, 10-meter walk, and up-n-go. ResultsNine randomized control trials that compared aerobic exercise with a control group among stroke survivors (mean age, 56.95–68 yrs) were identified. Aerobic interventions lasted between 2 and 6 mos and primarily involved walking. Using the Comprehensive Meta-analysis software, it was found that two of the three mobility outcomes showed small to moderate effect sizes favoring the aerobic exercise group: 6-minute walk (g = 0.366, P < 0.001) and 10-meter walk (g = 0.411, P = 0.002), while the up-n-go test was not significant (g = −0.150, P = 0.330). ConclusionThese findings demonstrate that stroke survivors may continue to benefit from aerobic exercise after the subacute phase. Future research needs to examine the precise dose and recommendation for aerobic exercise, test other exercise modalities, and use larger samples to thoroughly determine long-term exercise effects on mobility in this population.
Quantitative Chemical Proteomics Reveals New Potential Drug Targets in Head and Neck Cancer*

Tumors of the head and neck represent a molecularly diverse set of human cancers, but relatively few proteins have actually been shown to drive the disease at the molecular level. To identify new targets for individualized diagnosis or therapeutic intervention, we performed a kinase centric chemical proteomics screen and quantified 146 kinases across 34 head and neck squamous cell carcinoma (HNSCC) cell lines using intensity-based label-free mass spectrometry. Statistical analysis of the profiles revealed significant intercell line differences for 42 kinases (p < 0.05), and loss of function experiments using siRNA in high and low expressing cell lines identified kinases including EGFR, NEK9, LYN, JAK1, WEE1, and EPHA2 involved in cell survival and proliferation. EGFR inhibition by the small molecule inhibitors lapatinib, gefitinib, and erlotinib as well as siRNA led to strong reduction of viability in high but not low expressing lines, confirming EGFR as a drug target in 10–20% of HNSCC cell lines. Similarly, high, but not low EPHA2-expressing cells showed strongly reduced viability concomitant with down-regulation of AKT and ERK signaling following EPHA2 siRNA treatment or EPHA1-Fc ligand exposure, suggesting that EPHA2 is a novel drug target in HNSCC. This notion is underscored by immunohistochemical analyses showing that high EPHA2 expression is detected in a subset of HNSCC tissues and is associated with poor prognosis. Given that the approved pan-SRC family kinase inhibitor dasatinib is also a very potent inhibitor of EPHA2, our findings may lead to new therapeutic options for HNSCC patients. Importantly, the strategy employed in this study is generic and therefore also of more general utility for the identification of novel drug targets and molecular pathway markers in tumors. This may ultimately lead to a more rational approach to individualized cancer diagnosis and therapy.
Adolescents with HIV and transition to adult care in the Caribbean, Central America and South America, Eastern Europe and Asia and Pacific regions

Introduction: The HIV epidemics in the Caribbean, Central America and South America (CCASA), Eastern Europe (EE) and Asia and Pacific (AP) regions are diverse epidemics affecting different key populations in predominantly middle‐income countries. This narrative review describes the populations of HIV‐positive youth approaching adolescence and adulthood in CCASA, EE and AP, what is known of their outcomes in paediatric and adult care to date, ongoing research efforts and future research priorities.
Increased Urinary Endothelin-1 -Like Immunoreactivity Excretion in NIDDM Patients With Albuminuria

OBJECTIVE To determine the urinary endothelin-1-like immunoreactivity (ET- 1-LI) in non-insulin-dependent diabetes mellitus (NIDDM) patients and toinvestigate whether urinary ET-l-LI excretion is elevated in patients with albuminuria. RESEARCH DESIGN AND METHODS Urinary ET-l-LI substance was determined byradioimmunoassay in 45 normoalbuminuric and 28 albuminuric NIDDM patients. RESULTS The mean amounts of 24-h ET-1 -LI excretion in NIDDM patients with normoalbuminuria and albuminuria were 154.9 ± 13.5 and 174.4 ± 12.9 ng/day, respectively. The latter was significantly higher thanthat of the 40 normal control subjects (111.8 ± 7.9 ng/day, P < 0.01). CONCLUSIONS The increase in urinary ET-l-LI substance excretion in patients with albuminuria suggests that ET-1 may be a pathogenetic factor in diabetic nephropathy.
Transforming careers:from linear to multidirectional career paths

Within the dynamic nature of labour markets, career systems have witnessed major changes in recent decades. This paper presents several career perspectives, to manifest a trend in career systems and their meaning and implications for individuals, organizations and society. This trend may be portrayed as a transition from what may be labelled “linear career system” into a “multidirectional career system”. Possible explanations to the phenomenon are presented, with suggested ideas for analysing and learning from the trend. The last section of the paper presents the academic career model as a prospective role model for future career systems, suggested as an intriguing idea and food for thought. Such a mental exercise of examining alternative career models, different from the traditional concept of careers, may be useful for both theory development and managerial practice.
Prominent expression of metalloproteinases in early stages of ovarian tumorigenesis

The role for matrix metalloproteinases (MMPs) in tumor cells invasion and metastasis is well established, and expression of MMPs is recognized as an indication of tumor cell malignancy. Previous studies suggest that the degradation of the basement membrane is a crucial early step in epithelial transformation and ovarian tumorigenesis. Thus, MMPs may also express and exert a role in preneoplastic lesions of ovarian tissues. We investigated the expression of the major metalloproteinases, gelatinase A, 72 kDa type IV collagenase (MMP‐2), and gelatinase B, 92 kDa type IV collagenase (MMP‐9), and the presence of basement membrane in ovarian tumors and tissues from prophylactic oophorectomies using immunostaining. MMP expression was also characterized in a panel of ovarian cancer cell lines and several nontumorigenic ovarian surface epithelial primary cells by zymography, Northern, and Western blots. We found, surprisingly, that MMP‐2 and MMP‐9 are expressed more frequently in early lesions than in established carcinomas. No correlation was found between the expression of MMPs and tumor grades or stages. In preneoplastic lesions, MMP‐2 or MMP‐9 expression often associates with the absence of basement membrane and morphological alterations. MMP‐2 is often expressed in nontumorigenic ovarian surface epithelial cells but reduced or absent in cancer cells. Thus, we conclude that MMPs expression does not correlate with the malignancy of ovarian epithelial cells as generally thought. Rather, increased metalloproteinase expression is an early event in ovarian tumorigenesis and associates with the loss of epithelial basement membrane and morphological transformation. We propose that the increased MMP activity is an etiological factor for ovarian cancer risk. We found that MMPs expression does not correlate with the malignancy of ovarian epithelial cells as generally thought. Rather, increased metalloproteinase expression is an early event in ovarian tumorigenesis. The finding suggests roles of MMP in tumor initiation in addition to invasion, and may impact on the strategy for use of MMP inhibitors in cancer prevention. © 2006 Wiley‐Liss, Inc.
Immunologic selection of simian virus 40 (SV40) T-antigen-negative tumor cells which arise by excision of early SV40 DNA

A clonal line of highly oncogenic spontaneously transformed mouse cells (104C) was transformed in tissue culture by simian virus 40 (SV40) and subsequently recloned (106CSC). This 106CSC cell line expressed T antigen and transplantation antigen but was about 100 times less tumorigenic than the 104C parent. When 10(5) 106CSC cells were injected into immunocompetent syngeneic mice, tumors were produced. From such tumors, cell lines were established in culture, all of which were consistently negative for T antigen. We found previously by solution DNA hybridization methods that the tumor cells were depleted in the early region of SV40 DNA which codes for the T antigen. We postulated that this loss occurs through a DNA rearrangement of unknown mechanism in one or a few 106CSC cells and that the tumors are then produced from such a cell or cells, whereas all the T-antigen-positive 106CSC cells are rejected by immunologic means. In this investigation we showed by the DNA transfer method using appropriately selected SV40 DNA probes that indeed the tumor cell clone (130CSCT) we selected to investigate came from one 106CSC cell in which the T-antigen-coding SV40 DNA sequences (but not all the early SV40 DNA sequences) were lost by an excision and recombination mechanism. We also showed that the 130CSCT cells, which are highly tumorigenic, could again be transformed by SV40 and that the resulting T-antigen-positive cloned derivative cells became much less tumorigenic (approximately 10(5)-fold), apparently again because of immunologic recognition and rejection. Indeed, when 10(7) T-antigen-positive cloned cells were injected, all the T-antigen-positive cells were rejected and the tumor was produced again from one or more T-antigen-negative cells. Thus, a one-step in vivo transplantation experiment allowed a selection (for tumorigenicity and against the SV40 T antigen) of a mutant mammalian cell with a DNA deletion at a definable site.