tbuckley/cabot-search huggingface dataset:
Transcriptional dynamics of bile salt export pump during pregnancy: Mechanisms and implications in intrahepatic cholestasis of pregnancy
Authors: Xiulong Song, Alexander Vasilenko, Yuan Chen, Leila Valanejad, Ruchi Verma, Bingfang Yan, Ruitang Deng
Journal: Hepatology (2014)

Bile salt export pump (BSEP) is responsible for biliary secretion of bile acids, a rate-limiting step in the enterohepatic circulation of bile acids and transactivated by nuclear receptor farnesoid X receptor (FXR). Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent disorder among diseases unique to pregnancy and primarily occurs in the third trimester of pregnancy, with a hallmark of elevated serum bile acids. Currently, the transcriptional regulation of BSEP during pregnancy and its underlying mechanisms and involvement in ICP are not fully understood. In this study the dynamics of BSEP transcription in vivo in the same group of pregnant mice before, during, and after gestation were established with an in vivo imaging system (IVIS). BSEP transcription was markedly repressed in the later stages of pregnancy and immediately recovered after parturition, resembling the clinical course of ICP in human. The transcriptional dynamics of BSEP was inversely correlated with serum 17β-estradiol (E2) levels before, during, and after gestation. Further studies showed that E2 repressed BSEP expression in human primary hepatocytes, Huh 7 cells, and in vivo in mice. Such transrepression of BSEP by E2 in vitro and in vivo required estrogen receptor α (ERα). Mechanistic studies with chromatin immunoprecipitation (ChIP), protein coimmunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC) assays demonstrated that ERα directly interacted with FXR in living cells and in vivo in mice. Conclusion: BSEP expression was repressed by E2 in the late stages of pregnancy through a nonclassical E2/ERα transrepressive pathway, directly interacting with FXR. E2-mediated repression of BSEP expression represents an etiological contributing factor to ICP and therapies targeting the ERα/FXR interaction may be developed for prevention and treatment of ICP. (Hepatology 2014;60:1992–2006)
[84] HEPATIC NODULES DETECTED IN CIRRHOTIC PATIENTS USING HIGH-PERFORMANCE MULTIDETECTOR COMPUTED TOMOGRAPHY (MDCT) AND MAGNETIC RESONANCE IMAGING (MRI): A RADIOLOGICAL-PATHOLOGICAL CORRELATION ON EXPLANTED LIVERS
Authors: A. Luca, M. Milazzo, S. Caruso, G. Marrone, G. Mamone, L. Maruzzelli, R. Miraglia, G. Vizzini, M. Minervini, B. Gridelli
Journal: Journal of Hepatology (2007)
A Serial Analysis of Gene Expression (SAGE) Database Analysis of Chemosensitivity
Authors: Wilfred D Stein, Thomas Litman, Tito Fojo, Susan E Bates
Journal: Cancer Research (2004)

Abstract Drug sensitivity and resistance has been most extensively studied in cell lines carried in tissue culture. Furthermore, cell lines have been widely used in testing new anticancer agents, despite the widely recognized observation that cell lines are more sensitive to cytotoxic drugs than are their corresponding solid tumors. We used the Serial Analysis of Gene Expression (SAGE) database to identify differences between solid tumors and cell lines, hoping to detect genes that could potentially explain differences in drug sensitivity. SAGE libraries were available for both solid tumors and cell lines from breast, colon, ovarian, pancreatic, and prostate carcinomas and from gliomas and medulloblastomas. Sixty-two genes were identified as overexpressed in tumors. The immune response and complement pathways were the significant common themes, with extracellular matrix (ECM) proteins third. For the 61 genes overexpressed in cell lines, protein synthesis was the dominant theme. We next used the SAGE database to identify genetic differences between tumor types that convey a broad range of survival to the patients that bear them as distant metastases. SAGE gene expression data were correlated with 5-year survivals documented in the SEER (Surveillance, Epidemiology and End-Results) database for patients diagnosed with “distant” or metastatic cancers. These are unlikely to be amenable to surgical resection; therefore, survival here reflects, to some extent, sensitivity to systemic therapy, i.e., chemotherapy. Using survival data as a surrogate of chemotherapy sensitivity, a spectrum can be generated, with testicular cancer at one end and pancreatic cancer at the other. Favorable 5-year survival, despite a distant presentation, correlates with expression of protein synthesis genes. Poor 5-year survival correlates with expression of cell adhesion, cytoskeletal, and ECM genes, a pattern similar to that found to distinguish solid tumors from the more cytotoxin-sensitive cancer cell lines. One interpretation is that resistance to chemotherapy may arise, in part, from the adherent, relatively inert condition (i.e., low in protein synthesis potential) of refractory cancers. Thus, attachment or ECM genes could be targets for anticancer therapy.
NHS likely to end financial year with £1bn surplus
Authors: Adrian O'Dowd
Journal: BMJ (2007)

Clinicians and patients are paying the price for a predicted surplus in the NHS, it has been claimed.

The Department of Health in its latest quarterly report says that the NHS in England will have achieved a surplus of almost £1bn (€1.5bn; $2bn) by the end of this financial year.

The department said that most NHS trusts would be in balance by April of next year, with an overall forecasted surplus of £983m. This compares with an end of year surplus of £510m in 2006-7 and a deficit of £547m in 2005-6.

A small number of trusts will finish the year with a deficit, …
TCR/CD3 coupling to Fas-based cytotoxicity.
Authors: F Vignaux, E Vivier, B Malissen, V Depraetere, S Nagata, P Golstein
Journal: The Journal of Experimental Medicine (1995)

We studied the coupling of the TCR/CD3 complex to a T cell effector function, namely Fas-based T-cell-mediated cytotoxicity. Encounter or re-encounter with antigen was mimicked by treating 5 d mixed lymphocyte culture cells or T cell hybridomas with anti-CD3 antibody. This TCR/CD3 engagement induced swift expression of Fas-based cytotoxicity in these cells. Induction of Fas-based cytotoxicity was Ca(2+)-dependent, while its execution was not; induction was sensitive to macromolecular synthesis inhibitors, in line with a demonstrable increase of the Fas ligand (Fas-L) message. We also used T cell hybridomas transfected with various constructs to dissect the involvement of distinct components of the TCR/CD3 complex. The cytoplasmic domain of the CD3 zeta chain was able to transduce by itself a signal leading to Fas-L expression, unless there were mutations in its activation receptor homology sequence 1 (ARH-1) motifs. On the one hand, these findings are relevant to signal transduction pathways coupled to the TCR/CD3, and on the other hand, to the involvement of Fas-based T cell-mediated cytotoxicity in various physiological and possibly pathophysiological situations.
Development of the Myocardium of the Atrioventricular Canal and the Vestibular Spine in the Human Heart
Authors: Jung-Sun Kim, Szabolcs Virágh, Antoon F. M. Moorman, Robert H. Anderson, Wouter H. Lamers
Journal: Circulation Research (2001)

Abstract —To establish the morphogenetic mechanisms underlying formation and separation of the atrioventricular connections, we studied the remodeling of the myocardium of the atrioventricular canal and the extracardiac mesenchymal tissue of the vestibular spine in human embryonic hearts from 4.5 to 10 weeks of development. Septation of the atrioventricular junction is brought about by downgrowth of the primary atrial septum, fusion of the endocardial cushions, and forward expansion of the vestibular spine between atrial septum and cushions. The vestibular spine subsequently myocardializes to form the ventral rim of the oval fossa. The connection of the atrioventricular canal with the atria expands evenly. In contrast, the expression patterns of creatine kinase M and GlN2, markers for the atrioventricular and interventricular junctions, respectively, show that the junction of the canal with the right ventricle forms by local growth in the inner curvature of the heart. Growth of the caudal portion of the muscular ventricular septum to make contact with the inferior endocardial cushion occurs only after the canal has expanded rightward. The atrioventricular node develops from that part of the canal myocardium that retains its continuity with the ventricular myocardium.
Management of HBV- and HCV-induced end stage liver disease
Authors: David J Mutimer, Anna Lok
Journal: Gut (2012)

Hepatitis B and hepatitis C infections are important causes of end-stage liver disease and primary liver cancer. Successful antiviral treatment prior to the development of cirrhosis will prevent most of the morbidity and mortality associated with those infections. This can be achieved for a high proportion of patients. However, many patients present with end-stage liver disease and ongoing and clinically significant viral replication. Antiviral treatment of HBV can effect recovery of liver function and restores many patients to a state of well compensated cirrhosis. The antiviral treatment of end-stage HCV poses much greater challenges. Interferon remains an essential element of HCV antiviral treatment, but has reduced efficacy and significant toxicity at this stage of cirrhosis. Though yet to be evaluated in the setting of advanced liver disease, the development of direct acting antivirals for HCV offers hope for improved outcomes at this stage of cirrhosis.
Users' Guides to the Medical Literature
Authors: Finlay A. McAlister, Sharon E. Straus, Gordon H. Guyatt, R. Brian Haynes, None for the Evidence-Based Medicine Working Group
Journal: JAMA (2000)

Clinicians can use research results to determine optimal care for an individual patient by using a patient's baseline risk estimate, clinical prediction guidelines that quantitate an individual patient's potential for benefit, and published articles. We propose that when clinicians are determining the likelihood that treatment will prevent the target event (at the expense of adverse events) in a patient that they also incorporate the patient's values. The 3 main elements to joint clinical decision making are disclosure of information about the risks and benefits of therapeutic alternatives, exploration of the patient's values about both the therapy and potential outcomes, and the actual decision. In addressing the patient's risk of adverse events without treatment and risk of harm with therapy, clinicians must recognize that patients are rarely identical to the average study patient. Differences between study participants and patients in real-world practice tend to be quantitative (differences in degree of risk of the outcome or responsiveness to therapy) rather than qualitative (no risk or adverse response to therapy). The number needed to treat and number needed to harm can be used to generate patient-specific estimates relative to the risk of the outcome event. Clinicians must consider a patient's risk of adverse events from any intervention and incorporate the patient's values in clinical decision making by using information about the risks and benefits of therapeutic alternatives.
Manometry based randomised trial of endoscopic sphincterotomy for sphincter of Oddi dysfunction
Authors: J Toouli
Journal: Gut (2000)

Endoscopic sphincterotomy for biliary-type pain after cholecystectomy remains controversial despite evidence of efficacy in some patients with a high sphincter of Oddi (SO) basal pressure (SO stenosis).To evaluate the effects of sphincterotomy in patients randomised on the basis of results from endoscopic biliary manometry.Endoscopic biliary manometry was performed in 81 patients with biliary-type pain after cholecystectomy who had a dilated bile duct on retrograde cholangiography, transient increases in liver enzymes after episodes of pain, or positive responses to challenge with morphine/neostigmine. The manometric record was categorised as SO stenosis, SO dyskinesia, or normal, after which the patient was randomised in each category to sphincterotomy or to a sham procedure in a prospective double blind study. Symptoms were assessed at intervals of three months for 24 months by an independent observer, and the effects of sphincterotomy on sphincter function were monitored by repeat manometry after three and 24 months.In the SO stenosis group, symptoms improved in 11 of 13 patients treated by sphincterotomy and in five of 13 subjected to a sham procedure (p = 0.041). When manometric records were categorised as dyskinesia or normal, results from sphincterotomy and sham procedures did not differ. Complications were rare, but included mild pancreatitis in seven patients (14 episodes) and a collection in the right upper quadrant, presumably related to a minor perforation. At three months, the endoscopic incision was extended in 19 patients because of manometric evidence of incomplete division of the sphincter.In patients with presumed SO dysfunction, endoscopic sphincterotomy is helpful in those with manometric features of SO stenosis.
Matrix metalloproteinase-9 Inhibition Down-Regulates Radiation-Induced Nuclear Factor-κB Activity Leading to Apoptosis in Breast Tumors
Authors: Sateesh Kunigal, Sajani S. Lakka, Pushpa Joseph, Norman Estes, Jasti S. Rao
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Novel strategies are needed to prevent the high mortality rates of several types of cancer. These high rates stem from tumor resistance to radiation therapy, which is thought to result from the induction of matrix metalloproteinases (MMP) and plasminogen activators. In the present study, we show that the modulation of MMP-9 expression, using adenoviral-mediated transfer of the antisense MMP-9 gene (MMP-9 adenoviral construct, Ad-MMP-9), affects breast cancer sensitivity to radiation. Experimental Design: In the present study, we used antisense Ad-MMP-9 to down-regulate the expression of MMP-9 in MDA MB 231 breast cancer cell lines in vitro before irradiation and subsequently incubated cells in hypoxic condition. In vivo studies were done with orthotopic breast tumors, and radiosensitivity was evaluated both in vitro and in vivo. Results: Ad-MMP-9 infection resulted in down-regulation of radiation-induced levels of hypoxia-inducible factor 1α and MMP-9 under hypoxic conditions in MDA MB 231 breast cancer cells. In addition, Ad-MMP-9, in combination with radiation, decreased levels of the transcription factors nuclear factor-κB and activator protein 1, both of which contribute to the radioresistance of breast tumors. Finally, the triggering of the Fas–Fas ligand apoptotic cascade, which resulted in the cleavage of PARP-1 and caspase-10, caspase-3, and caspase-7, signifies the efficiency of combined treatment of Ad-MMP-9 and radiation. Treatment with Ad-MMP-9 plus radiation completely regressed tumor growth in orthotopic breast cancer model. Conclusions: In summary, integrating gene therapy (adenovirus-mediated inhibition of MMP-9) with radiotherapy could have a synergistic effect, thereby improving the survival of patients with breast cancer.
Surgical Site Infection and the Routine Use of Perioperative Hyperoxia in a General Surgical Population
Authors: Kane O. Pryor, Thomas J. Fahey III, Cynthia A. Lien, Peter A. Goldstein
Journal: JAMA (2004)

ContextSurgical site infection (SSI) in the general surgical population is a significant public health issue. The use of a high fractional inspired concentration of oxygen (FIO2) during the perioperative period has been reported to be of benefit in selected patients, but its role as a routine intervention has not been investigated.ObjectiveTo determine whether the routine use of high FIO2 during the perioperative period alters the incidence of SSI in a general surgical population.Design, Setting, and PatientsDouble-blind, randomized controlled trial conducted between September 2001 and May 2003 at a large university hospital in metropolitan New York City of 165 patients undergoing major intra-abdominal surgical procedures under general anesthesia.InterventionsPatients were randomly assigned to receive either 80% oxygen (FIO2 of 0.80) or 35% oxygen (FIO2 of 0.35) during surgery and for the first 2 hours after surgery.Main Outcome MeasuresPresence of clinically significant SSI in the first 14 days after surgery, as determined by clinical assessment, a management change, and at least 3 prospectively defined objective criteria.ResultsThe study groups were closely matched in a large number of clinical variables. The overall incidence of SSI was 18.1%. In an intention-to-treat analysis, the incidence of infection was significantly higher in the group receiving FIO2 of 0.80 than in the group with FIO2 of 0.35 (25.0% vs 11.3%; P = .02). FIO2 remained a significant predictor of SSI (P = .03) in multivariate regression analysis. Patients who developed SSI had a significantly longer length of hospitalization after surgery (mean [SD], 13.3 [9.9] vs 6.0 [4.2] days; P&lt;.001).ConclusionsThe routine use of high perioperative FIO2 in a general surgical population does not reduce the overall incidence of SSI and may have predominantly deleterious effects. General surgical patients should continue to receive oxygen with cardiorespiratory physiology as the principal determinant.
Reassessing the “Duon” Hypothesis of Protein Evolution
Authors: Ke Xing, Xionglei He
Journal: Molecular Biology and Evolution (2015)

There are two distinct types of DNA sequences, namely coding sequences and regulatory sequences, in a genome. A recent study of the occupancy of transcription factors (TFs) in human cells suggested that protein-coding sequences also serve as the codes of TF occupancy, and proposed a "duon" hypothesis in which up to 15% of codons of human protein genes are constrained by the additional coding requirements that regulate gene expression. This hypothesis challenges our basic understanding on the human genome. We reanalyzed the data and found that the previous study was confounded by ascertainment bias related to base composition. Using an unbiased comparison in which G/C and A/T sites are considered separately, we reveal a similar level of conservation between TF-bound codons and TF-depleted codons, suggesting largely no extra purifying selection provided by the TF occupancy on the codons of human genes. Given the generally short binding motifs of TFs and the open chromatin structure during transcription, we argue that the occupancy of TFs on protein-coding sequences is mostly passive and evolutionarily neutral, with to-be-determined functions in the regulation of gene expression.
Monitoring transplanted adipose tissue-derived stem cells combined with heparin in the liver by fluorescence imaging using quantum dots
Authors: Hiroshi Yukawa, Masaki Watanabe, Noritada Kaji, Yukihiro Okamoto, Manabu Tokeshi, Yoshitaka Miyamoto, Hirofumi Noguchi, Yoshinobu Baba, Shuji Hayashi
Journal: Biomaterials (2011)
Antioxidant Intake in Pregnancy in Relation to Wheeze and Eczema in the First Two Years of Life
Authors: Sheelagh Martindale, Geraldine McNeill, Graham Devereux, Doris Campbell, George Russell, Anthony Seaton
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Two thousand women were recruited for a prospective investigation of the influence of maternal antioxidant intake in pregnancy on the development of asthma and eczema in children. A food frequency questionnaire was used to characterize diet during pregnancy and blood antioxidant levels were measured. Postal questionnaires were used to follow up the 1,924 singleton children born to the cohort at 6, 12, and 24 months of age. There were no associations between maternal antioxidant intake and wheezing symptoms and eczema in the children's first year. In the children's second year, maternal vitamin E intake during pregnancy was negatively associated with wheeze in the absence of a "cold" (p for trend 0.010) and, in children whose mothers were atopic, there was a negative association between maternal vitamin E intake and childhood eczema (p for trend 0.024). Maternal vitamin C intake during pregnancy was positively associated with "ever wheeze" and eczema during the children's second year. This study suggests that maternal dietary antioxidant intakes during pregnancy may modify the risks of developing wheeze and eczema during early childhood. Further follow up of the cohort will determine whether maternal diet during pregnancy is associated with asthma and atopic disease in later childhood.
Real-Time Catheter Molecular Sensing of Inflammation in Proteolytically Active Atherosclerosis
Authors: Farouc A. Jaffer, Claudio Vinegoni, Michael C. John, Elena Aikawa, Herman K. Gold, Aloke V. Finn, Vasilis Ntziachristos, Peter Libby, Ralph Weissleder
Journal: Circulation (2008)

To enable intravascular detection of inflammation in atherosclerosis, we developed a near-infrared fluorescence (NIRF) catheter-based strategy to sense cysteine protease activity during vascular catheterization.The NIRF catheter design was based on a clinical coronary artery guidewire. In phantom studies of NIRF plaques, blood produced only a mild (<30%) attenuation of the fluorescence signal compared with saline, affirming the favorable optical properties of the NIR window. Catheter evaluation in vivo used atherosclerotic rabbits (n=11). Rabbits received an injection of a cysteine protease-activatable NIRF imaging agent (Prosense750; excitation/emission, 750/770 nm) or saline. Catheter pullbacks through the blood-filled iliac artery detected NIRF signals 24 hours after injection of the probe. In the protease agent group, the in vivo peak plaque target-to-<0.05). Ex vivo fluorescence reflectance imaging corroborated these results (target-to-<0.01). In the protease group only, saline flush-modulated NIRF signal profiles further distinguished atheromata from normal segments in vivo (P<0.01). Good correlation between the in vivo and ex vivo plaque target-to-=0.82, P<0.01). Histopathological analyses demonstrated strong NIRF signal in plaques only from the protease agent group. NIRF signals colocalized with immunoreactive macrophages and the cysteine protease cathepsin B.An intravascular fluorescence catheter can detect cysteine protease activity in vessels the size of human coronary arteries in real time with an activatable NIRF agent. This strategy could aid in the detection of inflammation and high-risk plaques in small arteries.
Does the SOC theory avoid unconscious rule use?
Authors: Carol A. Seger
Journal: Behavioral and Brain Sciences (2002)

There are striking similarities between Perruchet &amp; Vinter's SOC theory and the theories that they claim to be in opposition to. First, both kinds of theory lead to the induction of knowledge of complex patterns in the environment that serve the function of rules. Second, both involve unconscious mental processes of induction resulting in at least some conscious knowledge.