tbuckley/cabot-search huggingface dataset:
Evidence of unexpected oxidative stress in airways of adolescents born very pre-term
Authors: Marco Filippone, Gea Bonetto, Massimo Corradi, Anna Chiara Frigo, Eugenio Baraldi
Journal: European Respiratory Journal (2012)

Prematurity and its main respiratory complication, bronchopulmonary dysplasia (BPD), are potentially associated with lifelong respiratory morbidities and/or lung function abnormalities. The mechanisms behind these long-term respiratory problems are still unclear. We assessed airway oxidative stress in adolescents born very pre-term (≤32 gestational weeks) by measuring 8-isoprostane concentration in exhaled breath condensate (EBC). In addition, the study protocol included spirometry and measurement of exhaled nitric oxide fraction ( F eNO ). The study groups included 34 ex-pre-term adolescents with BPD, 18 ex-pre-term adolescents without BPD and 34 healthy controls born at term. Regardless of a history of BPD, the ex-premature adolescents had higher EBC 8-isoprostane levels (median (interquartile range) BPD 9.5 (7.3–12.2) pg·mL −1 ; pre-term non-BPD 10 (8.1–16) pg·mL −1 ) than the controls (3.2 (1.9–6.5) pg·mL −1 ) (p&lt;0.001). Forced expiratory volume in 1 s was lower in the BPD group (mean± sd Z-score -2.1±1.58) than in the pre-term non-BPD individuals (-1.13±1.15), who showed in turn significantly lower values than the controls (0.18±0.83; p&lt;0.001). F eNO was similar in the three groups (p=0.55). Our data show that, after premature birth, evidence of oxidative stress in the airways may be detected into adolescence, suggesting that long-term respiratory abnormalities after pre-term birth may be associated with an ongoing airway disease and not just a stabilised structural lung damage.
Hepatocyte nuclear factor 4α attenuates hepatic fibrosis in rats
Authors: H-Y Yue, C Yin, J-L Hou, X Zeng, Y-X Chen, W Zhong, P-F Hu, X Deng, Y-X Tan, J-P Zhang, B-F Ning, J Shi, X Zhang, H-Y Wang, Y Lin, W-F Xie
Journal: Gut (2009)

Background and aims Hepatocyte nuclear factor 4α (HNF4α) is a central transcriptional regulator of hepatocyte differentiation and function. The aim of this study was to evaluate the effect of HNF4α on attenuation of hepatic fibrosis. Methods The adenoviruses carrying HNF4α gene or containing siRNA targeting HNF4α were injected through tail vein on two distinct hepatic fibrosis models either induced by dimethylnitrosamine or by bile duct ligation in rats. Moreover, HNF4α, epithelial–mesenchymal transition (EMT)-related and fibrotic markers in hepatocytes, hepatic stellate cells (HSCs) and liver tissues were detected by real time PCR, immunofluorescence or immunohistochemistry. Results We demonstrated that decreased expression of HNF4α and epithelial markers accompanied by enhanced expression of mesenchymal markers occurred in fibrotic liver. More importantly, forced expression of HNF4α remarkably alleviated hepatic fibrosis and improved liver function with suppression of EMT in both fibrosis models. In contrast, downregulation of HNF4α by siRNA aggravated hepatic fibrosis and decreased the expression of E-cadherin in association with the enhanced expression of vimentin and fibroblast-specific protein-1. In vitro study revealed that HNF4α could suppress the EMT process of hepatocytes induced by transforming growth factor-β1 and increase the expression of liver-specific genes. A similar phenomenon of the EMT process was observed during the activation of HSCs, which was abrogated by HNF4α. Additionally, HNF4α deactivated the myofibroblasts through inducing the mesenchymal-to-epithelial transition and inhibited their proliferation. Conclusions Our study suggests that HNF4α is critical for hepatic fibrogenesis and upregulation of HNF4α might present as an ideal option for the treatment of hepatic fibrosis.
Clonal nature of the immune response to phosphorylcholine (PC). V. Cross-idiotypic specificity among heavy chains of murine anti-PC antibodies and PC-binding myeloma proteins.
Authors: J L Claflin, J M Davie
Journal: The Journal of Experimental Medicine (1975)

Seven mouse myeloma proteins with specificity for phosphorylcholine (PC) were found to share a common antigenic determinant. This group of proteins contained members which differed in genetic origin, heavy chain class, kappa-chain subgroup, individual antigenic determinants and specificity for choline analogues. The cross-idiotypic determinant, VH-PC, was antigenically similar in each of the proteins and was associated with the variable portion of the heavy chain in the region of the antibody combining site. Further studies showed that an indistinguishable determinant was present on IgM anti-PC antibodies isolated from all strains of mice tested regardless of histocompatibility or heavy chain allotype. In view of the finding that this cross-idiotypic determinant was not found on antibodies or myeloma proteins which lacked specificity for PC, the data strongly suggest that a particular heavy chain variable region has been preserved in all mouse antibodies with specificity for PC.
Severe hypothyroidism after thalidomide treatment
Authors: N. de Savary, R. Lee, B. Vaidya
Journal: Journal of the Royal Society of Medicine (2004)

An important but little recognized side-effect of thalidomide is hypothyroidism. CASE HISTORYA man aged 49 reported lethargy and back pain and was found to have multiple myeloma.The treatment began with radiotherapy to the spine and repeated courses of vincristine, doxorubicin and dexamethasone.Then, on reaching plateau phase, he underwent autologous stem-cell transplantation following high-dose melphalan.This led to complete remission of the myeloma.As a part of a clinical trial investigating thalidomide as maintenance therapy for multiple myeloma, he was randomized to receive this drug, initially at 50 mg/day.The dose was increased to 100 mg/day after two weeks and to 200 mg/day after eight weeks.Three months after starting thalidomide, he reported increasing lethargy, constipation and cold intolerance.He had slow-relaxing ankle jerks.There was no goitre.Thyroid function tests revealed gross biochemical hypothyroidism, with thyrotropin (TSH) 4100 mu/L (normal range 0.25-5.5)and free T4 (FT4) 1.8 pmol/L (9.7-25.7).Thyroid peroxidase (TPO) antibodies were present.Two days before starting thalidomide his thyroid function had been essentially normal (TSH 0.21 mu/L, FT4 23.4 pmol/L), and there was no family history of thyroid disease.After the diagnosis of hypothyroidism he was taken off thalidomide and started on thyroxine, with resolution of his symptoms.On thyroxine 125 mg daily he remained euthyroid and his multiple myeloma was still in remission eighteen months from diagnosis.The UK Committee on Safety of Medicines say that they received no other reports of thalidomide-induced hypothyroidism between 1966 and 2003. COMMENTThalidomide was originally marketed in 1956 as a sedative and was withdrawn 5 years later because of teratogenicity.Recently, however, the discovery of its immunomodulatory,
Phase III Trial of Weekly Methotrexate or Pulsed Dactinomycin for Low-Risk Gestational Trophoblastic Neoplasia: A Gynecologic Oncology Group Study
Authors: Raymond J. Osborne, Virginia Filiaci, Julian C. Schink, Robert S. Mannel, Angeles Alvarez Secord, Joseph L. Kelley, Diane Provencher, David Scott Miller, Allan L. Covens, Janice M. Lage
Journal: Journal of Clinical Oncology (2011)

Purpose There is no consensus on the best regimen for the primary treatment of low-risk gestational trophoblastic neoplasia (GTN). Patients and Methods Two commonly used single-drug regimens were compared with respect to the proportion of patients meeting the criteria for a complete response (CR) in a randomized phase III trial conducted by the Gynecologic Oncology Group. Eligibility was purposefully broad to maximize the generalizability of the results and included patients with a WHO risk score of 0 to 6 and patients with metastatic disease (limited to lung lesions &lt; 2 cm, adnexa, or vagina) or choriocarcinoma. Results Two hundred forty women were enrolled, and 216 were deemed eligible. Biweekly intravenous dactinomycin 1.25 mg/m 2 was statistically superior to weekly intramuscular (IM) methotrexate 30 mg/m 2 (CR: 70% v 53%; P = .01). Similarly, in patients with low-risk GTN as defined before the 2002 WHO risk score revisions (risk score of 0 to 4 and excluding choriocarcinoma), response was 58% and 73% in the methotrexate and dactinomycin arms, respectively (P = .03). Both regimens were less effective if the WHO risk score was 5 or 6 or if the diagnosis was choriocarcinoma (CR: 9% and 42%, respectively). There were two potential recurrences; one at 4 months (dactinomycin) and one at 22 months (methotrexate). Not all patients completed follow-up. Both regimens were well tolerated. Conclusion The biweekly dactinomycin regimen has a higher CR rate than the weekly IM methotrexate regimen in low-risk GTN, a generally curable disease.
A systematic review of filler agents for aesthetic treatment of HIV facial lipoatrophy (FLA)
Authors: Jared Jagdeo, Derek Ho, Alex Lo, Alastair Carruthers
Journal: Journal of the American Academy of Dermatology (2015)

HIV facial lipoatrophy (FLA) is characterized by facial volume loss. HIV FLA affects the facial contours of the cheeks, temples, and orbits, and is associated with social stigma. Although new highly active antiretroviral therapy medications are associated with less severe FLA, the prevalence of HIV FLA among treated individuals exceeds 50%. The goal of our systematic review is to examine published clinical studies involving the use of filler agents for aesthetic treatment of HIV FLA and to provide evidence-based recommendations based on published efficacy and safety data. A systematic review of the published literature was performed on July 1, 2015, on filler agents for aesthetic treatment of HIV FLA. Based on published studies, poly-L-lactic acid is the only filler agent with grade of recommendation: B. Other reviewed filler agents received grade of recommendation: C or D. Poly-L-lactic acid may be best for treatment over temples and cheeks, whereas calcium hydroxylapatite, with a Food and Drug Administration indication of subdermal implantation, may be best used deeply over bone for focal enhancement. Additional long-term randomized controlled trials are necessary to elucidate the advantages and disadvantages of fillers that have different biophysical properties, in conjunction with cost-effectiveness analysis, for treatment of HIV FLA.
Nitric oxide enhances de novo formation of endothelial gap junctions
Authors: A Hoffmann
Journal: Cardiovascular Research (2003)

Gap junctions (formed by connexins, Cx) are important for functional coordination of cells in the vascular wall. However, little is known about their physiological regulation in this tissue. We examined the effects of nitric oxide (NO), an important mediator of vasomotion, wound healing and angiogenesis, on the formation of gap junctions in endothelial cells (human umbilical vein endothelial cells, HUVEC).Flow cytometry was used to determine dye transfer through newly formed gap junctions between acutely coincubated HUVECs. Parallel experiments in wild-type HeLa cells (no connexins) and transfected HeLa cells exclusively expressing Cx43, Cx40 or Cx37 were performed to determine the specific role of Cx subtypes. The intracellular distribution of Cx40 was examined after fractionation with triton by Western blotting. Intracellular levels of cGMP and cAMP were measured by radioimmunoassay.The NO donor SNAP (1 microM) enhanced gap-junctional coupling in HUVECs by about 40%. This was associated with an enhanced incorporation of Cx40 into the membrane. Both effects were restricted to Cx40 as analyzed in experiments with Cx-selective HeLa cells. The NO-induced increase in cell coupling was elicited by a corresponding rise of cGMP, which secondarily increased intracellular cAMP levels. The latter was an integral part of the signal cascade, since the protein kinase A (PKA) inhibitor H89 blocked the SNAP-induced incorporation of Cx40 into the plasma membrane.We conclude that NO is a potent modulator of gap-junctional coupling in endothelial cells. It enhances de novo formation of endothelial gap junctions by increasing incorporation of Cx40 into the plasma membrane due to PKA activation.
COOH terminus of membrane IgM is essential for an antigen-specific induction of some but not all early activation events in mature B cells.
Authors: V S Parikh, C Nakai, S J Yokota, R B Bankert, P W Tucker
Journal: The Journal of Experimental Medicine (1991)

Transfectants of mature B cell lines that bind phosphorylcholine were made in order to understand the role of the COOH terminus of the mu chain of membrane IgM (mIgM) in generation of antigen-specific signals. A chimeric receptor (I-A alpha tail) was constructed by replacing 40 amino acids from the mu COOH terminus with that of major histocompatibility complex class II I-A alpha chain. The effect of wild-type and chimeric tails were studied on representative immediate-early antigen-specific signals. The I-A alpha tail hybrid, but not the wild-type receptor, was defective in antigen-driven Ca2+ mobilization, although it could effectively endocytose ligand-receptor complexes. Signal(s) transduced through the wild-type receptor led to transient induction of selected immediate-early gene messages (Egr-1, c-fos, Jun) above basal levels. However, the signal(s) generated after crosslinking of the I-A alpha tail receptor either showed no effect (c-fos) or actually repressed basal level expression of Egr-1 and Jun. Thus, we have established that receptor-mediated endocytosis can be distinguished from other early events associated with B cell activation, based on their differential dependence upon the structural fidelity of the COOH-terminal sequence of mIgM.
Validation and refinement of survival models for liver retransplantation
Authors: Hugo R. Rosen, Martin Prieto, Teresa Casanovas-Taltavull, Valentin Cuervas-Mons, Olaf Guckelberger, Paolo Muiesan, Russell W. Strong, Wolf O. Bechstein, John O'Grady, Atif Zaman, Benjamin Chan, Joaquin Berenguer, Roger Williams, Nigel Heaton, Peter Neuhaus
Journal: Hepatology (2003)

Orthotopic liver retransplantation (re-OLT) is highly controversial. The objectives of this study were to determine the validity of a recently developed United Network for Organ Sharing (UNOS) multivariate model using an independent cohort of patients undergoing re-OLT outside the United States, to determine whether incorporation of other variables that were incomplete in the UNOS registry would provide additional prognostic information, to develop new models combining data sets from both cohorts, and to evaluate the validity of the model for end-stage liver disease (MELD) in patients undergoing re-OLT. Two hundred eighty-one adult patients undergoing re-OLT (between 1986 and 1999) at 6 foreign transplant centers comprised the validation cohort. We found good agreement between actual survival and predicted survival in the validation cohort; 1-year patient survival rates in the low-, intermediate-, and high-risk groups (as assigned by the original UNOS model) were 72%, 68%, and 36%, respectively (P <.0001). In the patients for whom the international normalized ratio (INR) of prothrombin time was available, MELD correlated with outcome following re-OLT; the median MELD scores for patients surviving at least 90 days compared with those dying within 90 days were 20.75 versus 25.9, respectively (P =.004). Utilizing both patient cohorts (n = 979), a new model, based on recipient age, total serum bilirubin, creatinine, and interval to re-OLT, was constructed (whole model chi(2) = 105, P <.0001). Using the c-statistic with 30-day, 90-day, 1-year, and 3-year mortality as the end points, the area under the receiver operating characteristic (ROC) curves for 4 different models were compared. In conclusion, prospective validation and use of these models as adjuncts to clinical decision making in the management of patients being considered for re-OLT are warranted.
Prodding the Beast: Assessing the Impact of Treatment-Induced Metastasis
Authors: John M.L. Ebos
Journal: Cancer Research (2015)

Abstract The arsenal of treatments for most cancers fit broadly into the categories of surgery, chemotherapy, radiation, and targeted therapy. All represent proven and successful strategies, yet each can trigger local (tumor) and systemic (host) processes that elicit unwanted, often opposing, influences on cancer growth. Under certain conditions, nearly all cancer treatments can facilitate metastatic spread, often in parallel (and sometimes in clear contrast) with tumor reducing benefits. The paradox of treatment-induced metastasis (TIM) is not new. Supporting preclinical studies span decades, but are often overlooked. With recent evidence of prometastatic effects following treatment with targeted agents blocking the tumor microenvironment, a closer inspection of this literature is warranted. The TIM phenomena may diminish the impact of effective therapies and play a critical role in eventual resistance. Alternatively, it may simply exemplify the gap between animal and human studies, and therefore have little impact for patient disease and treatment. This review will focus on the preclinical model systems used to evaluate TIM and explore the mechanisms that influence overall treatment efficacy. Understanding the role of TIM in established and emerging drug treatment strategies may help provide rationales for future drug combination approaches with antimetastatic agents to improve outcomes and reduce resistance. Cancer Res; 75(17); 3427–35. ©2015 AACR.
Incomplete screening flexible sigmoidoscopy associated with female sex, age, and increased risk of colorectal cancer
Authors: V P Doria-Rose
Journal: Gut (2005)

<b>Background:</b> Several previous studies have found that females and older individuals are at greater risk of having incomplete flexible sigmoidoscopy. However, no prior study has reported the subsequent risk of colorectal cancer (CRC) following incomplete sigmoidoscopy. <b>Methods:</b> Using data from 55 791 individuals screened as part of the Colon Cancer Prevention (CoCaP) programme of Kaiser Permanente of Northern California, we evaluated the likelihood of having an inadequate (&lt;40 cm) examination by age and sex, and estimated the risk of distal CRC according to depth of sigmoidoscope insertion at the baseline screening examination. Multivariate estimation of risks was performed using Poisson regression. <b>Results:</b> Older individuals were at a much greater risk of having an inadequate examination (relative risk (RR) for age 80+ years compared with 50–59 years 2.6 (95% confidence interval (CI) 2.3–3.0)), as were females (RR 2.3 (95% CI 2.2–2.5)); these associations were attenuated but remained strong if Poisson models were further adjusted for examination limitations (pain, stool, and angulation). There was an approximate threefold increase in the risk of distal CRC if the baseline sigmoidoscopy did not reach a depth of at least 40 cm; a smaller increase in risk was observed for examinations that reached 40–59 cm. <b>Conclusions:</b> Older individuals and women are at an increased risk of having inadequate sigmoidoscopy. Because inadequate sigmoidoscopy results in an increased risk of subsequent CRC, physicians should consider steps to maximise the depth of insertion of the sigmoidoscope or, failing this, should consider an alternative screening test.
Cancer in pregnancy: maternal and fetal implications
Authors: Boaz Weisz, Eyal Schiff, Michael Lishner
Journal: Human Reproduction Update (2001)

Cancer is the second leading cause of death in women during their reproductive years, and complicates approximately 0.1% of all pregnancies. When cancer occurs during gestation it poses immense pressure on the pregnant patient, her relatives and her physicians. As cancer is diagnosed during gestation, it raises conflicts between optimal maternal therapy and fetal well-being. In this review, the available data are analysed regarding the impact of pregnancy on the course of the disease, and the effects of the malignant process and its treatment on both the mother and her fetus. Here, attention is focused on the most common malignancies associated with pregnancy; cervical and breast cancer, malignant melanoma and lymphoma. In addition, attention is focused on the available data regarding the impact of cytotoxic and radiation treatments on the mother and fetus.
Reducing the Impact of the Next Influenza Pandemic Using Household-Based Public Health Interventions
Authors: Joseph T Wu, Steven Riley, Christophe Fraser, Gabriel M Leung
Journal: PLoS Medicine (2006)

The outbreak of highly pathogenic H5N1 influenza in domestic poultry and wild birds has caused global concern over the possible evolution of a novel human strain [1]. If such a strain emerges, and is not controlled at source [2,3], a pandemic is likely to result. Health policy in most countries will then be focused on reducing morbidity and mortality.
The plasmacytoid dendritic cell: at the cross-roads in asthma
Authors: Jason P. Lynch, Stuart B. Mazzone, Matthew J. Rogers, Jaisy J. Arikkatt, Zhixuan Loh, Antonia L. Pritchard, John W. Upham, Simon Phipps
Journal: European Respiratory Journal (2013)

The onset, progression and exacerbations of asthma are frequently associated with viral infections of the lower respiratory tract. An emerging paradigm suggests that this relationship may be underpinned by a defect in the host’s antiviral response, typified by the impaired production of type I and type III interferons (IFNs). The failure to control viral burden probably causes damage to the lung architecture and contributes to an aberrant immune response, which together compromise lung function. Although a relatively rare cell type, the plasmacytoid dendritic cell dedicates much of its transcriptome to the synthesis of IFNs and is pre-armed with virus-sensing pattern recognition receptors. Thus, plasmacytoid dendritic cells are specialised to ensure early viral detection and the rapid induction of the antiviral state to block viral replication and spread. In addition, plasmacytoid dendritic cells can limit immunopathology, and promote peripheral tolerance to prevent allergic sensitisation to harmless antigens, possibly through the induction of regulatory T-cells. Thus, this enigmatic cell may lie at an important intersection, orchestrating the immediate phase of antiviral immunity to effect viral clearance while regulating tolerance. Here, we review the evidence to support the hypothesis that a primary defect in plasmacytoid dendritic function may underlie the development of asthma.