tbuckley/cabot-search huggingface dataset:
Molecular Clocks Do Not Support the Cambrian Explosion
Authors: Jaime E. Blair, S. Blair Hedges
Journal: Molecular Biology and Evolution (2004)

The fossil record has long supported the view that most animal phyla originated during a brief period approximately 520 MYA known as the Cambrian explosion. However, molecular data analyses over the past 3 decades have found deeper divergences among animals (∼800 to 1,200 MYA), with and without the assumption of a global molecular clock. Recently, two studies have instead reported time estimates apparently consistent with the fossil record. Here, we demonstrate that methodological problems in these studies cast doubt on the accuracy and interpretations of the results obtained. In the study by Peterson et al., young time estimates were obtained because fossil calibrations were used as maximum limits rather than as minimum limits, and not because invertebrate calibrations were used. In the study by Aris-Brosou and Yang, young time estimates were obtained because of problems with rate models and other methods specific to the study, and not because Bayesian methods were used. This also led to many anomalous findings in their study, including a primate-rodent divergence at 320 MYA. With these results aside, molecular clocks continue to support a long period of animal evolution before the Cambrian explosion of fossils.
Combined Treatment with Mycophenolate Mofetil and an Angiotensin II Receptor Antagonist Fully Protects from Chronic Rejection in a Rat Model of Renal Allograft
Authors: MARINA NORIS, NADIA AZZOLLINI, ANGELA PEZZOTTA, MARILENA MISTER, ARIELA BENIGNI, GIANFRANCO MARCHETTI, ELENA GAGLIARDINI, NORBERTO PERICO, GIUSEPPE REMUZZI
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Antigen-dependent and antigen-independent factors have been implicated in the pathophysiology of chronic allograft rejection, but their relative role is not well established. In the Fisher 344→Lewis rat kidney transplant model, we sought (1) to compare the relative efficacy of the novel immunosuppressant, mycophenolate mofetil (MMF), with that of the AT1 receptor blocker, losartan, in preventing the development of chronic graft rejection when given for 52 wk; (2) to examine whether combining MMF with losartan affords better protection than each of the drugs alone. For comparison, the effect of cyclosporine (CsA) to control chronic graft rejection was also assessed. Administration of MMF alone or losartan alone to the kidney allografted rats resulted in a partial decrease in the amount of proteinuria, preservation of glomerular and tubulo-interstitial graft structure, limitation of intragraft cell infiltration, and improvement of graft survival compared with corresponding parameters in untreated, transplanted control rats. Combined treatment with MMF and losartan completely prevented the development of proteinuria, largely reduced glomerular and tubulointerstitial injury, and suppressed intragraft cell infiltration, and all animals survived at the end of the follow-up. Similarly, CsA treatment largely prevented graft injury but failed to achieve 100% animal survival. We have shown that MMF synergizes with the angiotensin II receptor antagonist, losartan, in simultaneously targeting complementary pathways of chronic allograft rejection. Combining MMF and angiotensin II receptor blocker offers superior long-term renoprotection as compared with CsA. Together, these findings provide the basis to prevent chronic injury and progressive dysfunction after renal transplantation.
Bioavailability of aminolaevulinic acid and methylaminolaevulinate in basal cell carcinomas: a perfusion study using microdialysis<i>in vivo</i>
Authors: C. Sandberg, C.B. Halldin, M.B. Ericson, O. Larkö, A.-L. Krogstad, A.-M. Wennberg
Journal: British Journal of Dermatology (2008)

Photodynamic therapy is becoming a popular treatment for superficial nonmelanoma precancerous and cancerous lesions, showing excellent cosmetic results. Nevertheless, the reported cure rates vary and the transdermal penetration of drugs has been discussed as a limiting factor, particularly for treatment of nodular basal cell carcinoma (BCC).To investigate the transdermal penetration of aminolaevulinic acid (ALA) and methylaminolaevulinate (MAL) in BCC in vivo using a microdialysis technique. The different prodrugs were compared and the effect of curettage was studied.Twenty patients with 27 histologically verified BCCs (13 superficial, 14 nodular) were included. All lesions were located at the front of the body (head and face excluded). The first 10 patients included were treated with MAL (13 BCCs), and the following 10 patients with ALA (14 BCCs). A light curettage was performed on every second lesion (curettage, n = 13; noncurettage, n = 14). Microdialysis catheters were inserted into the tumours at tissue depths varying from 0.4 to 1.9 mm. Dialysates were collected at 15-30-min intervals for 4 h and the interstitial concentrations of MAL and ALA were determined using high-performance liquid chromatography.No significant difference in interstitial drug concentration was observed between lesions treated with ALA or MAL during the 4-h measurement period. However, for the lesions with deeper catheter locations, i.e. at or below 1 mm (n = 11), drug concentrations above the detection limit were obtained in only six lesions. All but one BCC with superficial catheter location, i.e. < 1 mm (n = 16), exhibited detectable drug concentration (P = 0.026). The interstitial peak concentrations were reached within 90 min in 23 of the 27 BCCs, but were not found to be correlated with the depth of the catheters. No difference was found when comparing superficial and nodular BCCs, and the effect of curettage was found to be negligible.The results imply that there is no significant difference in transdermal penetration of ALA and MAL in tumour tissue. Detectable levels of drug were not obtained in almost 50% of the lesions where catheters were situated 1-1.9 mm in the lesion. Curettage was not found to affect the interstitial concentration, indicating that penetration of drug indeed might be a problem when treating BCCs thicker than 1 mm.
Population Pharmacokinetics of Busulfan in Children: Increased Evidence for Body Surface Area and Allometric Body Weight Dosing of Busulfan in Children
Authors: Mirjam N. Trame, Martin Bergstrand, Mats O. Karlsson, Joachim Boos, Georg Hempel
Journal: Clinical Cancer Research (2011)

To evaluate the best method for dosing busulfan in children, we retrospectively analyzed two different data sets from three different dosing regimens by means of population pharmacokinetics using NONMEM.The development data set consisted of plasma samples from 94 children, in the age range of 0.4 to 18.8 years, receiving either oral or intravenous busulfan. The external model evaluation data set comprised 24 children, in the age range of 0.1 to 18.9 years, who belonged to the once-daily intravenous busulfan dosing regimen. A one-compartment model with first-order absorption using body surface area (BSA) or allometric body weight (BW) as covariate on clearance (CL) and BW as covariate on volume of distribution (V) were used to describe the results sufficiently. In addition to interindividual variability on all pharmacokinetic parameters, interoccasion variability was included for CL and V.CL values in the present study did not reflect the shape of the CL versus weight curve reported in previous investigations. By external model evaluation, we were able to confirm these findings. Furthermore, bioavailability was calculated to be between 93% and 99% for the development data set. On the basis of the final models, we simulated two dosing schemes according to allometric BW and BSA showing that we estimated to include about 30% more patients into the proposed therapeutic area under the curve (AUC) range of 900 to 1,500 μM*min and could, furthermore, achieve a reduction in the AUC variability when dosed according to the labeled European Medicines Agency (EMA) dosing recommendation.We recommend a BSA or an allometric BW dosing regimen for individualizing busulfan therapy in children to reduce variability in busulfan exposure and to improve safety and efficacy of busulfan treatment.
MACOP-B treatment in diffuse large-cell lymphoma: identification of prognostic groups in an Italian multicenter study.
Authors: U Vitolo, M Bertini, E Brusamolino, G B Cavallero, B Comotti, E Gallo, R Ghio, A Levis, G Luxi, V Meneghini
Journal: Journal of Clinical Oncology (1992)

The prognosis of advanced-stage diffuse large-cell lymphoma (DLCL) has improved with the use of the third-generation regimens such as methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B). However, different results have been reported. Therefore, we started a cooperative study to confirm the efficacy of MACOP-B. An analysis of prognostic factors was also performed to identify poor-prognosis patients.Between June 1986 and March 1989, 180 patients with advanced-stage DLCL were treated with MACOP-B. MACOP-B was given according to the original scheme. Numerous clinical features possibly predictive for complete response (CR), disease-free survival (DFS), and survival were analyzed in univariate and multivariate analyses.One hundred twenty-seven patients (71%) achieved a complete remission, 20 (11%) achieved a partial remission, 24 (13%) had unchanged or progressive disease, and nine (5%) died due to toxicity. With a median follow-up of 28 months, 71% of 127 CRs remain in first remission. Predicted 3-year survival for all 180 patients is 60%, and 3-year DFS for the 127 CRs is 67%. Overall toxicity was acceptable, with mucositis being the most frequent severe side effect. A multivariate regression analysis identified lactate dehydrogenase (LDH) level, bone marrow involvement, and tumor burden as independent risk factors for survival. These factors were also important for achievement of remission and DFS and allowed us to identify three distinct risk groups of patients with good, intermediate, and poor prognosis, with 3-year survival rates of 80%, 59%, and %29, respectively.These results confirm the effectiveness of MACOP-B in advanced-stage DLCL at low or intermediate risk; however, high-risk patients are in urgent need of new therapeutic approaches. A better definition of prognostic features would allow a more reliable comparison of different treatment regimens, as well as an effective tailoring of therapy by prognostic groups.
CD34 Is Required for Dendritic Cell Trafficking and Pathology in Murine Hypersensitivity Pneumonitis
Authors: Marie-Renée Blanchet, Jami L. Bennett, Matthew J. Gold, Elena Levantini, Daniel G. Tenen, Melissa Girard, Yvon Cormier, Kelly M. McNagny
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Although recent work has shown that CD34 plays an important role in the trafficking of inflammatory cells during Th2-biased inflammatory responses, its role in Th1/Th17-biased disease as well as dendritic cell (DC) trafficking is unknown.We used CD34-deficient mice (Cd34(-/-)) to investigate the role of CD34 in the Th1/Th17-biased lung inflammatory disease, hypersensitivity pneumonitis (HP).HP was induced in wild-type (wt) and Cd34(-/-) mice by repeated intranasal administration of Saccharopolyspora rectivirgula antigen. Lung inflammation was assessed by histology and analysis of bronchoalveolar lavage cells. Primary and secondary immune responses were evaluated by cytokine recall responses of pulmonary inflammatory cells as well as draining lymph node cells.Cd34(-/-) mice were highly resistant to the development of HP and exhibited an inflammatory pattern more reflective of a primary response to S. rectivirgula rather than the chronic lymphocytosis that is typical of this disease. Cytokine recall responses from Cd34(-/-) lymph node cells were dampened and consistent with a failure of antigen-loaded Cd34(-/-) DCs to deliver antigen and prime T cells in the draining lymph nodes. In agreement with this interpretation, adoptive transfer of wt DCs into Cd34(-/-) mice was sufficient to restore normal sensitivity to HP. CD34 was found to be expressed by wt DCs, and Cd34(-/-) DCs exhibited an impaired ability to chemotax toward a subset of chemokines in vitro. Finally, expression of human CD34 in Cd34(-/-) mice restored normal susceptibility to HP.We conclude that CD34 is expressed by mucosal DCs and plays an important role in their trafficking through the lung and to the lymph nodes. Our data also suggest that CD34 may play a selective role in the efficient migration of these cells to a subset of chemokines.
Neglected evidence in idiopathic pulmonary fibrosis: from history to earlier diagnosis
Authors: Jean-François Cordier, Vincent Cottin
Journal: European Respiratory Journal (2013)

This perspective highlights some evidence that has hitherto been neglected, especially because it may not have been sufficiently explicated in the clinical respiratory medicine literature. Idiopathic pulmonary fibrosis (IPF) has appeared only in the second half of the 20th century and, like lung cancer and chronic obstructive pulmonary disease, may be a direct consequence of the cigarette smoking epidemic. It is a disease of lung ageing, with most affected patients being >70 years of age. The relationship between lung ageing and pulmonary fibrosis is further illustrated in the bleomycin mouse model, in which older males develop more fibrosis than young female mice. Earlier diagnosis of IPF is a prerequisite for significant progress to be made in the long-term outcome and prognosis. We consider that only two different yet complementary and realistic approaches could lead to earlier diagnosis of IPF and possibly to allowing more efficient disease management: 1) investigating any patients with early Velcro crackles at lung auscultation through proactive education of, and commitment from, primary care physicians; and 2) using current large-scale lung cancer screening strategies with low-dose high-resolution computed tomography in smokers for the detection of subclinical interstitial lung disease and especially early IPF.
HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth
Authors: Markus A. Queisser, Laura A. Dada, Nimrod Deiss-Yehiely, Martin Angulo, Guofei Zhou, Fotini M. Kouri, Lawrence M. Knab, Jing Liu, Alexander H. Stegh, Malcolm M. DeCamp, G. R. Scott Budinger, Navdeep S. Chandel, Aaron Ciechanover, Kazuhiro Iwai, Jacob I. Sznajder
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Protein kinase C zeta (PKCζ) has been reported to act as a tumor suppressor. Deletion of PKCζ in experimental cancer models has been shown to increase tumor growth. However, the mechanisms of PKCζ down-regulation in cancerous cells have not been previously described.To determine the molecular mechanisms that lead to decreased PKCζ expression and thus increased survival in cancer cells and tumor growth.The levels of expression of heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), HOIL-1-interacting protein (HOIP), Shank-associated RH domain-interacting protein (SHARPIN), and PKCζ were analyzed by Western blot and/or quantitative real-time polymerase chain reaction in different cell lines. Coimmunoprecipitation experiments were used to demonstrate the interaction between HOIL-1L and PKCζ. Ubiquitination was measured in an in vitro ubiquitination assay and by Western blot with specific antibodies. The role of hypoxia-inducible factor (HIF) was determined by gain/loss-of-function experiments. The effect of HOIL-1L expression on cell death was investigated using RNA interference approaches in vitro and on tumor growth in mice models. Increased HOIL-1L and decreased PKCζ expression was assessed in lung adenocarcinoma and glioblastoma multiforme and documented in several other cancer types by oncogenomic analysis.Hypoxia is a hallmark of rapidly growing solid tumors. We found that during hypoxia, PKCζ is ubiquitinated and degraded via the ubiquitin ligase HOIL-1L, a component of the linear ubiquitin chain assembly complex (LUBAC). In vitro ubiquitination assays indicate that HOIL-1L ubiquitinates PKCζ at Lys-48, targeting it for proteasomal degradation. In a xenograft tumor model and lung cancer model, we found that silencing of HOIL-1L increased the abundance of PKCζ and decreased the size of tumors, suggesting that lower levels of HOIL-1L promote survival. Indeed, mRNA transcript levels of HOIL-1L were elevated in tumor of patients with lung adenocarcinoma, and in a lung adenocarcinoma tissue microarray the levels of HOIL-1L were associated with high-grade tumors. Moreover, we found that HOIL-1L expression was regulated by HIFs. Interestingly, the actions of HOIL-1L were independent of LUBAC.These data provide first evidence of a mechanism of cancer cell adaptation to hypoxia where HIFs regulate HOIL-1L, which targets PKCζ for degradation to promote tumor survival. We provided a proof of concept that silencing of HOIL-1L impairs lung tumor growth and that HOIL-1L expression predicts survival rate in cancer patients suggesting that HOIL-1L is an attractive target for cancer therapy.
Effects of recurrent violence on post-traumatic stress disorder and severe distress in conflict-affected Timor-Leste: a 6-year longitudinal study
Authors: Derrick Silove, Belinda Liddell, Susan Rees, Tien Chey, Angela Nickerson, Natalino Tam, Anthony B Zwi, Robert Brooks, Lazaro Lelan Sila, Zachary Steel
Journal: The Lancet Global Health (2014)

Little is known about the effect of recurrent episodes of communal violence on mental health in countries recovering from mass conflict. We report results of a 6-year longitudinal study in post-conflict Timor-Leste assessing changes in mental health after a period of communal violence.We assessed 1022 adults (600 from a rural village, 422 from an urban district) exposed to mass conflict during the Indonesian occupation after independence in 2004, and again in 2010-11, following a period of internal conflict. We took a census of all adults living at the two sites. The survey included measures of post-traumatic stress disorder, severe distress, traumatic events, poverty, ongoing conflict, and injustice.1247 (80%) of 1554 invited adults participated in the baseline survey. 1038 (89% of those eligible) were followed up. The analysis included 1022 people who had sufficient data at baseline and follow-up. The prevalence of post-traumatic stress disorder increased from 23 of 1022 (2.3%) in 2004, to 171 of 1022 (16.7%) in 2010. The prevalence of severe distress also increased, from 57 of 1022 (5.6%) in 2004, to 162 of 1022 (15.9%) in 2010. Both these outcomes were associated with disability at follow-up. Having post-traumatic stress at follow-up was associated with being a woman (odds ratio [OR] 1.63, 95% CI 1.14-2.32), experience of human rights trauma (OR 1.25, 95% CI 1.07-1.47), or exposure to murder (OR 1.71, 95% CI 1.38-2.10) during the Indonesian occupation (1975-99), human rights trauma during the period of internal violence in 2006-07 (OR 1.46, 95% CI 1.04-2.03), and ongoing family or community conflict (OR 1.80, 95% CI 1.15-2.80) or preoccupations with injustice for two or three historical periods (OR 4.06, 2.63-6.28). Severe distress at follow-up was associated with health stress (OR 1.47, 1.14-1.90), exposure to murder (OR 1.57, 1.27-1.95), and natural disaster (OR 1.65, 1.03-2.64) during the Indonesian occupation, conflict-related trauma during the internal violence (OR 1.33, 1.02-1.74), and ongoing poverty (OR 1.53, 1.36-1.72) or preoccupations with injustice for two or three historical periods (OR 2.09, 1.25-3.50).Recurrent violence resulted in a major increase in post-traumatic stress disorder and severe distress in a community previously exposed to mass conflict. Poverty, ongoing community tensions, and persisting feelings of injustice contributed to mental disorders. The findings underscore the importance of preventing recurrent violence, alleviating poverty, and addressing injustices in countries emerging from conflict.Australian National Health and Medical Research Council.
Two Patterns of Adipokine and Other Biomarker Dynamics in a Long-Term Weight Loss Intervention
Authors: Matthias Blüher, Assaf Rudich, Nora Klöting, Rachel Golan, Yaakov Henkin, Eitan Rubin, Dan Schwarzfuchs, Yftach Gepner, Meir J. Stampfer, Martin Fiedler, Joachim Thiery, Michael Stumvoll, Iris Shai
Journal: Diabetes Care (2011)

Long-term dietary intervention frequently induces a rapid weight decline followed by weight stabilization/regain. Here, we sought to identify adipokine biomarkers that may reflect continued beneficial effects of dieting despite partial weight regain.We analyzed the dynamics of fasting serum levels of 12 traditional metabolic biomarkers and novel adipokines among 322 participants in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, Mediterranean, or low-carbohydrate diets for weight loss.We identified two distinct patterns: Pattern A includes biomarkers (insulin, triglycerides, leptin, chemerin, monocyte chemoattractant protein 1, and retinol-binding protein 4) whose dynamics tightly correspond to changes in body weight, with the trend during the weight loss phase (months 0-6) going in the opposite direction to that in the weight maintenance/regain phase (months 7-24) (P < 0.05 between phases, all biomarkers). Pattern B includes biomarkers (high molecular weight adiponectin, HDL cholesterol [HDL-C], high-sensitivity C-reactive protein [hsCRP], fetuin-A, progranulin, and vaspin) that displayed a continued, cumulative improvement (P < 0.05 compared with baseline, all biomarkers) throughout the intervention. These patterns were consistent across sex, diabetic groups, and diet groups, although the magnitude of change varied. Hierarchical analysis suggested similar clusters, revealing that the dynamic of leptin (pattern A) was most closely linked to weight change and that the dynamic of hsCRP best typified pattern B.hsCRP, HDL-C, adiponectin, fetuin-A, progranulin, and vaspin levels display a continued long-term improvement despite partial weight regain. This may likely reflect either a delayed effect of the initial weight loss or a continuous beneficial response to switching to healthier dietary patterns.