bluuebunny/crossref_metadata_2025 huggingface dataset:
A one-year prospective, randomized, placebo-controlled, quadruple-blinded, phase II safety pilot trial of combination therapy with interferon beta-1a and mycophenolate mofetil in early relapsing—remitting multiple sclerosis (TIME MS)
Authors: Remington Gina M. , Treadaway Katherine , Frohman Teresa , Salter Amber , Stüve Olaf , Racke Michael K. , Hawker Kathleen , Agosta Federica , Sormani Maria Pia , Filippi Massimo , Frohman Elliot M.
Published: January 2010

Background: Mycophenolate mofetil (MMF) is an oral DNA base synthesis inhibitor with immunomodulatory effects on B cells, T cells, and macrophages.

Objective: To conduct a safety and tolerability pilot study of interferon beta-1a (IFN-b1a) in combination with either placebo or oral MMF in multiple sclerosis (MS).

Methods: Twenty-four treatment-naïve R—RMS patients participated in a one-year prospective, placebo-controlled, blinded, safety pilot clinical trial. Every patient injected weekly intramuscular interferon beta-1a. The cohort was then randomized (1 : 1) to either active oral MMF or identical-appearing placebo tablets. Clinical evaluations were assessed every 3 months, along with brain MRI scans performed at baseline and repeated every 60 days for one year. Comprehensive laboratory assessments were monitored for safety, along with adverse events.

Results: In this small pilot investigation, no differences were identified between the two treatment groups with respect to patient-reported adverse events, MRI metrics, or laboratory abnormalities. Notwithstanding these observations, and the limited number of patients treated, trends appeared to favor the combination therapy regimen.

Conclusions: The combination treatment regimen of interferon beta-1a and MMF appeared to be well tolerated in this pilot study. Despite the small sample size, therapeutic trends were observed in favor of combination therapy. An adequately powered controlled trial of MMF in MS appears warranted.
Standing variation and new mutations both contribute to a fast response to selection for flowering time in maize inbreds
Authors: Durand Eléonore , Tenaillon Maud I , Ridel Céline , Coubriche Denis , Jamin Philippe , Jouanne Sophie , Ressayre Adrienne , Charcosset Alain , Dillmann Christine
Published: January 2010

Background

In order to investigate the rate and limits of the response to selection from highly inbred genetic material and evaluate the respective contribution of standing variation and new mutations, we conducted a divergent selection experiment from maize inbred lines in open-field conditions during 7 years. Two maize commercial seed lots considered as inbred lines,F252 andMBS847, constituted two biological replicates of the experiment. In each replicate, we derived an Early and a Late population by selecting and selfing the earliest and the latest individuals, respectively, to produce the next generation.

Results

All populations, except the EarlyMBS847, responded to selection despite a short number of generations and a small effective population size. Part of the response can be attributed to standing genetic variation in the initial seed lot. Indeed, we identified one polymorphism initially segregating in theF252 seed lot at a candidate locus for flowering time, which explained 35% of the trait variation within the LateF252 population. However, the model that best explained our data takes into account both residual polymorphism in the initial seed lots and a constant input of heritable genetic variation by new (epi)mutations. Under this model, values of mutational heritability range from 0.013 to 0.025, and stand as an upper bound compare to what is reported in other species.

Conclusions

Our study reports a long-term divergent selection experiment for a complex trait, flowering time, conducted on maize in open-field conditions. Starting from a highly inbred material, we created within a few generations populations that strikingly differ from the initial seed lot for flowering time while preserving most of the phenotypic characteristics of the initial inbred. Such material is unique for studying the dynamics of the response to selection and its determinants. In addition to the fixation of a standing beneficial mutation associated with a large phenotypic effect, a constant input of genetic variance by new mutations has likely contributed to the response. We discuss our results in the context of the evolution and mutational dynamics of populations characterized by a small effective population size.
Molecular characterization of Legionella pneumophila-induced interleukin-8 expression in T cells
Authors: Takamatsu Reika , Teruya Hiromitsu , Takeshima Eriko , Ishikawa Chie , Matsumoto Kunihiro , Mukaida Naofumi , Li Jian-Dong , Heuner Klaus , Higa Futoshi , Fujita Jiro , Mori Naoki
Published: January 2010

Background

Legionella pneumophila is the causative agent of human Legionnaire's disease. During infection, the bacterium invades macrophages and lung epithelial cells, and replicates intracellularly. However, little is known about its interaction with T cells. We investigated the ability of L. pneumophila to infect and stimulate the production of interleukin-8 (IL-8) in T cells. The objective of this study was to assess whether L. pneumophila interferes with the immune system by interacting and infecting T cells.

Results

Wild-type L. pneumophila and flagellin-deficient Legionella, but not L. pneumophila lacking a functional type IV secretion system Dot/Icm, replicated in T cells. On the other hand, wild-type L. pneumophila and Dot/Icm-deficient Legionella, but not flagellin-deficient Legionella or heat-killed Legionella induced IL-8 expression. L. pneumophila activated an IL-8 promoter through the NF-κB and AP-1 binding regions. Wild-type L. pneumophila but not flagellin-deficient Legionella activated NF-κB, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase (JNK), and transforming growth factor β-associated kinase 1 (TAK1). Transfection of dominant negative mutants of IκBα, IκB kinase, NF-κB-inducing kinase, TAK1, MyD88, and p38 MAPK inhibited L. pneumophila-induced IL-8 activation. Inhibitors of NF-κB, p38 MAPK, and JNK blocked L. pneumophila-induced IL-8 expression. In addition, c-Jun, JunD, cyclic AMP response element binding protein, and activating transcription factor 1, which are substrates of p38 MAPK and JNK, bound to the AP-1 site of the IL-8 promoter.

Conclusions

Taken together, L. pneumophila induced a flagellin-dependent activation of TAK1, p38 MAPK, and JNK, as well as NF-κB and AP-1, which resulted in IL-8 production in human T cells, presumably contributing to the immune response in Legionnaire's disease.
Corynebacterium diphtheriae invasion-associated protein (DIP1281) is involved in cell surface organization, adhesion and internalization in epithelial cells
Authors: Ott Lisa , Höller Martina , Gerlach Roman G , Hensel Michael , Rheinlaender Johannes , Schäffer Tilman E , Burkovski Andreas
Published: January 2010

Background

Corynebacterium diphtheriae, the causative agent of diphtheria, is well-investigated in respect to toxin production, while little is known about C. diphtheriae factors crucial for colonization of the host. In this study, we investigated the function of surface-associated protein DIP1281, previously annotated as hypothetical invasion-associated protein.

Results

Microscopic inspection of DIP1281 mutant strains revealed an increased size of the single cells in combination with an altered less club-like shape and formation of chains of cells rather than the typical V-like division forms or palisades of growing C. diphtheriae cells. Cell viability was not impaired. Immuno-fluorescence microscopy, SDS-PAGE and 2-D PAGE of surface proteins revealed clear differences of wild-type and mutant protein patterns, which were verified by atomic force microscopy. DIP1281 mutant cells were not only altered in shape and surface structure but completely lack the ability to adhere to host cells and consequently invade these.

Conclusions

Our data indicate that DIP1281 is predominantly involved in the organization of the outer surface protein layer rather than in the separation of the peptidoglycan cell wall of dividing bacteria. The adhesion- and invasion-negative phenotype of corresponding mutant strains is an effect of rearrangements of the outer surface.
Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease
Authors: Vernon Anthony C , Johansson Saga M , Modo Michel M
Published: January 2010

Background

Predominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T2 water 1H relaxation or 1H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan in vivo brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin.

Results

Lactacystin induced parkinsonian-like behaviour, characterised by impaired contralateral forelimb grip strength and increased contralateral circling in response to apomorphine. T2-weighted MRI, 3-weeks post-lesion, revealed significant morphological changes in PD-relevant brain areas, including the striatum and ventral midbrain in addition to a decrease in T2 water 1H relaxation in the substantia nigra (SN), but not the striatum. Post-mortem histological analyses revealed extensive dopaminergic neuronal degeneration and α-synuclein aggregation in the SN. However, extensive neuronal loss could also be observed in extra-nigral areas, suggesting non-specific toxicity of lactacystin. Iron accumulation could also be observed throughout the midbrain reflecting changes in T2. Importantly, morphological, but not T2 relaxivity changes, were significantly associated with both behavioural and histological outcomes in this model.

Conclusions

A pattern of morphological changes in lactacystin-lesioned animals has been identified, as well as alterations in nigral T2 relaxivity. The significant relationship of morphological changes with behavioural and histological outcomes in this model raises the possibility that these may be useful non-invasive surrogate markers of nigrostriatal degeneration in vivo.
The Plasmodium falciparum merozoite surface protein-1 19 KD antibody response in the Peruvian Amazon predominantly targets the non-allele specific, shared sites of this antigen
Authors: Sutton Patrick L , Clark Eva H , Silva Claudia , Branch OraLee H
Published: January 2010

Background

Plasmodium falciparum re-emerged in Iquitos, Peru in 1994 and is now hypoendemic (< 0.5 infections/person/year). Purportedly non-immune individuals with discrete (non-overlapping) P. falciparum infections can be followed using this population dynamic. Previous work demonstrated a strong association between this population's antibody response to Pf MSP1-19KD and protection against febrile illness and parasitaemia. Therefore, some selection for Pf MSP1-19KD allelic diversity would be expected if the protection is to allele-specific sites of Pf MSP1-19KD. Here, the potential for allele-specific polymorphisms in this population is investigated, and the allele-specificity of antibody responses to Pf MSP1-19KD are determined.

Methods

The 42KD region in Pf MSP1 was genotyped from 160 individual infections collected between 2003 and 2007. Additionally, the polymorphic block 2 region of Pfmsp1 (Pfmsp1-B2) was genotyped in 781 infection-months to provide a baseline for population-level diversity. To test whether Pf MSP1-19KD genetic diversity had any impact on antibody responses, ELISAs testing IgG antibody response were performed on individuals using all four allele-types of Pf MSP1-19KD. An antibody depletion ELISA was used to test the ability of antibodies to cross-react between allele-types.

Results

Despite increased diversity in Pfmsp1-B2, limited diversity within Pfmsp1-42KD was observed. All 160 infections genotyped were Mad20-like at the Pfmsp1-33KD locus. In the Pfmsp1-19KD locus, 159 (99.4%) were the Q-KSNG-F haplotype and 1 (0.6%) was the E-KSNG-L haplotype. Antibody responses in 105 individuals showed that Q-KNG and Q-TSR alleles generated the strongest immune responses, while Q-KNG and E-KNG responses were more concordant with each other than with those from Q-TSR and E-TSR, and vice versa. The immuno-depletion ELISAs showed all samples responded to the antigenic sites shared amongst all allelic forms of Pf MSP1-19KD.

Conclusions

A non-allele specific antibody response in Pf MSP1-19KD may explain why other allelic forms have not been maintained or evolved in this population. This has important implications for the use of Pf MSP1-19KD as a vaccine candidate. It is possible that Peruvians have increased antibody responses to the shared sites of Pf MSP1-19KD, either due to exposure/parasite characteristics or due to a human-genetic predisposition. Alternatively, these allelic polymorphisms are not immune-specific even in other geographic regions, implying these polymorphisms may be less important in immune evasion that previous studies suggest.
Epstein-Barr virus-encoded EBNA1 inhibits the canonical NF-κB pathway in carcinoma cells by inhibiting IKK phosphorylation
Authors: Valentine Robert , Dawson Christopher W , Hu Chunfang , Shah Khilan M , Owen Thomas J , Date Kathryn L , Maia Sonia P , Shao Jianyong , Arrand John R , Young Lawrence S , O'Neil John D
Published: January 2010

Background

The Epstein-Barr virus (EBV)-encoded EBNA1 protein is expressed in all EBV-associated tumours, including undifferentiated nasopharyngeal carcinoma (NPC), where it is indispensable for viral replication, genome maintenance and viral gene expression. EBNA1's transcription factor-like functions also extend to influencing the expression of cellular genes involved in pathways commonly dysregulated during oncogenesis, including elevation of AP-1 activity in NPC cell lines resulting in enhancement of angiogenesis in vitro. In this study we sought to extend these observations by examining the role of EBNA1 upon another pathway commonly deregulated during carcinogenesis; namely NF-κB.

Results

In this report we demonstrate that EBNA1 inhibits the canonical NF-κB pathway in carcinoma lines by inhibiting the phosphorylation of IKKα/β. In agreement with this observation we find a reduction in the phosphorylation of IκBα and reduced phosphorylation and nuclear translocation of p65, resulting in a reduction in the amount of p65 in nuclear NF-κB complexes. Similar effects were also found in carcinoma lines infected with recombinant EBV and in the EBV-positive NPC-derived cell line C666-1. Inhibition of NF-κB was dependent upon regions of EBNA1 essential for gene transactivation whilst the interaction with the deubiquitinating enzyme, USP7, was entirely dispensable. Furthermore, in agreement with EBNA1 inhibiting p65 NF-κB we demonstrate that p65 was exclusively cytoplasmic in 11 out of 11 NPC tumours studied.

Conclusions

Inhibition of p65 NF-κB in murine and human epidermis results in tissue hyperplasia and the development of squamous cell carcinoma. In line with this, p65 knockout fibroblasts have a transformed phenotype. Inhibition of p65 NF-κB by EBNA1 may therefore contribute to the development of NPC by inducing tissue hyperplasia. Furthermore, inhibition of NF-κB is employed by viruses as an immune evasion strategy which is also closely linked to oncogenesis during persistent viral infection. Our findings therefore further implicate EBNA1 in playing an important role in the pathogenesis of NPC.
Placental thrombomodulin expression in recurrent miscarriage
Authors: Stortoni Piergiorgio , Cecati Monia , Giannubilo Stefano R , Sartini Davide , Turi Angelo , Emanuelli Monica , Tranquilli Andrea L
Published: January 2010

Background

Early pregnancy loss can be associated with trophoblast insufficiency and coagulation defects. Thrombomodulin is an endothelial-associated anticoagulant protein involved in the control of hemostasis and inflammation at the vascular beds and it's also a cofactor of the protein C anticoagulant pathway.

Discussion

We evaluate the Thrombomodulin expression in placental tissue from spontaneous recurrent miscarriage and voluntary abortion as controls. Thrombomodulin mRNA was determined using real-time quantitative polymerase chain reaction. Reduced expression levels of thrombomodulin were found in recurrent miscarriage group compared to controls (1.82-fold of reduction), that corresponds to a reduction of 45% (from control group Delta CT) of thrombomodulin expression in spontaneous miscarriage group respect the control groups.

We cannot state at present the exact meaning of a reduced expression of Thrombomodulin in placental tissue. Further studies are needed to elucidate the biological pathway of this important factor in the physiopathology of the trophoblast and in reproductive biology.
Fast prediction of RNA-RNA interaction
Authors: Salari Raheleh , Backofen Rolf , Sahinalp S Cenk
Published: January 2010

Background

Regulatory antisense RNAs are a class of ncRNAs that regulate gene expression by prohibiting the translation of an mRNA by establishing stable interactions with a target sequence. There is great demand for efficient computational methods to predict the specific interaction between an ncRNA and its target mRNA(s). There are a number of algorithms in the literature which can predict a variety of such interactions - unfortunately at a very high computational cost. Although some existing target prediction approaches are much faster, they are specialized for interactions with a single binding site.

Methods

In this paper we present a novel algorithm to accurately predict the minimum free energy structure of RNA-RNA interaction under the most general type of interactions studied in the literature. Moreover, we introduce a fast heuristic method to predict the specific (multiple) binding sites of two interacting RNAs.

Results

We verify the performance of our algorithms for joint structure and binding site prediction on a set of known interacting RNA pairs. Experimental results show our algorithms are highly accurate and outperform all competitive approaches.
The F-box protein Cdc4/Fbxw7 is a novel regulator of neural crest development in Xenopus laevis
Authors: Almeida Alexandra D , Wise Helen M , Hindley Christopher J , Slevin Michael K , Hartley Rebecca S , Philpott Anna
Published: January 2010

Background

The neural crest is a unique population of cells that arise in the vertebrate ectoderm at the neural plate border after which they migrate extensively throughout the embryo, giving rise to a wide range of derivatives. A number of proteins involved in neural crest development have dynamic expression patterns, and it is becoming clear that ubiquitin-mediated protein degradation is partly responsible for this.

Results

Here we demonstrate a novel role for the F-box protein Cdc4/Fbxw7 in neural crest development. Two isoforms of Xenopus laevis Cdc4 were identified, and designated xCdc4α and xCdc4β. These are highly conserved with vertebrate Cdc4 orthologs, and the Xenopus proteins are functionally equivalent in terms of their ability to degrade Cyclin E, an established vertebrate Cdc4 target. Blocking xCdc4 function specifically inhibited neural crest development at an early stage, prior to expression of c-Myc, Snail2 and Snail.

Conclusions

We demonstrate that Cdc4, an ubiquitin E3 ligase subunit previously identified as targeting primarily cell cycle regulators for proteolysis, has additional roles in control of formation of the neural crest. Hence, we identify Cdc4 as a protein with separable but complementary functions in control of cell proliferation and differentiation.
Evaluation of biodistribution and safety of adenovirus vector containing MDR1 in mice
Authors: Zhao ZhenZhen , Liu Wei , Su YuXi , Zhu Jin , Zheng GaiHuan , Luo Qing , Jin XianQing
Published: January 2010

Background

The aim of this study is to examine the safety and distribution of Ad-EGFP-MDR1, an adenovirus encoding human multidurg resistance gene (human MDR1), in the mice colon carcinoma model.

Methods

After bone marrow cells (BMCs) were infected with Ad-EGFP-MDR1, they were administered by intra bone marrow-bone marrow transplantation (IBM-BMT). Total adenovirus antibody and serum adenovirus neutralizing factor (SNF) were determined. Biodistribution of Ad-EGFP-MDR1 was detected by in situ hybridization and immunohistochemistry. The peripheral hematocyte white blood cell (WBC), haemoglobin (Hb), red blood cell (RBC) and platelet (Plt) counts were analyzed.

Results

Neither total adenovirus antibody nor SNF increased weeks after BMT. In situ hybridization and immunohistochemistry demonstrated concordant expression of human MDR1 and P-gp which were found in lung, intestine, kidney and BMCs after BMT, but not detected in liver, spleen, brain and tumor. No significant abnormality of the recovery hematocyte was observed on Day 30 after treatment.

Conclusion

The results indicate that IBM-BMT administration of a replication defective adenovirus is a feasible mode of delivery, allowing exogenous transference. The findings in this study are conducted for the future long-term studies of safety assessment of Ad-EGFP-MDR1.
Acute kidney injury in severe trauma assessed by RIFLE criteria: a common feature without implications on mortality?
Authors: Gomes Ernestina , Antunes Rui , Dias Cláudia , Araújo Rui , Costa-Pereira Altamiro
Published: January 2010

Background

Acute kidney injury (AKI) has been hard to assess due to the lack of standard definitions. Recently, the Risk, Injury, Failure, Loss and End-Stage Kidney (RIFLE) classification has been proposed to classify AKI in a number of clinical settings. This study aims to estimate the frequency and levels of severity of AKI and to study its association with patient mortality and length of stay (LOS) in a cohort of trauma patients needing intensive care.

Methods

Between August 2001 and September 2007, 436 trauma patients consecutively admitted to a general intensive care unit (ICU), were assessed using the RIFLE criteria. Demographic data, characteristics of injury, and severity of trauma variables were also collected.

Results

Half of all ICU trauma admissions had AKI, which corresponded to the group of patients with a significantly higher severity of trauma. Among patients with AKI, RIFLE class R (Risk) comprised 47%, while I (Injury) and F (Failure) were, 36% and 17%, respectively. None of these patients required renal replacement therapy. No significant differences were found among these three AKI classes in relation to patient's age, gender, type and mechanism of injury, severity of trauma or mortality. Nevertheless, increasing severity of acute renal injury was associated with a longer ICU stay.

Conclusions

AKI is a common feature among trauma patients requiring intensive care. Although the development of AKI is associated with an increased LOS it does not appear to influence patient mortality.
Does the scientific evidence support the recovery model?
Authors: Warner Richard
Published: January 2010

This editorial addresses the question of whether some of the basic tenets of the recovery model – optimism about outcome, the value of work, the importance of empowerment of patients and the utility of user-run programmes – are supported by the scientific research.
Choice in mental health: participation and recovery
Authors: Sugarman Philip , Ikkos George , Bailey Sue
Published: January 2010

The Royal College of Psychiatrists has established a Working Group on Choice in Mental Health and held a conference to include service users in formulating a challenging view of the choice agenda for mental health. This is set out here to stimulate wider interest. Choice-based practice develops in a climate of trust and information, and goes beyond simple variety or individual consumerism. For some service users, limited initial areas of choice can be of great importance, but a true culture of choice requires the widespread participation of service users and carers in service improvement. It is important that psychiatrists champion the empowerment of their patients through choice, in policy and training, and in clinical practice.
Bortezomib As Induction Before Autologous Transplantation, Followed by Lenalidomide As Consolidation-Maintenance in Untreated Multiple Myeloma Patients
Authors: Palumbo Antonio , Gay Francesca , Falco Patrizia , Crippa Claudia , Montefusco Vittorio , Patriarca Francesca , Rossini Fausto , Caltagirone Simona , Benevolo Giulia , Pescosta Norbert , Guglielmelli Tommasina , Bringhen Sara , Offidani Massimo , Giuliani Nicola , Petrucci Maria Teresa , Musto Pellegrino , Liberati Anna Marina , Rossi Giuseppe , Corradini Paolo , Boccadoro Mario
Published: January 2010

Purpose

To evaluate the effect of bortezomib as induction therapy before autologous transplantation, followed by lenalidomide as consolidation-maintenance in myeloma patients.

Patients and Methods

Newly diagnosed patients age 65 to 75 years were eligible. Induction (bortezomib, doxorubicin, and dexamethasone [PAD]) included four 21-day cycles of bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), pegylated liposomal doxorubicin (30 mg/m2 on day 4), and dexamethasone (40 mg/d; cycle 1: days 1 to 4, 8 to 11, and 15 to 18; cycles 2 to 4: days 1 to 4). Autologous transplantation was tandem melphalan 100 mg/m2 (MEL100) and stem-cell support. Consolidation included four 28-day cycles of lenalidomide (25 mg/d on days 1 to 21 every 28 days) plus prednisone (50 mg every other day), followed by maintenance with lenalidomide (LP-L; 10 mg/d on days 1 to 21) until relapse. Primary end points were safety (incidence of grade 3 to 4 adverse events [AEs]) and efficacy (response rate).

Results

A total of 102 patients were enrolled. In a per-protocol analysis, after PAD, 58% of patients had very good partial response (VGPR) or better, including 13% with complete response (CR); after MEL100, 82% of patients had at least VGPR and 38% had CR; and after LP-L, 86% of patients had at least VGPR and 66% had CR. After median follow-up time of 21 months, the 2-year progression-free survival rate was 69%, and the 2-year overall survival rate was 86%. During induction, treatment-related mortality was 3%; grade 3 to 4 AEs included thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%). During consolidation-maintenance, grade 3 to 4 AEs were neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%).

Conclusion

Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance, is an effective regimen.
Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G1 Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2
Authors: Spratlin Jennifer L. , Cohen Roger B. , Eadens Matthew , Gore Lia , Camidge D. Ross , Diab Sami , Leong Stephen , O'Bryant Cindy , Chow Laura Q.M. , Serkova Natalie J. , Meropol Neal J. , Lewis Nancy L. , Chiorean E. Gabriela , Fox Floyd , Youssoufian Hagop , Rowinsky Eric K. , Eckhardt S. Gail
Published: January 2010

Purpose

To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2.

Patients and Methods

Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed.

Results

Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients.

Conclusion

Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.
Transformation to Aggressive Lymphoma in Nodular Lymphocyte-Predominant Hodgkin's Lymphoma
Authors: Al-Mansour Mubarak , Connors Joseph M. , Gascoyne Randy D. , Skinnider Brian , Savage Kerry J.
Published: January 2010

Purpose

Prior observations suggest a higher risk of transformation of nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), than in classical Hodgkin's lymphoma. We evaluated the frequency of transformation in all patients diagnosed with NLPHL at the British Columbia Cancer Agency with long-term follow-up.

Patients and Methods

The Lymphoid Cancer Database of the British Columbia Cancer Agency was searched to identify all patients diagnosed with NLPHL between 1965 and 2006. After pathologic review, 95 patients with NLPHL were confirmed.

Results

Patients with NLPHL had the following characteristics at diagnosis: median age of 37 years, 73% male, and 68% stage I or II disease. With a median follow-up time for living patients of 6.5 years (range, 2.5 to 33 years), 13 patients (14%) experienced transformation to aggressive lymphoma (median time to transformation, 8.1 years; range, 0.35 to 20.3 years). The actuarial risk of transformation to aggressive lymphoma was 7% and 30% at 10 and 20 years, respectively. Transformation was more likely in patients with initial splenic involvement (P = .006) at the time of diagnosis of NLPHL. The 10-year progression-free and overall survival rates in patients with transformed lymphoma were 52% and 62%, respectively.

Conclusion

The risk of transformation in patients with NLPHL to DLBCL is substantial and underappreciated. Because transformation can occur years after the primary diagnosis of NLPHL, long-term follow-up of these individuals is necessary to accurately estimate the risk of development of secondary DLBCL.
Circulating Serum Free Light Chains As Predictive Markers of AIDS-Related Lymphoma
Authors: Landgren Ola , Goedert James J. , Rabkin Charles S. , Wilson Wyndham H. , Dunleavy Kieron , Kyle Robert A. , Katzmann Jerry A. , Rajkumar S. Vincent , Engels Eric A.
Published: January 2010

Purpose

HIV-infected persons have an elevated risk of developing non-Hodgkin's lymphoma (NHL); this risk remains increased in the era of effective HIV therapy. We evaluated serum immunoglobulin (Ig) proteins as predictors of NHL risk among HIV-infected individuals.

Patients and Methods

By using three cohorts of HIV-infected persons (from 1982 to 2005), we identified 66 individuals who developed NHL and 225 matched (by cohort, sex, ethnicity, age, and CD4 count), HIV-infected, lymphoma-free controls who had available stored prediagnostic blood samples. Serum/plasma samples obtained 0 to 2 years and 2 to 5 years before diagnosis/selection were assayed for IgG, IgM, and IgA levels; monoclonal (M) Igs; and κ and λ free light chain (FLC) levels. Patients and matched controls were compared by using conditional logistic regression.

Results

The κ and λ FLCs were both significantly higher in patients (eg, in 2- to 5-year window: median κ, 4.24 v 3.43 mg/dL; median λ, 4.04 v 3.09 mg/dL) and strongly predicted NHL in a dose-response manner up to 2 to 5 years before diagnosis/selection (eg, NHL risk 3.76-fold higher with κ concentration at least 2.00 times the upper limit of normal, and 8.13-fold higher with λ concentration at least 2.00 times the upper limit of normal compared with normal levels). In contrast, IgG, IgM, and IgA levels were similar in patients and controls. M proteins were detected in only two patients with NHL (3%) and in nine controls (4%), and they were not significantly associated with NHL risk.

Conclusion

Elevated FLCs may represent sensitive markers of polyclonal B-cell activation and dysfunction and could be useful for identifying HIV-infected persons at increased NHL risk.
Caspase-1 targets the TLR adaptor Mal at a crucial TIR-domain interaction site
Authors: Ulrichts Peter , Bovijn Celia , Lievens Sam , Beyaert Rudi , Tavernier Jan , Peelman Frank
Published: January 2010

Toll-like receptors (TLRs) are crucial components of innate immunity, ensuring efficient responses against invading pathogens. After ligand binding, TLR signaling is initiated by recruitment of adaptor molecules, a step mediated by homotypic Toll-IL-1 receptor (TIR) domain interactions. Four TIR-containing TLR adaptor molecules are described, all of which are susceptible to modification and strict regulation. For example, caspase-1 is reported to cleave the TLR adaptor Mal at position D198, an event that is indispensible for Mal function. In this report, we use the mammalian two-hybrid technique MAPPIT to study the implications of Mal cleavage. We show that a Mal mutant, which mimics caspase-1 cleavage and a caspase-1-uncleavable MalD198A mutant, are abrogated in their bridging function and lose the ability to activate NF-κB. A MalD198E mutant is still fully functional, suggesting that caspase-1 cleavage of Mal is not necessary for Mal-mediated signaling. D198 of Mal is conserved in MyD88 and TLR4 TIR domains and the negatively charged amino acid at this position is crucial for the interactions and function of Mal, MyD88 and TLR4 TIR. Our data suggest an inhibitory, rather than an activating role for caspase-1 in Mal regulation, and show that the caspase-1 cleavage site in Mal is part of a TIR-domain interaction site.
Canonical Notch signaling in the developing lung is required for determination of arterial smooth muscle cells and selection of Clara versus ciliated cell fate
Authors: Morimoto Mitsuru , Liu Zhenyi , Cheng Hui-Teng , Winters Niki , Bader David , Kopan Raphael
Published: January 2010

Lung development is the result of complex interactions between four tissues: epithelium, mesenchyme, mesothelium and endothelium. We marked the lineages experiencing Notch1 activation in these four cellular compartments during lung development and complemented this analysis by comparing the cell fate choices made in the absence of RBPjκ, the essential DNA binding partner of all Notch receptors. In the mesenchyme, RBPjκ was required for the recruitment and specification of arterial vascular smooth muscle cells (vSMC) and for regulating mesothelial epithelial-mesenchymal transition (EMT), but no adverse affects were observed in mice lacking mesenchymal RBPjκ. We provide indirect evidence that this is due to vSMC rescue by endothelial-mesenchymal transition (EnMT). In the epithelium, we show that Notch1 activation was most probably induced by Foxj1-expressing cells, which suggests that Notch1-mediated lateral inhibition regulates the selection of Clara cells at the expense of ciliated cells. Unexpectedly, and in contrast to Pofut1-null epithelium, Hes1 expression was only marginally reduced in RBPjκ-null epithelium, with a corresponding minimal effect on pulmonary neuroendocrine cell fate selection. Collectively, the primary roles for canonical Notch signaling in lung development are in selection of Clara cell fate and in vSMC recruitment. These analyses suggest that the impact of γ-secretase inhibitors on branching in vitro reflect a non-cell autonomous contribution from endothelial or vSMC-derived signals.
Golimumab: A Tumor Necrosis Factor Alpha Inhibitor for the Treatment of Rheumatoid Arthritis
Authors: McCluggage Lauren K , Scholtz Jean M
Published: January 2010

OBJECTIVE

To review the pharmacologic, pharmacokinetic, efficacy, and safety data of golimumab, an anti-tumor necrosis factor alpha (TNF-α) monoclonal antibody.

DATA SOURCES

A search of MEDLINE (1950-September 2009) was performed to identify any published clinical trials or review articles pertaining to golimumab. Key search terms included golimumab, rheumatoid arthritis, CNTO 148, and anti-TNF-α inhibitors. Bibliographies of selected articles were reviewed to identify other relevant citations. Abstracts from national and international meetings and information from the manufacturer were also reviewed.

STUDY SELECTION AND DATA EXTRACTION

All available published articles and abstracts describing golimumab's pharmacologic or pharmacokinetic profile, efficacy, and safety were included.

DATA SYNTHESIS

Golimumab is a fully humanized TNF-α monoclonal antibody that is specific for human TNF-α. Trials have investigated the use of golimumab in patients who have rheumatoid arthritis (RA) and are on methotrexate, are methotrexate-naïve, and have previously tried TNF-α inhibition therapy. When used in combination with methotrexate or another disease-modifying antirheumatic drug, golimumab therapy results in improvements of clinical outcomes including the American College of Rheumatology parameters in all of the aforementioned populations. Although multiple doses and dosing regimens have been studied, the Food and Drug Administration-approved dose is 50 mg subcutaneously every 4 weeks. The most common adverse effects include injection site erythema, headaches, and nausea. There were a limited number of incidences of serious infection or malignancy.

CONCLUSIONS

With 4 TNF-α monoclonal antibodies currently on the market, it is unclear what golimumab's place in therapy for RA will be. Some benefits include monthly injections, proven efficacy after previous TNF-α inhibitor therapy, and limited antibody development during therapy. However, with a lack of longer-term trials assessing efficacy and safety compared with other TNF-α inhibitors, golimumab should be reserved for use after other therapies fail.
Improvement of the cardiac marker N-terminal-pro brain natriuretic peptide through adjustment for renal function: a stratified multicenter trial
Authors: Luchner Andreas , Weidemann Alexander , Willenbrock Roland , Philipp Sebastian , Heinicke Norbert , Rambausek Matthias , Mehdorn Uta , Frankenberger Burkhard , Heid Iris M. , Eckardt Kai-Uwe , Holmer Stephan R.
Published: January 2010

Background: N-terminal-pro brain natriuretic peptide (NT-proBNP) is a useful cardiac marker that is also influenced by renal dysfunction. It was our objective to assess the relationship between NT-proBNP concentrations in plasma and worsening renal function, and to attempt adjustment of NT-proBNP for renal dysfunction in a prospective, stratified multi-center study.

Methods: We stratified 203 male patients according to their cardiac status and the estimated glomerular filtration rate (eGFR). Cardiac disease was assessed by medical history, physical examination and standardized echocardiography. Patients were stratified according to the following: absence of cardiac history and abnormalities (control, CTRL, n=66), cardiac history without left ventricular hypertrophy (LVH) or left ventricular systolic dysfunction (LVD) (history, n=30), LVH without systolic dysfunction (LVH, n=68), and LVD [ejection fraction (EF) <40%, LVD, n=39]. Renal disease was stratified according to the eGFR: 15–30 mL/min (n=52), 31–75 mL/min (n=99), and >75 mL/min (n=52).

Results: NT-proBNP was correlated with eGFR in the entire study population and for all levels of cardiac disease (all p<0.01). Regression analysis allowed adjustment of NT-proBNP for eGFR in a continuous manner, and this adjustment significantly improved the predictive value (receiver operating characteristic curve for symptomatic LVD from 0.80 to 0.86, p<0.01; sensitivity from 74% to 83% and specificity from 68% to 79%).

Conclusions: NT-proBNP correlates inversely and significantly with eGFR throughout all levels of cardiac strata. We propose for the first time a continuous adjustment algorithm which markedly improves the predictive values of NT-proBNP in male patients with impaired renal function.

Clin Chem Lab Med 2010;48:121–8.
Simple Y-Autosomal Incompatibilities Cause Hybrid Male Sterility in Reciprocal Crosses Between Drosophila virilis and D. americana
Authors: Sweigart Andrea L
Published: January 2010

Postzygotic reproductive isolation evolves when hybrid incompatibilities accumulate between diverging populations. Here, I examine the genetic basis of hybrid male sterility between two species of Drosophila, Drosophila virilis and D. americana. From these analyses, I reach several conclusions. First, neither species carries any autosomal dominant hybrid male sterility alleles: reciprocal F1 hybrid males are perfectly fertile. Second, later generation (backcross and F2) hybrid male sterility between D. virilis and D. americana is not polygenic. In fact, I identified only three genetically independent incompatibilities that cause hybrid male sterility. Remarkably, each of these incompatibilities involves the Y chromosome. In one direction of the cross, the D. americana Y is incompatible with recessive D. virilis alleles at loci on chromosomes 2 and 5. In the other direction, the D. virilis Y chromosome causes hybrid male sterility in combination with recessive D. americana alleles at a single QTL on chromosome 5. Finally, in contrast with findings from other Drosophila species pairs, the X chromosome has only a modest effect on hybrid male sterility between D. virilis and D. americana.
Bayesian Quantitative Trait Locus Mapping Using Inferred Haplotypes
Authors: Durrant Caroline , Mott Richard
Published: January 2010

We describe a fast hierarchical Bayesian method for mapping quantitative trait loci by haplotype-based association, applicable when haplotypes are not observed directly but are inferred from multiple marker genotypes. The method avoids the use of a Monte Carlo Markov chain by employing priors for which the likelihood factorizes completely. It is parameterized by a single hyperparameter, the fraction of variance explained by the quantitative trait locus, compared to the frequentist fixed-effects model, which requires a parameter for the phenotypic effect of each combination of haplotypes; nevertheless it still provides estimates of haplotype effects. We use simulation to show that the method matches the power of the frequentist regression model and, when the haplotypes are inferred, exceeds it for small QTL effect sizes. The Bayesian estimates of the haplotype effects are more accurate than the frequentist estimates, for both known and inferred haplotypes, which indicates that this advantage is independent of the effect of uncertainty in haplotype inference and will hold in comparison with frequentist methods in general. We apply the method to data from a panel of recombinant inbred lines of Arabidopsis thaliana, descended from 19 inbred founders.
?neñjasapp?ya-sutta and its Parallels on Imperturbability and the Contribution of Insight to the Development of Tranquillity
Authors: Anālayo Bhikkhu
Published: January 2010

The present article studies the meditative approaches to imperturbability depicted in the ?neñjasapp?ya-sutta and its Chinese and Tibetan parallels. By way of introduction to the main theme broached in this discourse, I briefly survey P?li discourses relevant to the early Buddhist notion of imperturbability. Next I examine the presentation given in the ?neñjasapp?ya-sutta based on translated extracts from its Madhyama-?gama parallel, noting variations between these two and a Tibetan version extant in ?amathadeva’s commentary on the Abhidharmako?abh??ya. In the concluding part of the article, I turn to the relationship between tranquillity and insight reflected in the ?neñjasapp?ya-sutta.
Padrões clínicos de acne em mulheres de diferentes faixas etárias
Authors: Schmitt Juliano Vilaverde , Masuda Paula Yoshiko , Miot Hélio Amante
Published: January 2010

FUNDAMENTOS: Acne é dermatose comum que acomete ambos os gêneros e todas as faixas etárias. Mulheres apresentam diferentes padrões clínicos da doença, além de frequente persistência da acne após a adolescência. OBJETIVO: Analisar características clínicas e epidemiológicas associadas às diferentes faixas etárias acometidas por acne feminina. MÉTODOS: Estudo transversal envolvendo mulheres com diagnóstico de acne, atendidas em ambulatório de dermatologia geral. Variáveis relacionadas à doença e às pacientes foram avaliadas com o emprego de questionário padronizado. RESULTADOS: Avaliaram-se 103 pacientes, cuja idade média na época da consulta foi 21,7 ± 7,3 anos. Definiram-se dois subgrupos com idade de corte de 21 anos e idades médias de 15,8 ± 2,3 e 28,0 ± 5,1 anos. Houve correlação entre a duração do quadro e a idade das pacientes na consulta (R = 0,7). Observaram-se diferenças entre os grupos nas frequências de uso de contraceptivo oral combinado (OR = 48,1), lesões no colo (OR = 11,6), lesões no dorso (OR = 0,2), predominância na topografia superior da face (OR = 0,1) e idade de início das lesões (OR = 1,8). No grupo de mulheres adultas, 80% relataram início do quadro antes dos 20 anos. CONCLUSÕES: Identificaram-se padrões clínicos cronológicos e topográficos que caracterizaram a acne feminina em diferentes faixas etárias, alertando para a importância da abordagem diagnóstica e terapêutica individualizada.
Inflamação de queratoses seborreicas múltiplas induzida por quimioterapia com gencitabina
Authors: Siqueira Caio Roberto Shwafaty de , Miot Hélio Amante
Published: January 2010

São diversos e comuns os efeitos mucocutâneos dos quimioterápicos, alguns por ação citotóxica, outros por hipersensibilidade ao fármaco. Os autores relatam a ocorrência de inflamação em múltiplas queratoses seborreicas pré-existentes, após terapia citorredutora com gencitabina, em paciente sob tratamento para neoplasia de pâncreas. Discutem, ainda, a benignidade do evento e alertam para a necessidade de adequada identificação dos efeitos cutâneos decorrentes da quimioterapia sistêmica.
Cross-sectional study on the weight and length of infants in the interior of the State of São Paulo, Brazil: associations with sociodemographic variables and breastfeeding
Authors: Bernardi Julia Laura Delbue , Jordão Regina Esteves , Barros Filho Antônio de Azevedo
Published: January 2010

CONTEXT AND OBJECTIVE: Increasing obesity is starting to occur among Brazilians. The aim of this study was to investigate the weight and length of children under two years of age in relation to sociodemographic variables and according to whether they were breastfed. DESIGN AND SETTING: Cross-sectional randomized study conducted in 2004-2005, based on the declaration of live births (SINASC) in Campinas, Brazil. METHODS: 2,857 mothers of newborns were interviewed and answered a questionnaire seeking socioeconomic and breastfeeding information. The newborns' weights and lengths were measured at the end of the interviews and the body mass index was calculated. Percentiles (< 15 and > 85) and Z-scores (< -1 and > +1) were used for classification based on the new growth charts recommended by WHO (2006). The log-rank test, multiple linear regression and binomial test (Z) were used. The statistical significance level used was 5%. RESULTS: The predominant social level was class C. The median for exclusive breastfeeding was 90 days; 61.25% of the children were between P15 and P85 for body mass index and 61.12% for length, respectively. Children whose mothers studied for nine to eleven years and children whose mothers were unemployed presented lower weight. Children whose mothers worked in health-related professions presented lower length when correlated with breastfeeding. CONCLUSION: The breastfeeding, maternal schooling and maternal occupation levels had an influence on nutrition status and indicated that obesity is occurring in early childhood among the infants living in the municipality.