bluuebunny/crossref_metadata_2025_split huggingface dataset:
The road to commercialization in Africa: lessons from developing the sickle-cell drug Niprisan
Authors: Perampaladas Kumar , Masum Hassan , Kapoor Andrew , Shah Ronak , Daar Abdallah S , Singer Peter A 
Published: January 2011

Abstract

Background
Developing novel drugs from traditional medicinal knowledge can serve as a means to improve public health. Yet countries in sub-Saharan Africa face barriers in translating traditional medicinal knowledge into commercially viable health products. Barriers in moving along the road towards making a new drug available include insufficient manufacturing capacity; knowledge sharing between scientists and medical healers; regulatory hurdles; quality control issues; pricing and distribution; and lack of financing. The case study method was used to illustrate efforts to overcome these barriers during the development in Nigeria of Niprisan – a novel drug for the treatment of sickle cell anemia, a chronic blood disorder with few effective therapies.

Discussion
Building on the knowledge of a traditional medicine practitioner, Nigeria’s National Institute for Pharmaceutical Research and Development (NIPRD) developed the traditional herbal medicine Niprisan. The commercialization of Niprisan reached a number of commercial milestones, including regulatory approval in Nigeria; securing US-based commercial partner XeChem; demonstrating clinical efficacy and safety; being awarded orphan drug status by the US Food and Drug Administration; and striking important relationships with domestic and international groups. Despite these successes, however, XeChem did not achieve mainstream success for Niprisan in Nigeria or in the United States. A number of reasons, including inconsistent funding and manufacturing and management challenges, have been put forth to explain Niprisan’s commercial demise. As of this writing, NIPRD is considering options for another commercial partner to take the drug forward.

Summary
Evidence from the Niprisan experience suggests that establishing benefit-sharing agreements, fostering partnerships with established research institutions, improving standardization and quality control, ensuring financial and managerial due diligence, and recruiting entrepreneurial leaders capable of holding dual scientific and business responsibilities should be incorporated into future drug development initiatives based on traditional medicines. Country-level supporting policies and conditions are also important. With more experience and support, and an improved environment for innovation, developing new drugs from traditional medicines may be an attractive approach to addressing diseases in sub-Saharan Africa and other regions.
Automated estimation of parasitaemia of Plasmodium yoelii-infected mice by digital image analysis of Giemsa-stained thin blood smears
Authors: Ma Charles , Harrison Paul , Wang Lina , Coppel Ross L 
Published: January 2011

Abstract

Background
Parasitaemia, the percentage of infected erythrocytes, is used to measure progress of experimental Plasmodium infection in infected hosts. The most widely used technique for parasitaemia determination is manual microscopic enumeration of Giemsa-stained blood films. This process is onerous, time consuming and relies on the expertise of the experimenter giving rise to person-to-person variability. Here the development of image-analysis software, named Plasmodium AutoCount, which can automatically generate parasitaemia values from Plasmodium-infected blood smears, is reported.

Methods
Giemsa-stained blood smear images were captured with a camera attached to a microscope and analysed using a programme written in the Python programming language. The programme design involved foreground detection, cell and infection detection, and spurious hit filtering. A number of parameters were adjusted by a calibration process using a set of representative images. Another programme, Counting Aid, written in Visual Basic, was developed to aid manual counting when the quality of blood smear preparation is too poor for use with the automated programme.

Results
This programme has been validated for use in estimation of parasitemia in mouse infection by Plasmodium yoelii and used to monitor parasitaemia on a daily basis for an entire challenge infection. The parasitaemia values determined by Plasmodium AutoCount were shown to be highly correlated with the results obtained by manual counting, and the discrepancy between automated and manual counting results were comparable to those found among manual counts of different experimenters.

Conclusions
Plasmodium AutoCount has proven to be a useful tool for rapid and accurate determination of parasitaemia from infected mouse blood. For greater accuracy when smear quality is poor, Plasmodium AutoCount, can be used in conjunction with Counting Aid.
MicroRNA-148b is frequently down-regulated in gastric cancer and acts as a tumor suppressor by inhibiting cell proliferation
Authors: Song Yong-Xi , Yue Zhen-Yu , Wang Zhen-Ning , Xu Ying-Ying , Luo Yang , Xu Hui-Mian , Zhang Xue , Jiang Li , Xing Cheng-Zhong , Zhang Yong 
Published: January 2011

AbstractBackgroundMicroRNAs (miRNAs) are involved in cancer development and progression, acting as tumor suppressors or oncogenes. Our previous studies have revealed that miR-148a and miR-152 are significantly down-regulated in gastrointestinal cancers. Interestingly, miR-148b has the same "seed sequences" as miR-148a and miR-152. Although aberrant expression of miR-148b has been observed in several types of cancer, its pathophysiologic role and relevance to tumorigenesis are still largely unknown. The purpose of this study was to elucidate the molecular mechanisms by which miR-148b acts as a tumor suppressor in gastric cancer.ResultsWe showed significant down-regulation of miR-148b in 106 gastric cancer tissues and four gastric cancer cell lines, compared with their non-tumor counterparts by real-time RT-PCR.In situhybridization of ten cases confirmed an overt decrease in the level of miR-148b in gastric cancer tissues. Moreover, the expression of miR-148b was demonstrated to be associated with tumor size (P = 0.027) by a Mann-Whitney U test. We also found that miR-148b could inhibit cell proliferationin vitroby MTT assay, growth curves and an anchorage-independent growth assay in MGC-803, SGC-7901, BGC-823 and AGS cells. An experiment in nude mice revealed that miR-148b could suppress tumorigenicityin vivo. Using a luciferase activity assay and western blot, CCKBR was identified as a target of miR-148b in cells. Moreover, an obvious inverse correlation was observed between the expression of CCKBR protein and miR-148b in 49 pairs of tissues (P = 0.002, Spearman's correlation).ConclusionsThese findings provide important evidence that miR-148b targets CCKBR and is significant in suppressing gastric cancer cell growth. Maybe miR-148b would become a potential biomarker and therapeutic target against gastric cancer.
Overexpression of proto-oncogene FBI-1 activates membrane type 1-matrix metalloproteinase in association with adverse outcome in ovarian cancers
Authors: Jiang LiLi , Siu Michelle KY , Wong Oscar GW , Tam Kar Fai , Lam Eric W-F , Ngan Hextan YS , Le Xiao-Feng , Wong Esther SY , Chan Hoi Yan , Cheung Annie NY 
Published: January 2011

Abstract

Background
FBI-1 (f actor that b inds to the i nducer of short transcripts of human immunodeficiency virus-1) is a member of the POK (POZ and Kruppel) family of transcription factors and play important roles in cellular differentiation and oncogenesis. Recent evidence suggests that FBI-1 is expressed at high levels in a subset of human lymphomas and some epithelial solid tumors. However, the function of FBI-1 in human ovarian cancers remains elusive.

Results
In this study, we investigated the role of FBI-1 in human ovarian cancers, in particularly, its function in cancer cell invasion via modulating membrane type 1-matrix metalloproteinase (MT1-MMP). Significantly higher FBI-1 protein and mRNA expression levels were demonstrated in ovarian cancers samples and cell lines compared with borderline tumors and benign cystadenomas. Increased FBI-1 mRNA expression was correlated significantly with gene amplification (P = 0.037). Moreover, higher FBI-1 expression was found in metastatic foci (P = 0.036) and malignant ascites (P = 0.021), and was significantly associated with advanced stage (P = 0.012), shorter overall survival (P = 0.032) and disease-free survival (P = 0.016). In vitro, overexpressed FBI-1 significantly enhanced cell migration and invasion both in OVCA 420 and SKOV-3 ovarian carcinoma cells, irrespective of p53 status, accompanied with elevated expression of MT1-MMP, but not MMP-2 or TIMP-2. Moreover, knockdown of MT1-MMP abolished FBI-1-mediated cell migration and invasion. Conversely, stable knockdown of FBI-1 remarkably reduced the motility of these cells with decreased expression of MT1-MMP. Promoter assay and chromatin immunoprecipitation study indicated that FBI-1 could directly interact with the promoter spanning ~600bp of the 5'-flanking sequence of MT1-MMP and enhanced its expression in a dose-dependent manner. Furthermore, stable knockdown and ectopic expression of FBI-1 decreased and increased cell proliferation respectively in OVCA 420, but not in the p53 null SKOV-3 cells.

Conclusions
Our results suggested an important role of FBI-1 in ovarian cancer cell proliferation, cell mobility, and invasiveness, and that FBI-1 can be a potential target of chemotherapy.
VEGF121b and VEGF165b are weakly angiogenic isoforms of VEGF-A
Authors: Catena Raúl , Larzabal Leyre , Larrayoz Marta , Molina Eva , Hermida Jose , Agorreta Jackeline , Montes Ramon , Pio Ruben , Montuenga Luis M , Calvo Alfonso 
Published: January 2011

Abstract

Background
Different isoforms of VEGF-A (mainly VEGF121, VEGF165 and VEGF189) have been shown to display particular angiogenic properties in the generation of a functional tumor vasculature. Recently, a novel class of VEGF-A isoforms, designated as VEGFxxxb, generated through alternative splicing, have been described. Previous studies have suggested that these isoforms may inhibit angiogenesis. In the present work we have produced recombinant VEGF121/165b proteins in the yeast Pichia pastoris and constructed vectors to overexpress these isoforms and assess their angiogenic potential.

Results
Recombinant VEGF121/165b proteins generated either in yeasts or mammalian cells activated VEGFR2 and its downstream effector ERK1/2, although to a lesser extent than VEGF165. Furthermore, treatment of endothelial cells with VEGF121/165b increased cell proliferation compared to untreated cells, although such stimulation was lower than that induced by VEGF165. Moreover, in vivo angiogenesis assays confirmed angiogenesis stimulation by VEGF121/165b isoforms. A549 and PC-3 cells overexpressing VEGF121b or VEGF165b (or carrying the PCDNA3.1 empty vector, as control) and xenotransplanted into nude mice showed increased tumor volume and angiogenesis compared to controls. To assess whether the VEGFxxxb isoforms are differentially expressed in tumors compared to healthy tissues, immunohistochemical analysis was conducted on a breast cancer tissue microarray. A significant increase (p < 0.05) in both VEGFxxxb and total VEGF-A protein expression in infiltrating ductal carcinomas compared to normal breasts was observed. A positive significant correlation (r = 0.404, p = 0.033) between VEGFxxxb and total VEGF-A was found.

Conclusions
Our results demonstrate that VEGF121/165b are not anti-angiogenic, but weakly angiogenic isoforms of VEGF-A. In addition, VEGFxxxb isoforms are up-regulated in breast cancer in comparison with non malignant breast tissues. These results are to be taken into account when considering a possible use of VEGF121/165b-based therapies in patients.
The adsorption of biomolecules to multi-walled carbon nanotubes is influenced by both pulmonary surfactant lipids and surface chemistry
Authors: Gasser Michael , Rothen-Rutishauser Barbara , Krug Harald F , Gehr Peter , Nelle Mathias , Yan Bing , Wick Peter 
Published: January 2011

AbstractBackgroundDuring production and processing of multi-walled carbon nanotubes (MWCNTs), they may be inhaled and may enter the pulmonary circulation. It is essential that interactions with involved body fluids like the pulmonary surfactant, the blood and others are investigated, particularly as these interactions could lead to coating of the tubes and may affect their chemical and physical characteristics. The aim of this study was to characterize the possible coatings of different functionalized MWCNTs in a cell free environment.ResultsTo simulate the first contact in the lung, the tubes were coated with pulmonary surfactant and subsequently bound lipids were characterized. The further coating in the blood circulation was simulated by incubating the tubes in blood plasma. MWCNTs were amino (NH2)- and carboxyl (-COOH)-modified, in order to investigate the influence on the bound lipid and protein patterns. It was shown that surfactant lipids bind unspecifically to different functionalized MWCNTs, in contrast to the blood plasma proteins which showed characteristic binding patterns. Patterns of bound surfactant lipids were altered after a subsequent incubation in blood plasma. In addition, it was found that bound plasma protein patterns were altered when MWCNTs were previously coated with pulmonary surfactant.ConclusionsA pulmonary surfactant coating and the functionalization of MWCNTs have both the potential to alter the MWCNTs blood plasma protein coating and to determine their properties and behaviour in biological systems.
Descriptive epidemiology of screen and non-screen sedentary time in adolescents: a cross sectional study
Authors: Olds Tim S , Maher Carol A , Ridley Kate , Kittel Daniella M 
Published: January 2011

AbstractBackgroundMuch attention has been paid to adolescents' screen time, however very few studies have examined non-screen sedentary time (NSST). This study aimed to (1) describe the magnitude and composition of screen sedentary time (SST) and NSST in Australian adolescents, (2) describe the socio-demographic correlates of SST and NSST, and (3) determine whether screen time is an adequate surrogate for total sedentary behaviour in this population.Methods2200 9-16 year old Australians provided detailed use of time data for four days. Non-screen sedentary time (NSST) included time spent participating in activities expected to elicit <3 METs whilst seated or lying down (other than sleeping), excluding screen-based activities (television, playing videogames or using computers). Total sedentary time was the sum of screen time and NSST.ResultsAdolescents spent a mean (SD) of 345 (105) minutes/day in NSST, which constituted 60% of total sedentary time. School activities contributed 42% of NSST, socialising 19%, self-care (mainly eating) 16%, and passive transport 15%. Screen time and NSST showed opposite patterns in relation to key socio-demographic characteristics, including sex, age, weight status, household income, parental education and day type. Because screen time was negatively correlated with NSST (r = -0.58), and exhibited a moderate correlation (r = 0.53) with total sedentary time, screen time was only a moderately effective surrogate for total sedentary time.ConclusionsTo capture a complete picture of young people's sedentary time, studies should endeavour to measure both screen time and NSST.
Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children
Authors: Zhang Bodi , Angelidou Asimenia , Alysandratos Konstantinos-Dionysios , Vasiadi Magdalini , Francis Konstantinos , Asadi Shahrzad , Theoharides Athanasios , Sideri Kyriaki , Lykouras Lefteris , Kalogeromitros Dimitrios , Theoharides Theoharis C 
Published: January 2011

Abstract
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by difficulties in communication, cognitive and learning deficits, as well as stereotypic behaviors. For the majority of cases there are no reliable biomarkers or distinct pathogenesis. However, increasing evidence indicates ASD may be associated with some immune dysregulation, and may have a neuroimmune component. We recently showed that the peptide neurotensin (NT) is increased in autistic children. We now show that NT induces release of extracellular mitochondrial DNA (mtDNA) that could act as "autoimmune" trigger. We further show that serum from young autistic patients contains mtDNA (n = 20; cytochrome B, p = 0.0002 and 7S, p = 0.006), and anti-mitochondrial antibody Type 2 (n = 14; p = 0.001) as compared to normally developing, unrelated controls (n = 12). Extracellular blood mtDNA and other components may characterize an autistic endophenotype and may contribute to its pathogenesis by activating autoimmune responses.
Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions
Authors: Seabrook Timothy J , Littlewood-Evans Amanda , Brinkmann Volker , Pöllinger Bernadette , Schnell Christian , Hiestand Peter C 
Published: January 2011

Abstract

Background
Angiogenesis is a common finding in chronic inflammatory diseases; however, its role in multiple sclerosis (MS) is unclear. Central nervous system lesions from both MS and experimental autoimmune encephalomyelitis (EAE), the animal model of MS, contain T cells, macrophages and activated glia, which can produce pro-angiogenic factors. Previous EAE studies have demonstrated an increase in blood vessels, but differences between the different phases of disease have not been reported. Therefore we examined angiogenic promoting factors in MS and EAE lesions to determine if there were changes in blood vessel density at different stages of EAE.

Methods
In this series of experiments we used a combination of vascular casting, VEGF ELISA and immunohistochemistry to examine angiogenesis in experimental autoimmune encephalomyelitis (EAE). Using immunohistochemistry we also examined chronic active MS lesions for angiogenic factors.

Results
Vascular casting and histological examination of the spinal cord and brain of rats with EAE demonstrated that the density of patent blood vessels increased in the lumbar spinal cord during the relapse phase of the disease (p < 0.05). We found an increased expression of VEGF by inflammatory cells and a decrease in the recently described angiogenesis inhibitor meteorin. Examination of chronic active human MS tissues demonstrated glial expression of VEGF and glial and blood vessel expression of the pro-angiogenic receptor VEGFR2. There was a decreased expression of VEGFR1 in the lesions compared to normal white matter.

Conclusions
These findings reveal that angiogenesis is intimately involved in the progression of EAE and may have a role in MS.
Alzheimer's disease gene signature says: beware of brain viral infections
Authors: Porcellini Elisa , Carbone Ilaria , Ianni Manuela , Licastro Federico 
Published: January 2011

Abstract

Background
Recent findings from a genome wide association investigation in a large cohort of patients with Alzheimer's disease (AD) and non demented controls (CTR) showed that a limited set of genes was in a strong association (p > l0-5) with the disease.

Presentation of the hypothesis
In this report we suggest that the polymorphism association in 8 of these genes is consistent with a non conventional interpretation of AD etiology.
Nectin-2 (NC-2), apolipoprotein E (APOE), glycoprotein carcinoembryonic antigen related cell adhesion molecule- 16 (CEACAM-16), B-cell lymphoma-3 (Bcl-3), translocase of outer mitochondrial membrane 40 homolog (T0MM-40), complement receptor-1 (CR-l), APOJ or clusterin and C-type lectin domain A family-16 member (CLEC-16A) result in a genetic signature that might affect individual brain susceptibility to infection by herpes virus family during aging, leading to neuronal loss, inflammation and amyloid deposition.

Implications of the hypothesis
We hypothesized that such genetic trait may predispose to AD via complex and diverse mechanisms each contributing to an increase of individual susceptibility to brain viral infections
Prime immunization with rotavirus VLP 2/6 followed by boosting with an adenovirus expressing VP6 induces protective immunization against rotavirus in mice
Authors: Zhou Hongli , Guo Li , Wang Min , Qu Jianguo , Zhao Zhendong , Wang Jianwei , Hung Tao 
Published: January 2011

Abstract

Background
Rotavirus (RV) is the main cause of severe gastroenteritis in children. An effective vaccination regime against RV can substantially reduce morbidity and mortality. Previous studies have demonstrated the efficacy of virus-like particles formed by RV VP2 and VP6 (VLP2/6), as well as that of recombinant adenovirus expressing RV VP6 (rAd), in eliciting protective immunities against RV. However, the efficacy of such prime-boost strategy, which incorporates VLP and rAd in inducing protective immunities against RV, has not been addressed. We assessed the immune effects of different regimens in mice, including rAd prime-VLP2/6 boost (rAd+VLP), VLP2/6 prime-rAd boost (VLP+rAd), rAd alone, and VLP alone.

Results
Mice immunized with the VLP+rAd regimen elicit stronger humoral, mucosal, and cellular immune responses than those immunized with other regimens. RV challenging experiments showed that the highest reduction (92.9%) in viral shedding was achieved in the VLP+rAd group when compared with rAd+VLP (25%), VLP alone (75%), or rAd alone (40%) treatment groups. The reduction in RV shedding in mice correlated with fecal IgG (r = 0.95773, P = 0.04227) and IgA (r = 0.96137, P = 0.038663).

Conclusions
A VLP2/6 prime-rAd boost regimen is effective in conferring immunoprotection against RV challenge in mice. This finding may lay the groundwork for an alternative strategy in novel RV vaccine development.
Blocking Spinal CCR2 with AZ889 Reversed Hyperalgesia in a Model of Neuropathic Pain
Authors: Serrano Alexandre , Paré Michel , McIntosh Fraser , Elmes Steven JR , Martino Giovanni , Jomphe Claudia , Lessard Etienne , Lembo Paola MC , Vaillancourt François , Perkins Martin N , Cao Chang Qing 
Published: January 2011

Background:The CCR2/CCL2 system has been identified as a regulator in the pathogenesis of neuropathy-induced pain. However, CCR2 target validation in analgesia and the mechanism underlying antinociception produced by CCR2 antagonists remains poorly understood. In this study, in vitro and in vivo pharmacological approaches using a novel CCR2 antagonist, AZ889, strengthened the hypothesis of a CCR2 contribution to neuropathic pain and provided confidence over the possibilities to treat neuropathic pain with CCR2 antagonists.Results:We provided evidence that dorsal root ganglia (DRG) cells harvested from CCI animals responded to stimulation by CCL2 with a concentration-dependent calcium rise involving PLC-dependent internal stores. This response was associated with an increase in evoked neuronal action potentials suggesting these cells were sensitive to CCR2 signalling. Importantly, treatment with AZ889 abolished CCL2-evoked excitation confirming that this activity is CCR2-mediated. Neuronal and non-neuronal cells in the spinal cord were also excited by CCL2 applications indicating an important role of spinal CCR2 in neuropathic pain. We next showed that in vivo spinal intrathecal injection of AZ889 produced dose-dependent analgesia in CCI rats. Additionally, application of AZ889 to the exposed spinal cord inhibited evoked neuronal activity and confirmed that CCR2-mediated analgesia involved predominantly the spinal cord. Furthermore, AZ889 abolished NMDA-dependent wind-up of spinal withdrawal reflex pathway in neuropathic animals giving insight into the spinal mechanism underlying the analgesic properties of AZ889.Conclusions:Overall, this study strengthens the important role of CCR2 in neuropathic pain and highlights feasibility that interfering on this mechanism at the spinal level with a selective antagonist can provide new analgesia opportunities.