Transplantation of canine olfactory ensheathing cells producing chondroitinase ABC promotes chondroitin sulphate proteoglycan digestion and axonal sprouting following spinal cord injury

Olfactory ensheathing cell (OEC) transplantation is a promising strategy for treating spinal cord injury (SCI), as has been demonstrated in experimental SCI models and naturally occurring SCI in dogs. However, the presence of chondroitin sulphate proteoglycans within the extracellular matrix of the glial scar can inhibit efficient axonal repair and limit the therapeutic potential of OECs. Here we have used lentiviral vectors to genetically modify canine OECs to continuously deliver mammalian chondroitinase ABC at the lesion site in order to degrade the inhibitory chondroitin sulphate proteoglycans in a rodent model of spinal cord injury. We demonstrate that these chondroitinase producing canine OECs survived at 4 weeks following transplantation into the spinal cord lesion and effectively digested chondroitin sulphate proteoglycans at the site of injury. There was evidence of sprouting within the corticospinal tract rostral to the lesion and an increase in the number of corticospinal axons caudal to the lesion, suggestive of axonal regeneration. Our results indicate that delivery of the chondroitinase enzyme can be achieved with the genetically modified OECs to increase axon growth following SCI. The combination of these two promising approaches is a potential strategy for promoting neural regeneration following SCI in veterinary practice and human patients

Beliefs about others' intentions determine whether cooperation is the faster choice

Is collaboration the fast choice for humans? Past studies proposed that cooperation is a behavioural default, based on Response Times (RT) findings. Here we contend that the individual’s reckoning of the immediate social environment shapes her predisposition to cooperate and, hence, response latencies. In a social dilemma game, we manipulate the beliefs about the partner’s intentions to cooperate and show that they act as a switch that determines cooperation and defection RTs; when the partner’s intention to cooperate is perceived as high, cooperation choices are speeded up, while defection is slowed down. Importantly, this social context effect holds across varying expected payoffs, indicating that it modulates behaviour regardless of choices’ similarity in monetary terms. Moreover, this pattern is moderated by individual variability in social preferences: Among conditional cooperators, high cooperation beliefs speed up cooperation responses and slow down defection. Among free-riders, defection is always faster and more likely than cooperation, while high cooperation beliefs slow down all decisions. These results shed new light on the conflict of choices account of response latencies, as well as on the intuitive cooperation hypothesis, and can help to correctly interpret and reconcile previous, apparently contradictory results, by considering the role of context in social dilemmas

Bioprocessing strategies to enhance the challenging isolation of neuro-regenerative cells from olfactory mucosa

Olfactory ensheathing cells (OECs) are a promising potential cell therapy to aid regeneration. However, there are significant challenges in isolating and characterizing them. In the current study, we have explored methods to enhance the recovery of cells expressing OEC marker p75NTR from rat mucosa. With the addition of a 24-hour differential adhesion step, the expression of p75NTR was significantly increased to 73 ± 5% and 46 ± 18% on PDL and laminin matrices respectively. Additionally, the introduction of neurotrophic factor NT-3 and the decrease in serum concentration to 2% FBS resulted in enrichment of OECs, with p75NTR at nearly 100% (100 ± 0% and 98 ± 2% on PDL and laminin respectively), and candidate fibroblast marker Thy1.1 decreased to zero. Culturing OECs at physiologically relevant oxygen tension (2–8%) had a negative impact on p75NTR expression and overall cell survival. Regarding cell potency, co-culture of OECs with NG108-15 neurons resulted in more neuronal growth and potential migration at atmospheric oxygen. Moreover, OECs behaved similarly to a Schwann cell line positive control. In conclusion, this work identified key bioprocessing fundamentals that will underpin future development of OEC-based cell therapies for potential use in spinal cord injury repair. However, there is still much work to do to create optimized isolation methods

Gray zones around diffuse large B cell lymphoma. Conclusions based on the workshop of the XIV meeting of the European Association for Hematopathology and the Society of Hematopathology in Bordeaux, France

The term “gray-zone” lymphoma has been used to denote a group of lymphomas with overlapping histological, biological, and clinical features between various types of lymphomas. It has been used in the context of Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL), including classical HL (CHL), and primary mediastinal large B cell lymphoma, cases with overlapping features between nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B cell lymphoma, CHL, and Epstein–Barr-virus-positive lymphoproliferative disorders, and peripheral T cell lymphomas simulating CHL. A second group of gray-zone lymphomas includes B cell NHL with intermediate features between diffuse large B cell lymphoma and classical Burkitt lymphoma. In order to review controversial issues in gray-zone lymphomas, a joint Workshop of the European Association for Hematopathology and the Society for Hematopathology was held in Bordeaux, France, in September 2008. The panel members reviewed and discussed 145 submitted cases and reached consensus diagnoses. This Workshop summary is focused on the most controversial aspects of gray-zone lymphomas and describes the panel’s proposals regarding diagnostic criteria, terminology, and new prognostic and diagnostic parameters

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Effect of Calophyllum Inophyllum biodiesel-diesel blends on combustion, performance, exhaust particulate matter and gaseous emissions in a multi-cylinder diesel engine

In this work, the effects of adding of inedible Calophyllum Inophyllum biodiesel to diesel fuel on performance, gaseous emissions, particulate matter (PM) and combustion characteristics were studied in a medium-duty, high-pressure common-rail turbocharged four-cylinder diesel engine under different speed and torque conditions. The key physicochemical properties of neat biodiesel, biodiesel-diesel blends and diesel were characterized and analysed. The test fuels used were a fossil diesel fuel, B10, B20, B30, and B50 of biodiesel-diesel fuels. The results indicated that all blends of biodiesel fuels have physicochemical properties relatively close to those of petroleum diesel. The experimental results also demonstrated that there are some drawbacks in engine brake power, brake specific fuel consumption (BSFC), and nitrogen oxide (NOx) with the blend of biodiesel in the fuel. Besides, refinement in brake thermal efficiency (BTE) and exhaust emissions were recorded across all engine speeds. Moreover, the emission improvement was characterized by lower carbon monoxide (CO) and reduced in both of the smoke and PM emissions. Also, reduction in the magnitude of peak combustion pressure and heat release rate (HRR) were also found with biodiesel blends. Overall, the results indicated that Calophyllum Inophyllum biodiesel can be used satisfactorily in an unmodified multi-cylinder high-pressure common-rail diesel engine

Impact of two-stage injection fuel quantity on engine-out responses of a common-rail diesel engine fueled with coconut oil methyl esters-diesel fuel blends

Two-stage injection with different biodiesel percentage is investigated where first and second injections were implemented with different SOI timings at various mass ratio under constant speed of 2000 rpm and 60 Nm of torque. The results reveal that maximum BTE of 32.4% and minimum BSFC of 245.5 g/kWh can be achieved simultaneously with injection mass ratio of 50:50 at advanced SOI timing using baseline diesel. A considerably lower level of NOx below 90 ppm is achievable via late SOI timing by using B20 or B50 biodiesel blends with injection mass ratio of 25:75. Specifically, the lowest NOx of 82 ppm can be achieved with smoke emission level still remains below 5% when B50 biodiesel blend and 25:75 injection mass ratio is tested. The highest reduction of 5.3% of smoke compared to diesel was achieved when B50 was used with 50:50 mass ratio at retarded SOI of 2°ATDC. It was found that simultaneous NOx and smoke reduction compared to that of fossil diesel is feasible with the application of B50 biodiesel blend and execution of retarded SOI timing and injection mass ratio of 25:75. Lastly, two-stage fuel injection is a practical strategy to simultaneously decrease NOx and smoke emissions

Clinical efficacy of 60-mg dexlansoprazole and 40-mg esomeprazole after 24 weeks for the on-demand treatment of gastroesophageal reflux disease grades A and B: a prospective randomized trial

Hung-Hsien Chiang,1 Deng-Chyang Wu,2 Pin-I Hsu,3 Chao-Hung Kuo,2 Wei-Chen Tai,1 Shih-Cheng Yang,1 Keng-Liang Wu,1 Chih-Chien Yao,1 Cheng-En Tsai,1 Chih-Ming Liang,1 Yao-Kuang Wang,2 Jiunn-Wei Wang,2 Chih-Fang Huang,4 Seng-Kee Chuah,1  on behalf of the Taiwan Acid-Related Disease Study Group 1Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan; 3Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, National Yang-Ming University, Kaohsiung, Taiwan; 4Division of Family Physicians, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, TaiwanPurpose: Research comparing the clinical efficacy of dexlansoprazole and esomeprazole has been limited. This study aims to compare the clinical efficacy of single doses of dexlansoprazole (modified-release 60 mg) and esomeprazole (40 mg) after 24-week follow-up in patients with mild erosive esophagitis.Methods: We enrolled 86 adult GERD subjects, randomized in a 1:1 ratio to two sequence groups defining the order in which they received single doses of dexlansoprazole (n=43) and esomeprazole (n=43) for 8 weeks as initial treatment. Patients displaying complete symptom resolution (CSR) by the end of initial treatment (8 weeks) were switched to on-demand therapy until the end of 24 weeks. Follow-up endoscopy was performed either at the end of 24 weeks or when severe reflux symptoms occurred. Five patients were lost to follow-up, leaving 81 patients (dexlansoprazole, n=41; esomeprazole, n=40) in the per-protocol analysis.Results: The GERDQ scores at 4-, 8-, 12-, 16-, 20-, and 24-week posttreatment were less than the baseline score. The CSR, rate of symptom relapse, days to symptom resolution, sustained healing rate of erosive esophagitis, treatment failure rate, and the number of tablets taken in 24 weeks were similar in both groups. The esomeprazole group had more days with reflux symptoms than the dexlansoprazole group (37.3±37.8 vs 53.9±54.2; P=0.008). In the dexlansoprazole group, patients exhibited persistent improvement in the GERDQ score during the on-demand period (week 8 vs week 24; P<0.001) but not in the esomeprazole group (week 8 vs week 24; P=0.846).Conclusions: This study suggests that the symptom relief effect for GERD after 24 weeks was similar for dexlansoprazole and esomeprazole. Dexlansoprazole exhibited fewer days with reflux symptoms in the 24-week study period, with better persistent improvement in the GERDQ score in the on-demand period.(ClinicalTrials. gov number: NCT03128736)Keywords: dexlansoprazole, esomeprazole, 24-week response, gastroesophageal reflux disease, on-demand, GERDQ scor

A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor

The mechanisms responsible for the low factor VIII (fVIII) activity in the plasma of patients with mild/moderate hemophilia A are poorly understood. In such patients, we have identified a series of fVIII mutations (Ile2098Ser, Ser2119Tyr, Asn2129Ser, Arg2150His, and Pro2153Gln) clustered in the C1 domain and associated with reduced binding of fVIII to von Willebrand factor (vWf). For each patient plasma, the specific activity of mutated fVIII was close to that of normal fVIII. Scatchard analysis showed that the affinity for vWf of recombinant Ile2098Ser, Ser2119Tyr, and Arg2150His fVIII mutants was reduced 8-fold, 80-fold, and 3-fold, respectively, when compared with normal fVIII. Given the importance of vWf for the stability of fVIII in plasma, these findings suggested that the reduction of fVIII binding to vWf resulting from the above-mentioned mutations could contribute to patients' low fVIII plasma levels. We, therefore, analyzed the effect of vWf on fVIII production by Chinese hamster ovary (CHO) cells transfected with expression vectors for recombinant B domain-deleted normal, Ile2098Ser, Ser2119Tyr, and Arg2150His fVIII. These 3 mutations impaired the vWf-dependent accumulation of functional fVIII in culture medium. Analysis of fVIII production by transiently transfected CHO cells indicated that, in addition to the impaired stabilization by vWf, the secretion of functional Ile2098Ser and Arg2150His fVIII was reduced about 2-fold and 6-fold, respectively, by comparison to Ser2119Tyr and normal fVIII. These findings indicate that C1-domain mutations resulting in reduced fVIII binding to vWf are an important cause of mild/moderate hemophilia A.status: publishe