Enhanced recruitment of genetically modified CX3CR1-positive human T cells into Fractalkine/CX3CL1 expressing tumors: importance of the chemokine gradient.

BACKGROUND: Adoptive T-cell based immunotherapies constitute a promising approach to treat cancer, however, a major problem is to obtain effective and long-lasting anti-tumor responses. Lack of response may be due to insufficient trafficking of specific T cells to tumors. A key requirement for efficient migration of cytotoxic T cells is that they express chemokine receptors that match the chemokines produced by tumor or tumor-associated cells. METHODS: In this study, we investigated whether the in vivo tumor trafficking of activated T cells could be enhanced by the expression of the chemokine receptor CX3CR1. Two human colorectal cancer cell lines were used to set up a xenograft tumor model in immunodeficient mice; the NCI-H630, constitutively expressing the chemokine ligand CX3CL1 (Fractalkine), and the RKO cell line, transduced to express CX3CL1. RESULTS: Human primary T cells were transduced with the receptor CX3CR1-eGFP. Upon in vivo adoptive transfer of genetically modified CX3CR1-T cells in mice bearing NCI-H630 tumors, enhanced lymphocyte migration and tumor trafficking were observed, compared to mice receiving Mock-T cells, indicating improved homing ability towards ligand-expressing tumor cells. Furthermore, significant inhibition of tumor growth was found in mice receiving modified CX3CR1-T cells. In contrast, tumors formed by RKO cells transduced with the ligand (RKO-CX3CL1) were not affected, nor more infiltrated upon transfer of CX3CR1-T lymphocytes, likely because high levels of the chemokine were shed by tumor cells in the systemic circulation, thus nullifying the blood-tissue chemokine gradient. CONCLUSIONS: This study demonstrates that ectopic expression of CX3CR1 enhanced the homing of adoptively transferred T cells towards CX3CL1-producing tumors, resulting in increased T cell infiltration in tumor tissues and decreased tumor growth. Our results also establish that a correct chemokine gradient between the systemic circulation and the tumor is an essential requirement in adoptive T-cell based immunotherapy to efficiently recruit T cell effectors at the correct sites

Extended Huckel theory for bandstructure, chemistry, and transport. II. Silicon

In this second paper, we develop transferable semi-empirical parameters for the technologically important material, silicon, using Extended Huckel Theory (EHT) to calculate its electronic structure. The EHT-parameters areoptimized to experimental target values of the band dispersion of bulk-silicon. We obtain a very good quantitative match to the bandstructure characteristics such as bandedges and effective masses, which are competitive with the values obtained within an $sp^3 d^5 s^*$ orthogonal-tight binding model for silicon. The transferability of the parameters is investigated applying them to different physical and chemical environments by calculating the bandstructure of two reconstructed surfaces with different orientations: Si(100) (2x1) and Si(111) (2x1). The reproduced $\pi$- and $\pi^*$-surface bands agree in part quantitatively with DFT-GW calculations and PES/IPES experiments demonstrating their robustness to environmental changes. We further apply the silicon parameters to describe the 1D band dispersion of a unrelaxed rectangular silicon nanowire (SiNW) and demonstrate the EHT-approach of surface passivation using hydrogen. Our EHT-parameters thus provide a quantitative model of bulk-silicon and silicon-based materials such as contacts and surfaces, which are essential ingredients towards a quantitative quantum transport simulation through silicon-based heterostructures.Comment: 9 pages, 9 figure

Triterpenoid saponins from Acorus calamus

473-47

Lack of benefit of granulocyte macrophage or granulocyte colony stimulating factor in patients with febrile neutropenia

Objectives: To compare the clinical benefits of granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF) plus standard supportive care to supportive care alone among cancer patients with febrile neutropenia. Methods: Clinical data were collected retrospectively from 148 consecutive cancer patients with neutropenia and fever. Patients had hematologic (i.e., acute leukemias or lymphoproliferative disorders) or non-hematologic malignancies (i.e., solid tumors including carcinoma of breast, lung, or colon). Clinical variables analyzed included: age and sex; underlying malignancies; chemotherapy regimens; symptoms at time of presentation; duration of fever prior to study enrollment; days from chemotherapy until administration of GM-CSF or G-CSF; number of previous neutropenic episodes; duration of fever and day of defervescence; absolute neutrophil count on day of defervescence; duration of neutropenia; number and types of antibiotics used; day amphotericin B begun; number of culture-documented infective episodes involving bloodstream, lung, pleura, urinary tract, gastrointestinal tract, intravenous cannulae, or skin; types of antimicrobial isolates; cost of cytokine therapy; length of hospital stay and clinical outcome. Results:The use of myeloid growth factors increased the number of circulating peripheral white blood cells, but no significant effect was noted in terms of duration of neutropenia or fever, number of culture-proven infections (except pneumonia; p \u3c 0.04), length of hospital stay, or survival. Conclusion: In areas with limited health care resources, expensive treatment with GM-CSF or G-CSF should be reserved for patients with complicated febrile neutropenia where the expected risk of infection is high and the documented infections that are refractory to antibiotic duration of neutropenia is prolonged, or those with treatment (JPMA 52: 206, 2002)

A Novel Approach to Railway Track Faults Detection Using Acoustic Analysis.

Regular inspection of railway track health is crucial for maintaining safe and reliable train operations. Factors, such as cracks, ballast issues, rail discontinuity, loose nuts and bolts, burnt wheels, superelevation, and misalignment developed on the rails due to non-maintenance, pre-emptive investigations and delayed detection, pose a grave danger and threats to the safe operation of rail transport. The traditional procedure of manually inspecting the rail track using a railway cart is both inefficient and prone to human error and biases. In a country like Pakistan where train accidents have taken many lives, it is not unusual to automate such approaches to avoid such accidents and save countless lives. This study aims at enhancing the traditional railway cart system to address these issues by introducing an automatic railway track fault detection system using acoustic analysis. In this regard, this study makes two important contributions: data collection on Pakistan railway tracks using acoustic signals and the application of various classification techniques to the collected data. Initially, three types of tracks are considered, including normal track, wheel burnt and superelevation, due to their common occurrence. Several well-known machine learning algorithms are applied such as support vector machines, logistic regression, random forest and decision tree classifier, in addition to deep learning models like multilayer perceptron and convolutional neural networks. Results suggest that acoustic data can help determine the track faults successfully. Results indicate that the best results are obtained by RF and DT with an accuracy of 97%

Classification of radical hysterectomy adopted by the Gynecological Cancer Group of the European Organization for Research and Treatment of Cancer

The Piver classification of radical hysterectomy for the treatment of cervical cancer is outdated and misused. The Surgery Committee of the Gynecological Cancer Group of the European Organization for Research and Treatment of Cancer (EORTC) produced, approved, and adopted a revised classification. It is hoped that at least within the EORTC participating centers, a standardization of procedures is achieved. The clinical indications of the new classification are discussed

A novel case of MSTO1 gene related congenital muscular dystrophy with progressive neurological involvement

Recessive mutations in the MSTO1 gene, encoding for a mitochondrial distribution and morphology regulator, have been recently described in a very limited number of patients with multisystem involvement, mostly characterized by myopathy or dystrophy, cerebellar ataxia, pigmentary retinopathy and raised creatine kinase levels. Here we report an additional patient with recessive MSTO1-related muscular dystrophy (MSTO1-RD), and clinical and radiological evidence of progressive cerebellar involvement. Whole-exome sequencing identified two novel MSTO1 missense variants, c.766C > T (p. (Arg256Trp) and c.1435C > T (p. (Pro479Ser), predicted as damaging by in silico tools. We also report a distinct pattern of selective involvement on muscle MRI in MSTO1-RD. This case confirms a consistent MSTO1-related neuromuscular phenotype and in addition suggests a progressive neurological component at least in some patients, in keeping with the mitochondrial role of the defective protein

Two new anthraquinone derivatives from the seeds of Cassia angustifolia

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Flavone and isoflavone derivative from the seeds of Derris robusta with pods

419-42

Behavioural support and nicotine replacement therapy for Smokeless Tobacco cessation:Protocol for a pilot randomised-controlled multi-country trial

Background Smokeless tobacco (ST) is consumed globally by more than 350 million people, with approximately 85% of all users based in South and Southeast Asia. In this region, ST products are cheap and easily accessible. Evidence-based interventions to people quit ST use are lacking. This study aims to test the feasibility of conducting a future definitive trial of ST cessation, using a culturally adapted behavioural intervention, and/or nicotine replacement therapy (NRT) in three South Asian countries. Methods We will conduct a factorial design, randomised-controlled pilot trial in Bangladesh, India and Pakistan. Daily ST users will be recruited from primary health care settings in Dhaka, Noida and Karachi. Participants will be individually randomised to receive intervention A (4 or 6 mg NRT chewing gum for 8-weeks), intervention B (BISCA: face-to-face behavioural support for ST cessation), a combination of interventions A and B or usual care (Very Brief Advice - VBA). The participants will provide demographic and ST use related data at baseline, and at 6, 12 and 26 weeks of follow-up. Salivary cotinine samples will be collected at baseline and 26 weeks. The analyses will undertake an assessment of the feasibility of recruitment, randomisation, data collection and participant retention, as well as the feasibility of intervention delivery. We will also identify potential cessation outcomes to inform the main trial, understand the implementation, context and mechanisms of impact through a process evaluation and, thirdly, establish health resource use and impact on the quality of life through health economic data. Discussion The widespread and continued use of ST products in South Asia is consistent with a high rate of associated diseases and negative impact on the quality of life. The identification of feasible, effective and cost-effective interventions for ST is necessary to inform national and regional efforts to reduce ST use at the population level. The findings of this pilot trial will inform the development of larger trials for ST cessation among South Asian users, with relevance to wider regions and populations having high rates of ST use. Trial registration ISRCTN identifier 6510939