Prognostic impact of tumor-associated immune cell infiltrates at radical cystectomy for bladder cancer

Objectives: To assess whether the presence and location of tumor-associated immune cell infiltrates (TAIC) on histological slides obtained from cystectomy specimens impacts on oncological outcomes of patients with bladder cancer (BC). Material and methods: A total of 320 consecutive patients staged with cM0 bladder cancer underwent radical cystectomy (RC) between 2004 and 2013. The presence of TAIC (either located peritumorally [PIC] and/or intratumorally [IIC]) on histological slides was retrospectively assessed and correlated with outcomes. Kaplan-Meier analyses were used to estimate the impact of TAIC on recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS). Multivariable Cox-regression analysis was carried out to evaluate risk factors of recurrence. The median follow-up was 37 months (IQR: 10-55). Results: Of the 320 patients, 42 (13.1%) exhibited IIC, 141 (44.1%) PIC and 137 (42.8%) no TAIC in the cystectomy specimens. Absence of TAIC was associated with higher ECOG performance status (P = 0.042), histologically advanced tumor stage (≥pT3a; P < 0.001), lymph node tumor involvement (pN+; P = 0.022), positive soft tissue surgical margins (P = 0.006), lymphovascular invasion (P < 0.001), and elevated serum C-reactive protein levels (P < 0.001). The rate of never smokers was significantly higher in the IIC-group (64.3%) compared to the PIC-group (39.7%, P = 0.007) and those without TAIC (35.8%, P = 0.001). The 3-year RFS/CSS/OS was 73.9%/88.5%/76.7% for patients with IIC, 69.4%/85.2%/70.1% for PIC and 47.6%/68.5%/56.1% for patients without TAIC (P < 0.001/<0.001/0.001 for TAIC vs. no TAIC). In multivariable analysis, adjusted for all significant parameters of univariable analysis, histologically advanced tumor stage (P = 0.003), node-positive disease (P = 0.002), and the absence of TAIC (P = 0.035) were independent prognosticators for recurrence. Conclusions: In this analysis, the presence and location of TAIC in cystectomy specimens was a strong prognosticator for RFS after RC. This finding suggests that the capability of immune cells to migrate into the tumor at the time of RC is prognostically important in invasive bladder cancer

Lessons in cat herding: methods used for managing a large international collaborative engineering project, the Ariel mission payload

The Ariel space mission will characterize spectroscopically the atmospheres of a large and diverse sample of hundreds of exoplanets.. Ariel is an ESA Medium class science mission (M4) with a spacecraft bus developed by industry under contract to ESA, and a Payload provided by a consortium of national funding agencies in ESA member states, plus contributions from NASA, the CSA and JAXA. With the payload being provided by a consortium of scientific institutes and industrial partners funded through their respective European national funding agencies, and additional contributions provided by ESA, NASA, CSA and JAXA, the coordination and management of this team is vital to the successful delivery of the mission. This paper will describe how we have tailored the standard systems engineering approaches taken for space instrumentation and implemented these in the large consortium structure. This has been done in order to try to maximise the efficiency of the consortium work and to allow as close to a seamless flow of information as possible. We outline the key tools being deployed by the payload management, systems engineering and product assurance teams in the consortium

The C-terminal domain of eukaryotic initiation factor 5 promotes start codon recognition by its dynamic interplay with eIF1 and eIF2 beta

Recognition of the proper start codon on mRNAs is essential for protein synthesis, which requires scanning and involves eukaryotic initiation factors (eIFs) eIF1, eIF1A, eIF2, and eIF5. The carboxyl terminal domain (CTD) of eIF5 stimulates 43S preinitiation complex (PIC) assembly; however, its precise role in scanning and start codon selection has remained unknown. Using nuclear magnetic resonance (NMR) spectroscopy, we identified the binding sites of eIF1 and eIF2β on eIF5-CTD and found that they partially overlapped. Mutating select eIF5 residues in the common interface specifically disrupts interaction with both factors. Genetic and biochemical evidence indicates that these eIF5-CTD mutations impair start codon recognition and impede eIF1 release from the PIC by abrogating eIF5-CTD binding to eIF2β. This study provides mechanistic insight into the role of eIF5-CTD's dynamic interplay with eIF1 and eIF2β in switching PICs from an open to a closed state at start codons.publishedVersio

The instrument control unit of the AIRS instrument on-board the ARIEL mission: design status after PDR

ARIEL (Atmospheric Remote-sensing InfraRed Large-survey) is the fourth medium-class mission (M4) of the European Space Agency, part of the Cosmic Vision program, whose launch is planned by late 2029. ARIEL aims to study the composition of exoplanet atmospheres, their formation and evolution. The ARIEL’s target will be a sample of about 1000 planets observed with one or more of the following methods: transit, eclipse and phase-curve spectroscopy, in both visible and infrared light. The scientific payload is composed by a reflective telescope having a 1m-class elliptical primary mirror, built in solid Aluminum, and two focal-plane instruments: FGS and AIRS. FGS (Fine Guidance System)3 has the double purpose of performing photometry (0.50-0.55 µm) and low resolution spectrometry over three bands (from 0.8 to 1.95 µm) and, simultaneously, to provide data to the spacecraft AOCS (Attitude and Orbit Control System). AIRS (ARIEL InfraRed Spectrometer) instrument will perform IR spectrometry in two wavelength ranges: between 1.95 and 3.9 µm (with a spectral resolution R > 100) and between 3.9 and 7.8 µm with a spectral resolution R > 30. This paper provides the status of the ICU (Instrument Control Unit), an electronic box whose purpose is to command and supply power to the AIRS warm front-end (as well as acquire science data from its two channels) and to command and control the TCU (Telescope Control Unit)

Insecticide susceptibility status of Phlebotomus (Paraphlebotomus) sergenti and Phlebotomus (Phlebotomus) papatasi in endemic foci of cutaneous leishmaniasis in Morocco

<p>Abstract</p> <p>Background</p> <p>In Morocco, cutaneous leishmaniasis is transmitted by <it>Phlebotomus sergenti </it>and <it>Ph. papatasi</it>. Vector control is mainly based on environmental management but indoor residual spraying with synthetic pyrethroids is applied in many foci of <it>Leishmania tropica</it>. However, the levels and distribution of sandfly susceptibility to insecticides currently used has not been studied yet. Hence, this study was undertaken to establish the susceptibility status of <it>Ph. sergenti </it>and <it>Ph. papatasi </it>to lambdacyhalothrin, DDT and malathion.</p> <p>Methods</p> <p>The insecticide susceptibility status of <it>Ph. sergenti </it>and <it>Ph. papatasi </it>was assessed during 2011, following the standard WHO technique based on discriminating dosage. A series of twenty-five susceptibility tests were carried out on wild populations of <it>Ph. sergenti </it>and <it>Ph. papatasi </it>collected by CDC light traps from seven villages in six different provinces. Knockdown rates (KDT) were noted at 5 min intervals during the exposure to DDT and to lambdacyhalothrin. After one hour of exposure, sandflies were transferred to the observation tubes for 24 hours. After this period, mortality rate was calculated. Data were analyzed by Probit analysis program to determine the knockdown time 50% and 90% (KDT50 and KDT90) values.</p> <p>Results</p> <p>Study results showed that <it>Ph.sergenti </it>and <it>Ph. papatasi </it>were susceptible to all insecticides tested. Comparison of KDT values showed a clear difference between the insecticide knockdown effect in studied villages. This effect was lower in areas subject to high selective public health insecticide pressure in the framework of malaria or leishmaniasis control.</p> <p>Conclusion</p> <p><it>Phlebotomus sergenti </it>and <it>Ph. papatasi </it>are susceptible to the insecticides tested in the seven studied villages but they showed a low knockdown effect in Azilal, Chichaoua and Settat. Therefore, a study of insecticide susceptibility of these vectors in other foci of leishmaniasis is recommended and the level of their susceptibility should be regularly monitored.</p

Heterogeneity assessment of functional T cell avidity.

The potency of cellular immune responses strongly depends on T cell avidity to antigen. Yet, functional avidity measurements are rarely performed in patients, mainly due to the technical challenges of characterizing heterogeneous T cells. The mean functional T cell avidity can be determined by the IFN-γ Elispot assay, with titrated amounts of peptide. Using this assay, we developed a method revealing the heterogeneity of functional avidity, represented by the steepness/hillslope of the peptide titration curve, documented by proof of principle experiments and mathematical modeling. Our data show that not only natural polyclonal CD8 T cell populations from cancer patients, but also monoclonal T cells differ strongly in their heterogeneity of functional avidity. Interestingly, clones and polyclonal cells displayed comparable ranges of heterogeneity. We conclude that besides the mean functional avidity, it is feasible and useful to determine its heterogeneity (hillslope) for characterizing T cell responses in basic research and patient investigation

Insecticide resistance in the sand fly, Phlebotomus papatasi from Khartoum State, Sudan

<p>Abstract</p> <p>Background</p> <p><it>Phlebotomus papatasi </it>the vector of cutaneous leishmaniasis (CL) is the most widely spread sand fly in Sudan. No data has previously been collected on insecticide susceptibility and/or resistance of this vector, and a first study to establish a baseline data is reported here.</p> <p>Methods</p> <p>Sand flies were collected from Surogia village, (Khartoum State), Rahad Game Reserve (eastern Sudan) and White Nile area (Central Sudan) using light traps. Sand flies were reared in the Tropical Medicine Research Institute laboratory. The insecticide susceptibility status of first progeny (F1) of <it>P. papatasi </it>of each population was tested using WHO insecticide kits. Also, <it>P. papatasi </it>specimens from Surogia village and Rahad Game Reserve were assayed for activities of enzyme systems involved in insecticide resistance (acetylcholinesterase (AChE), non-specific carboxylesterases (EST), glutathione-S-transferases (GSTs) and cytochrome p450 monooxygenases (Cyt p450).</p> <p>Results</p> <p>Populations of <it>P. papatasi </it>from White Nile and Rahad Game Reserve were sensitive to dichlorodiphenyltrichloroethane (DDT), permethrin, malathion, and propoxur. However, the <it>P. papatasi </it>population from Surogia village was sensitive to DDT and permethrin but highly resistant to malathion and propoxur. Furthermore, <it>P. papatasi </it>of Surogia village had significantly higher insecticide detoxification enzyme activity than of those of Rahad Game Reserve. The sand fly population in Surogia displayed high AChE activity and only three specimens had elevated levels for EST and GST.</p> <p>Conclusions</p> <p>The study provided evidence for malathion and propoxur resistance in the sand fly population of Surogia village, which probably resulted from anti-malarial control activities carried out in the area during the past 50 years.</p

International clinical assessment of smell:An international, cross-sectional survey of current practice in the assessment of olfaction

Objectives: Olfactory dysfunction (OD) is common and carries significant personal and societal burden. Accurate assessment is necessary for good clinical and research practice but is highly dependent on the assessment technique used. Current practice with regards to UK/international clinical assessment is unknown. We aimed to capture current clinical practice, with reference to contemporaneously available guidelines. We further aimed to compare UK to international practice. Design: Anonymous online questionnaire with cross-sectional non-probability sampling. Subgroup analysis according to subspeciality training in rhinology (‘rhinologists’ and ‘non-rhinologists’) was performed, with geographical comparisons only made according to subgroup. Participants: ENT surgeons who assess olfaction. Results: Responses were received from 465 clinicians (217 from UK and 17 countries total). Country-specific response rate varied, with the lowest rate being obtained from Japan (1.4%) and highest from Greece (72.5%). Most UK clinicians do not perform psychophysical smell testing during any of the presented clinical scenarios—though rhinologists did so more often than non-rhinologists. The most frequent barriers to testing related to service provision (e.g., time/funding limitations). Whilst there was variability in practice, in general, international respondents performed psychophysical testing more frequently than those from the UK. Approximately 3/4 of all respondents said they would like to receive training in psychophysical smell testing. Patient reported outcome measures were infrequently used in the UK/internationally. More UK respondents performed diagnostic MRI scanning than international respondents. Conclusions: To our knowledge, this is the most comprehensive UK-based, and only international survey of clinical practice in the assessment of OD. We present recommendations to improve practice, including increased education and funding for psychophysical smell testing. We hope this will promote accurate and reliable olfactory assessment, as is the accepted standard in other sensory systems

The Ariel payload design post-PDR

The Ariel space mission will characterize spectroscopically the atmospheres of a large and diverse sample of hundreds of exoplanets. Through the study of targets with a wide range of planetary parameters (mass, density, equilibrium temperature) and host star types the origin for the diversity observed in known exoplanets will be better understood. Ariel is an ESA Medium class science mission (M4) with a spacecraft bus developed by industry under contract to ESA, and a Payload provided by a consortium of national funding agencies in ESA member states, plus contributions from NASA, the CSA and JAXA. The payload is based on a 1-meter class telescope operated at below 60K, built all in Aluminium, which feeds two science instruments. A multi-channel photometer and low-resolution spectrometer instrument (the FGS, Fine Guidance System instrument) operating from 0.5 – 1.95 microns in wavelength provides both guidance information for stabilizing the spacecraft pointing as well as vital scientific information from spectroscopy in the near-infrared and photometry in the visible channels. The Ariel InfraRed Spectrometer (AIRS) instrument provides medium resolution spectroscopy from 1.95 – 7.8 microns wavelength coverage over two instrument channels. Supporting subsystems provide the necessary mechanical, thermal and electronics support to the cryogenic payload. This paper presents the overall picture of the payload for the Ariel mission. The payload tightly integrates the design and analysis of the various payload elements (including for example the integrated STOP analysis of the Telescope and Common Optics) in order to allow the exacting photometric stability requirements for the mission to be met. The Ariel payload has passed through the Preliminary Design Review (completed in Q2 2023) and is now developing and building prototype models of the Telescope, Instruments and Subsystems (details of which will be provided in other contributions to this conference). This paper will present the current status of the development work and outline the future plans to complete the build and verification of the integrated payload