Characterization and prognostic impact of ACTBL2-positive tumor-infiltrating leukocytes in epithelial ovarian cancer.

Actin beta-like 2 (ACTBL2) was recently identified as a new mediator of migration in ovarian cancer cells. Yet, its impact on tumor-infiltrating and thus migrating leukocytes (TILs) remains to date unknown. This study characterizes the subset of ACTBL2-expressing TILs in epithelial ovarian cancer (EOC) and elucidates their prognostic influence on the overall survival of EOC patients with special regard to different histological subtypes. Comprehensive immunohistochemical analyses of Tissue-Microarrays of 156 ovarian cancer patients revealed, that a tumor infiltration by ACTBL2-positive leukocytes was significantly associated with an improved overall survival (OS) (61.2 vs. 34.4 months; p = 0.006) and was identified as an independent prognostic factor (HR = 0.556; p = 0.038). This significant survival benefit was particularly evident in patients with low-grade serous carcinoma (OS: median not reached vs. 15.6 months, p < 0.001; HR = 0.058, p = 0.018). In the present cohort, ACTBL2-positive TILs were mainly composed of CD44-positive cytotoxic T-cells (CD8+) and macrophages (CD68+), as depicted by double-immunofluorescence and various immunohistochemical serial staining. Our results provide significant evidence of the prognostic impact and cellular composition of ACTBL2-expressing TILs in EOC. Complementary studies are required to analyze the underlying molecular mechanisms of ACTBL2 as a marker for activated migrating leukocytes and to further characterize its immunological impact on ovarian carcinogenesis.

Alveolar gradients in breath analysis. A pilot study with comparison of room air and inhaled air by simultaneous measurements using ion mobility spectrometry.

Analyzing exhaled breath samples, especially using a highly sensitive method such as MCC/IMS (multi-capillary column/ion mobility spectrometry), may also detect analytes that are derived from exogenous production. In this regard, there is a discussion about the optimal interpretation of exhaled breath, either by considering volatile organic compounds (VOCs) only in exhaled breath or by additionally considering the composition of room air and calculating the alveolar gradients. However, there are no data on whether the composition and concentration of VOCs in room air are identical to those in truly inhaled air directly before analyzing the exhaled breath. The current study aimed to determine whether the VOCs in room air, which are usually used for the calculation of alveolar gradients, are identical to the VOCs in truly inhaled air. For the measurement of inhaled air and room air, two IMS, each coupled with an MCC that provided a pre-separation of the VOCs, were used in parallel. One device was used for sampling room air and the other for sampling inhaled air. Each device was coupled with a newly invented system that cleaned room air and provided a clean carrier gas, whereas formerly synthetic air had to be used as a carrier gas. In this pilot study, a healthy volunteer underwent three subsequent runs of sampling of inhaled air and simultaneous sampling and analysis of room air. Three of the selected 11 peaks (P4-unknown, P5-1-Butanol, and P9-Furan, 2-methyl-) had significantly higher intensities during inspiration than in room air, and four peaks (P1-1-Propanamine, N-(phenylmethylene), P2-2-Nonanone, P3-Benzene, 1,2,4-trimethyl-, and P11-Acetyl valeryl) had higher intensities in room air. Furthermore, four peaks (P6-Benzaldehyde, P7-Pentane, 2-methyl-, P8-Acetone, and P10-2-Propanamine) showed inconsistent differences in peak intensities between inhaled air and room air. To the best of our knowledge, this is the first study to compare simultaneous sampling of room air and inhaled air using MCC/IMS. The simultaneous measurement of inhaled air and room air showed that using room air for the calculation of alveolar gradients in breath analysis resulted in different alveolar gradient values than those obtained by measuring truly inhaled air.

Prevalence and correlates of 30-day suicidal ideation and intent: Results of the South African National Student Mental Health Survey.

BACKGROUND: Although suicide prevention is recognised as a priority among university students in South Africa (SA), it is unclear what proportion of students require urgent indicated interventions and what the characteristics are of these students. OBJECTIVE: To assess the prevalence and sociodemographic correlates of 30-day suicidal ideation, frequency of ideation and self-reported intention to act on ideation in the next year among a national sample of SA university students. METHODS: Self-report cross-sectional data were collected online from students (N=28 268) at 17 universities across SA as part of the national student mental health survey. Students reported suicidal ideation in the past 30 days, frequency of ideation and intention to act on ideation in the next year. Data were weighted within institutions by gender and population group, and across the four main types of universities (historically white, historically disadvantaged, technical and distance learning) to correct for response rate discrepancies. Prevalence was estimated with these weighted in the total sample and across types of universities. Poisson regression with robust error variances was used to investigate associations of sociodemographic characteristics with ideation and intention to act on suicidal ideation. Results are reported as relative risks (RRs) with design-based 95% confidence intervals (CIs). RESULTS: Thirty-day prevalence of suicidal ideation was 24.4% (standard error (SE) 0.3), with 2.1% (SE 0.1) and 4.1% (SE 0.1), respectively, reporting suicidal ideation all/almost all the time, or most of the time. A total of 1.5% (SE 0.1) of respondents reported being very likely to act on their suicidal ideation, while 3.9% (SE 0.2) were somewhat likely, 8.7% (SE 0.2) were not very likely and 85.8 (SE 0.5) either reported no suicidal ideation or that they were not at all likely to act on this ideation. Risk of suicidal ideation with high intent in the total sample was elevated among females (RR 1.9, 95% CI 1.3 - 2.7) and gender non-conforming students (RR 4.3, 95% CI 1.4 - 13.0) relative to males, black African students compared with white students (RR 3.6, 95% CI 1.9 - 7.1), students whose parents did not progress to secondary school compared with students whose parents had a university education (RR 1.6, 95% CI 1.0 - 2.5) and sexual minority students compared with heterosexual students (RR 1.9, 95% CI 1.3 - 2.6). Among students with 30-day ideation (controlling for frequency of ideation), only two of these predictors of high intent remained significant: identifying as black African (RR 2.7, 95% CI 1.4 - 5.1), and having parents with less than secondary education (RR 1.5, 95% CI 1.0 - 2.1). CONCLUSION: Scalable suicide prevention interventions are needed to reach the large number of SA students who report suicidal ideation with intent.

Translational and post-translational regulation of polyamine metabolic enzymes in plants.

Polyamines are small organic and basic polycations that perform essential regulatory functions in all living organisms. Fluctuations in polyamine content have been observed to occur during growth, development and under stress conditions, implying that polyamines play pivotal roles in diverse cellular and physiological processes. To achieve polyamine homeostasis, the entire metabolic pathway is subjected to a fine-tuned regulation of its biosynthetic and catabolic genes and enzymes. In this review, we describe and discuss the most important mechanisms implicated in the translational and post-translational regulation of polyamine metabolic enzymes in plants. At the translational level, we emphasize the role of polyamines in the modulation of upstream open reading frame (uORF) activities that control the translation of polyamine biosynthetic and catabolic mRNAs. At the post-translational level, different aspects of the regulation of polyamine metabolic proteins are depicted, such as the proteolytic activation of enzyme precursors, the importance of dimerization in protein stability as well as in protein intracellular localization.

Comparison of transcatheter edge-to-edge and surgical repair in patients with functional mitral regurgitation using a meta-analytic approach.

Background: Evidence regarding favorable treatment of patients with functional mitral regurgitation (FMR) using transcatheter edge-to-edge repair (TEER) is constantly growing. However, there is only few data directly comparing TEER and surgical mitral valve repair (SMVr). Aims: To compare baseline characteristics, short-term and 1-year outcomes in FMR patients undergoing mitral valve (MV) TEER or SMVr using a meta-analytic approach. Methods: Systematic database search identified 1,703 studies reporting on TEER or SMVr for treatment of FMR between January 2010 and December 2020. A meta-analytic approach was used to compare outcomes from single-arm and randomized studies based on measures by means of their corresponding 95% confidence intervals (CI). Statistical significance was assumed if CIs did not overlap. A total of 21 TEER and 37 SMVr studies comprising 4,304 and 3,983 patients were included. Results: Patients in the TEER cohort presented with higher age (72.0 ± 1.7 vs. 64.7 ± 4.7 years, p < 0.001), greater burden of comorbidities like hypertension (p < 0.001), atrial fibrillation (p < 0.001), lung disease (p < 0.001) and chronic renal disease (p = 0.005) as well as poorer left ventricular ejection fraction (30.9 ± 5.7 vs. 36.6 ± 5.3%, p < 0.001). In-hospital mortality was significantly lower with TEER [3% (95%-CI 0.02-0.03) vs. 5% (95%-CI 0.04-0.07)] and 1-year mortality did not differ significantly [18% (95%-CI 0.15-0.21) vs. 11% (0.07-0.18)]. NYHA [1.06 (95%-CI 0.87-1.26) vs. 1.15 (0.74-1.56)] and MR reduction [1.74 (95%-CI 1.52-1.97) vs. 2.08 (1.57-2.59)] were comparable between both cohorts. Conclusion: Despite considerably higher age and comorbidity burden, in-hospital mortality was significantly lower in FMR patients treated with TEER, whereas a tendency toward increased 1-year mortality was observed in this high-risk population. In terms of functional status and MR grade reduction, comparable 1-year results were achieved.

Achieving nitrogen and phosphorus removal at low C/N ratios without aeration through a novel phototrophic process.

Conventional wastewater treatment technologies for biological nutrient removal (BNR) are highly dependent on aeration for oxygen supply, which represents a major operational cost of the process. Recently, phototrophic enhanced biological phosphorus removal (photo-EBPR) has been suggested as an alternative system for phosphorus removal, based on a consortium of photosynthetic microorganisms and chemotrophic bacteria, eliminating the need for costly aeration. However, wastewater treatment plants must couple nitrogen and phosphorus removal to achieve discharge limits. For this reason, a new microalgae-bacterial based system for phosphorus and nitrogen removal is proposed in this work. The photo-BNR system studied here consists of a sequencing batch reactor operated with dark anaerobic, light aerobic, dark anoxic and idle periods, to allow both N and P removal. Results of the study show that the photo-BNR system was able to remove 100% of the 40 mg N/L of ammonia fed to the reactor and 94 ± 3% of the total nitrogen (Influent COD:N ratio of 300:40, similar to domestic wastewater). Moreover, an average of 25 ± 9.2 mg P/L was simultaneously removed in the photo-BNR tests, representing the P removal capacity of this system, which exceeds the level of P removal required from typical domestic wastewater. Full ammonia removal was achieved during the light phase, with 67 ± 5% of this ammonia being assimilated by the microbial culture and the remaining 33 ± 5% being converted into nitrate. The assimilated P corresponded to 2.8 ± 0.23 mg P/L, which only represented, approximately, 1/9 of the P removal capacity of the system. Half of the nitrified ammonia was subsequently denitrified during the dark anoxic phase (50 ± 24%). Overall, the photo-BNR system represents the first treatment alternative for N and P from domestic wastewater with no need of mechanical aeration or supplemental carbon addition, representing an alternative low-energy technology of interest.

Melanocytic tumours of the nasal planum in cats: 10 cases (2004-2019).

OBJECTIVES: To better characterise signalment, biologic behaviour, and treatment outcome in melanocytic tumours of the nasal planum in cats. MATERIALS AND METHODS: Retrospective study in cats diagnosed with histopathologically confirmed melanocytic tumours on the nasal planum. RESULTS: Ten cats were identified with melanocytic tumours of the nasal planum. Pigmentation of the nasal planum seemed to be a predisposing factor. Seven cats were diagnosed histopathologically with a malignant melanoma, three with a benign melanocytoma. One of the cats developed a lymph node metastasis despite diagnosis of a well-differentiated melanocytic neoplasia. In four cases, a pigmented mass, which was initially stable over a long time, showed a sudden rapid progression suggesting malignant transformation. Treatments included hypofractionated radiation therapy (n = 6) and surgical resection (n = 1). In three cats no further treatment was pursued. Complete (n = 3) and partial (n = 3) remissions were observed in cats treated with radiation therapy; however, all experienced tumour progression or recurrence after a short period of time. Most of the cats (n = 7) had to be euthanased due to tumour progression (median survival time: 265 days). CLINICAL SIGNIFICANCE: The present case series provides insights in clinical presentation and clinical outcomes of cats with melanocytic tumours of the nasal planum.

GABAA Receptors in the Mongolian Gerbil: a PET Study Using [18F]Flumazenil to Determine Receptor Binding in Young and Old Animals.

PURPOSE: Plastic changes in the central auditory system involving the GABAergic system accompany age-related hearing loss. Such processes can be investigated with positron emission tomography (PET) imaging using [18F]flumazenil ([18F]FMZ). Here, [18F]FMZ PET-based modeling approaches allow a simple and reliable quantification of GABAA receptor binding capacity revealing regional differences and age-related changes. PROCEDURES: Sixty-minute list-mode PET acquisitions were performed in 9 young (range 5-6 months) and 11 old (range 39-42 months) gerbils, starting simultaneously with the injection of [18F]FMZ via femoral vein. Non-displaceable binding potentials (BPnd) with pons as reference region were calculated for auditory cortex (AC), inferior colliculus (IC), medial geniculate body (MGB), somatosensory cortex (SC), and cerebellum (CB) using (i) a two-tissue compartment model (2TCM), (ii) the Logan plot with image-derived blood-input (Logan (BI)), (iii) a simplified reference tissue model (SRTM), and (iv) the Logan reference model (Logan (RT)). Statistical parametric mapping analysis (SPM) comparing young and old gerbils was performed using 3D parametric images for BPnd based on SRTM. Results were verified with in vitro autoradiography from five additional young gerbils. Model assessment included the Akaike information criterion (AIC). Hearing was evaluated using auditory brainstem responses. RESULTS: BPnd differed significantly between models (p < 0.0005), showing the smallest mean difference between 2TCM as reference and SRTM as simplified procedure. SRTM revealed the lowest AIC values. Both volume of distribution (r2 = 0.8793, p = 0.018) and BPnd (r2 = 0.8216, p = 0.034) correlated with in vitro autoradiography data. A significant age-related decrease of receptor binding was observed in auditory (AC, IC, MGB) and other brain regions (SC and CB) (p < 0.0001, unpaired t test) being confirmed by SPM using pons as reference (p < 0.0001, uncorrected). CONCLUSION: Imaging of GABAA receptor binding capacity in gerbils using [18F]FMZ PET revealed SRTM as a simple and robust quantification method of GABAA receptors. Comparison of BPnd in young and old gerbils demonstrated an age-related decrease of GABAA receptor binding.

Functionalisation of TiO2 nanoparticles with a fluorescent organosilane: A synergy enabling their visualisation in biological cells and an enhanced photocatalytic activity.

Nanoparticles, such as TiO2 particles, have a great potential for biomedical applications due to their ultra-small size and large specific surface area. However, their detection within cells is to date more than challenging. Thus, implementing fluorescence properties to nanoparticles via their controlled functionalisation with an organic chromophore is an original and efficient strategy to enable their visualization. In this work, a silylated coupling agent bearing a luminescent rhodamine B group was synthesised and grafted on the surface of anatase nanoparticles. The successful functionalisation was demonstrated via zeta potential, dynamic light scattering and diffuse reflectance infrared Fourier transform analyses. Remarkably, the obtained luminescent TiO2 particles showed an improved photocatalytic activity compared to the pristine nanoparticles. Both, as-synthesised and functionalised TiO2 nanoparticles samples appear to be non-toxic towards malignant and non-malignant cells. Moreover, the detection of the functionalised particles within cultured cells was proven to be easy and efficient via confocal fluorescence microscopy.

[Robotic-assisted laparoscopic living donor nephrectomy: Study in donors and recipients from 155 cases]. / Néphrectomie laparoscopique assistée par robot dans le cadre du donneur-vivant : étude chez les donneurs et les receveurs à partir de 155 cas.

AIM: To evaluate morbidity and renal function of the donor and recipient during a robotic-assisted laparoscopic nephrectomy procedure. PATIENTS AND METHODS: It is a retrospective study of 155 consecutive patients by robot-assisted laparoscopy in the living donor. Mean operating time, warm ischemia time, blood loss, complications according to the Clavien classification and evolution of creatinine clearance were analyzed in the donors. Recovery of graft function, complications and changes in creatinine clearance were observed in recipients. RESULTS: The mean operating time was 176 (±23) minutes. The mean warm ischemia time was 4.8 (±0.6) minutes. Twenty seven complications were noted. The loss of renal function was 19% at 5 years in donors. Renal recovery was immediate for 153 recipients. Two were delayed due to sepsis. Two patients lost their graft at 15 and 18 months. Seventeen complications have been identified. The mean kidney function of the recipients is measured at 63ml/min at 5 years. CONCLUSION: Robotic-assisted laparoscopic nephrectomy procedure appears to provide the donor with low morbidity and a moderate decrease in creatinine clearance at 19% at 5 years. Morbidity is also low in recipients with very satisfactory 5-year mean renal function. The technique should promote donation. LEVEL OF EVIDENCE: 4.

Influence of permanent pacemaker implantation after transcatheter aortic valve implantation with new-generation devices.

OBJECTIVE: Permanent pacemaker implantation (PPMI) after transcatheter aortic valve implantation (TAVI) is the most common complication after the procedure. PPMI rates remain high with the new-generation TAVI devices despite improved outcomes concerning paravalvular aortic regurgitation and vascular access complications. However, the impact of PPMI on mortality and clinical outcome is still a matter of debate, and data with new-generation devices on this matter are scarce. Therefore, we sought to analyse the influence of PPMI in patients treated with the new-generation devices on one-year outcome. METHODS: We enrolled 612 consecutive patients without prior pacemaker undergoing transfemoral TAVI with the new-generation devices. Patients with or without PPMI were compared with respect to clinical outcome within one year. RESULTS: PPMI was performed in 168 patients (24.4% of the overall study population). There was no significant difference in one-year outcome concerning all-cause mortality (PPMI vs. no-PPMI: 12.2% vs. 12.5%, p = 0.94), rate of major adverse events including cardiac, cerebral or valve-related events and bleeding complications (22.1% vs. 24.5%, p = 0.55) or need for rehospitalisation due to cardiac symptoms (16.1% vs. 18.1%, p = 0.63). In patients with reduced ejection fraction (<45%) there was also no impact of PPMI on one-year mortality (14.3% vs. 15.7%, p = 0.86). Furthermore, multivariate analysis did not reveal PPMI to be independently associated with one-year mortality (odds ratio 0.94, 95% confidence interval 0.50-1.74, p = 0.83). CONCLUSIONS: In this large all-comers TAVI population with new-generation devices the need for postprocedural PPMI did not show a statistical significant impact on survival or combined endpoint of major adverse events within one year.

Treatment data and technical process challenges for practical big data efforts in radiation oncology.

The term Big Data has come to encompass a number of concepts and uses within medicine. This paper lays out the relevance and application of large collections of data in the radiation oncology community. We describe the potential importance and uses in clinical practice. The important concepts are then described and how they have been or could be implemented are discussed. Impediments to progress in the collection and use of sufficient quantities of data are also described. Finally, recommendations for how the community can move forward to achieve the potential of big data in radiation oncology are provided.

Impact of reduced exposure to calcineurin inhibitors on the development of de novo DSA: a cohort of non-immunized first kidney graft recipients between 2007 and 2014.

BACKGROUND: In low-immunological risk kidney transplant recipients (KTRs), reduced exposure to calcineurin inhibitor (CNI) appears particularly attractive for avoiding adverse events, but may increase the risk of developing de novo Donor Specific Antibodies (dnDSA). METHODS: CNI exposure was retrospectively analyzed in 247 non-HLA immunized first KTRs by taking into account trough levels (C0) collected during follow-up. Reduced exposure to CNI was defined as follows: C0 less than the lower limit of the international targets for ≥50% of follow-up. RESULTS: During a mean follow-up of 5.0 ± 2.0 years, 39 patients (15.8%) developed dnDSA (MFI ≥1000). Patients with DSA were significantly younger (46.6 ± 13.8 vs. 51.7 ± 14.0 years, p = 0.039), received more frequently poorly-matched grafts (59% with 6-8 A-B-DR-DQ HLA mismatches vs. 34.6%, p = 0.016) and had more frequently a reduced exposure to CNI (92.3% vs. 62.0%, p = 0.0002). Reduced exposure to CNI was associated with an increased risk of dnDSA (multivariable HR = 9.77, p = 0.002). Reduced exposure to CNI had no effect on patient survival, graft loss from any cause including death, or post-transplant cancer. CONCLUSIONS: Even in a low-immunological risk population, reduced exposure to CNI is associated with increased risk of dnDSA. Benefits and risks of under-immunosuppression must be carefully evaluated before deciding on CNI minimization.

Activation in the auditory pathway of the gerbil studied with 18F-FDG PET: effects of anesthesia.

Here, we present results from an 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) study in the Mongolian gerbil, a preferred animal model in auditory research. One major issue in preclinical nuclear imaging, as well as in most of the neurophysiological methods investigating auditory processing, is the need of anesthesia. We compared the usability of two types of anesthesia which are frequently employed in electrophysiology, ketamine/xylazine (KX), and fentanyl/midazolam/medetomidine (FMM), for valid measurements of auditory activation with 18F-FDG PET. Gerbils were placed in a sound-shielding box and injected with 18F-FDG. Two acoustic free-field conditions were used: (1) baseline (no stimulation, 25 dB background noise) and (2) 90 dB frequency-modulated tones (FM). After 40 min of 18F-FDG uptake, a 30 min acquisition was performed using a small animal PET/CT system. Blood glucose levels were measured after the uptake phase before scanning. Standardized uptake value ratios for relevant regions were determined after implementing image and volume of interest templates. Scans demonstrated a significantly higher uptake in the inferior colliculus with FM stimulation compared to baseline in awake subjects (+ 12%; p = 0.02) and with FMM anesthesia (+ 13%; p = 0.0012), but not with KX anesthesia. In non-auditory brain regions, no significant difference was detected. Blood glucose levels were significantly higher under KX compared to FMM anesthesia (17.29 ± 0.42 mmol/l vs. 14.30 ± 1.91 mmol/l; p = 0.024). These results suggest that valid 18F-FDG PET measurements of auditory activation comparable to electrophysiology can be obtained from gerbils during opioid-based anesthesia due to its limited effects on interfering blood glucose levels.

A zebrafish model for FHL1-opathy reveals loss-of-function effects of human FHL1 mutations.

Missense mutations in the four and a half LIM domain 1 (FHL1) gene were found to cause X-linked inherited myopathies of both skeletal and heart muscles. However, the mechanisms by which FHL1 mutations impact on FHL1 function and lead to alteration of muscle structure and function have not been deciphered yet. We generated here by Morpholino-modified antisense oligonucleotide-mediated gene knockdown fHL1-deficient zebrafish embryos. Similar to the human situation, fhl1a-morphants zebrafish displayed severe skeletal and heart muscle myopathy. Whereas ectopic expression of wild-type FHL1 (FHL1 wt) suppressed both skeletal and heart muscle myopathy in fhl1a-morphants zebrafish, overexpression of the FHL1-opathy associated human mutations FHL1-H123Y, FHL1-C132F or FHL1-C224W did not rescue skeletal and heart muscle myopathy in fhl1a-morphants. Overexpression of FHL1-H123Y, FHL1-C132F or FHL1-C224W in wild-type zebrafish did not induce myopathy in a dominant-negative mode. Altogether these results indicate that FHL1 mutations found to cause X-linked FHL1-opathies in humans consistently lead to severely impaired FHL1 function.

Combination toceranib and lomustine shows frequent high grade toxicities when used for treatment of non-resectable or recurrent mast cell tumours in dogs: A European multicentre study.

Mast cell tumours (MCTs) in dogs can present in a variety of forms. Non-resectable, recurrent or metastatic MCTs usually carry a poor prognosis and present a therapeutic challenge. Both toceranib and lomustine have shown single agent activity against MCTs in dogs. In this study, 10 dogs with advanced MCTs were enrolled prospectively and treated with toceranib (median dose 2.7mg/kg orally every other day), lomustine (median dose 60mg/m2 orally every 3 weeks) and prednisolone (1mg/kg orally every other day, alternating with toceranib). Severe adverse events (SAEs), requiring alterations in the protocol, occurred in all dogs. The objective response rate was 50%. Three dogs died or were euthanased due to SAEs and therefore enrolment of new dogs was discontinued prematurely. A long term response (>1year) was observed in two dogs. Modifications of the protocol are required for future prospective studies.

Comparison of a CHOP-LAsp-based protocol with and without maintenance for canine multicentric lymphoma.

The recommendation to treat canine lymphoma with a discontinuous protocol is based on small case numbers and mostly historic controls. This study compares duration of first remission (DFR) and overall survival time (ST) with a discontinuous protocol to the same protocol with maintenance phase. 408 dogs were treated with a CHOP-LAsp (C=cyclophosphamide; H=hydroxydaunorubicin; O=Oncovin; P=prednisolone; LAsp=l-asparaginase)-based 28-week induction protocol. In 75 dogs (cohort 1), this was followed by a maintenance phase consisting of vincristine, chlorambucil and actinomycin-D with a total treatment duration of two years. In the subsequent 333 dogs, therapy was discontinued after induction (cohort 2). Median DFR and ST in cohort 1 were 216 and 375 days and 184 and 304 days in cohort 2. 6-Month, 1-year and 2-year survival rates in cohort 1 were 73 per cent, 50 per cent, 24 per cent and 67 per cent, 39 per cent, 21 per cent in cohort 2. There was no significant difference between the two protocols (P=0.291 for ST, P=0.071 for DFR). On multivariate analysis, corticosteroid pretreatment (P=0.005), thrombocytopenia at diagnosis (P=0.019), stage (P=0.009), substage b at relapse (P<0.001), age (P=0.002) and incomplete or unstable remission necessitating intensification of therapy (P=0.004) were negatively correlated with ST in both groups. This study supports the use of a discontinuous protocol for canine multicentric lymphoma.

Pollinator adaptation and the evolution of floral nectar sugar composition.

A long-standing debate concerns whether nectar sugar composition evolves as an adaptation to pollinator dietary requirements or whether it is 'phylogenetically constrained'. Here, we use a modelling approach to evaluate the hypothesis that nectar sucrose proportion (NSP) is an adaptation to pollinators. We analyse ~ 2100 species of asterids, spanning several plant families and pollinator groups (PGs), and show that the hypothesis of adaptation cannot be rejected: NSP evolves towards two optimal values, high NSP for specialist-pollinated and low NSP for generalist-pollinated plants. However, the inferred adaptive process is weak, suggesting that adaptation to PG only provides a partial explanation for how nectar evolves. Additional factors are therefore needed to fully explain nectar evolution, and we suggest that future studies might incorporate floral shape and size and the abiotic environment into the analytical framework. Further, we show that NSP and PG evolution are correlated - in a manner dictated by pollinator behaviour. This contrasts with the view that a plant necessarily has to adapt its nectar composition to ensure pollination but rather suggests that pollinators adapt their foraging behaviour or dietary requirements to the nectar sugar composition presented by the plants. Finally, we document unexpectedly sucrose-poor nectar in some specialized nectarivorous bird-pollinated plants from the Old World, which might represent an overlooked form of pollinator deception. Thus, our broad study provides several new insights into how nectar evolves and we conclude by discussing why maintaining the conceptual dichotomy between adaptation and constraint might be unhelpful for advancing this field.

Temporal Trend and Time-Varying Effect of Preemptive Second Kidney Transplantation on Graft Survival: A 30-Year Single-Center Cohort Study.

BACKGROUND: There are discrepancies regarding the impact of preemptive 2nd kidney transplantation (PSKT) on graft survival. The present study aimed to determine whether the association between PSKT and outcome varies over time and whether this association is era dependent. METHODS: A total of 266 patients underwent SKT (244 non-PSKT, 22 PSKT) in our center from 1985 to 2015. Association between PSKT and graft survival (allograft failure from any cause including death) was assessed with the use of Cox models. RESULTS: During a median follow-up of 6.7 years, 116 events were recorded: 72 returns to dialysis and 44 deaths before return to dialysis. Survival curves diverged up to 5 years (5-year survivals: PSKT, 94.1 ± 5.7%; non-PSKT, 76.8 ± 2.9%) but they converged thereafter (12-year survivals: PSKT, 50.9 ± 15.2%; non-PSKT, 55.5 ± 3.9%). After adjustment for age and living-donor status, PSKT tended to be associated with better graft survival (hazard ratio [HR], 0.18; 95% confidence interval [CI], 0.02-1.27; P = .08) within the first 5 years of SKT but tended to be associated with worse outcome thereafter (HR, 2.36; 95% CI, 0.97-5.72; P = .06; P for interaction with time = .04). In addition, a significant interaction was identified between PSKT and SKT year (P for interaction = .04). In the multivariable model, the estimated HR for PSKT was 2.54 (95% CI, 0.88-7.35; P = .08) in 1990 as opposed to 0.16 (95% CI, 0.02-1.17; P = .07) in 2012. CONCLUSIONS: The effect of PSKT on graft survival varies over time and according to year of the procedure. Although the benefit observed within the first 5 years of SKT appears to fade over time, overall graft survival seemingly improved in more recent years.

Polycarboxylate ethers: The key towards non-toxic TiO2 nanoparticle stabilisation in physiological solutions.

Stable, non-agglomerated TiO2 nanoparticle (NP) dispersions are a crucial requirement for an accurate NP dosing in in vitro and in vivo experiments. In this study self-synthesised TiO2 NPs were stabilised in three different cell culture media (DMEM, RPMI, BEGM) with the help of stabilising agents. Cell culture tested stabilisers (bovine serum albumin, fetal bovine serum) were compared to non-tested commercial products which are commonly utilized in the cement industry (Melflux(®) 4930 F, Melpers(®) 4343, Sika(®) ViscoCrete(®)-10110178). For a quantitative evaluation and comparison of the degree of stabilisation, a sedimentation study using UV absorbance spectroscopy was carried out and the agglomerate size was measured via dynamic light scattering. The cytotoxicity of the novel surfactants and stabilised NPs was examined in a head and neck squamous cell carcinoma-derived FaDu cell line and in human mesenchymal stem cells. We successfully stabilised TiO2 NPs with Melflux(®) 4930 F in each cell culture medium, achieving perfect stability over at least one day and agglomerate sizes of less than 100nm, while the cytotoxicity of the NPs was not affected.