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Recent advances of data‐independent acquisition mass spectrometry‐based proteomics

Recent advances of data‐independent acquisition mass spectrometry‐based proteomics

Comparative activity of newer β-lactam/β-lactamase inhibitor combinations against Pseudomonas aeruginosa isolates from US medical centres (2020-2021).

To evaluate the in-vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-relebactam and comparator agents against contemporary Pseudomonas aeruginosa isolates from US hospitals. In total, 3184 isolates were collected consecutively from 71 US medical centres in 2020-2021, and susceptibility tested by reference broth microdilution. Clinical Laboratory Standard Institute breakpoints were applied. Ceftazidime-avibactam [97.0% susceptible (S)], ceftolozane-tazobactam (98.0%S), imipenem-relebactam (97.3%S) and tobramycin (96.4%S) were the most active agents against the aggregate P. aeruginosa isolate collection, and retained good activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and multi-drug-resistant (MDR) isolates. All other antimicrobials tested showed limited activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and MDR isolates. The most common infections were pneumonia (45.9%), skin and skin structure infections (19.0%), urinary tract infections (17.0%) and bloodstream infections (11.7%); ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam showed consistent activity against isolates from these infection types. Susceptibility to piperacillin-tazobactam and meropenem was lower among isolates from pneumonia compared with other infection types. Ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam were highly active, and exhibited similar coverage against a large contemporary collection of P. aeruginosa isolates from US hospitals. Cross-resistance among the newer β-lactams/β-lactam inhibitors (BL/BLIs) varied markedly; ≥72.1% of isolates resistant to one of the three newer BL/BLIs approved for P. aeruginosa treatment remained susceptible to at least one of the other two BL/BLIs, indicating that all three should be tested in the clinical laboratory. These three BL/BLIs represent valuable therapeutic options for P. aeruginosa infection.

Effect of 0.35 T and 1.5 T magnetic fields on superficial dose in MR-guided radiotherapy of laryngeal cancer

BackgroundTreatment of head and neck cancer on linear accelerators with on-board magnetic resonance imaging (MR-linac) might be beneficial to reduce side effects and increase accuracy. For many head and neck cancer patients, dose coverage of the often superficially located planning target volumes (PTVs) is required. This study examines the impact of the electron return effect (ERE) on the surface dose in MR-guided radiotherapy (MRgRT) compared to conventional radiotherapy. Materials and methodsFor this bicentric dosimetric study, 14 cases of laryngeal carcinomas with PTVs reaching up to the skin surface were included. For each patient, five different plans were compared, two VMAT plans (with and without a 5 mm bolus) and three IMRT MRgRT plans (0.35 T, 1.5 T and 0 T, each without bolus). Dose distributions were also validated with film measurements. ResultsA similar coverage on the most superficial 3–5 mm of the PTV was achieved in the VMAT plans with bolus and the MRgRT plans for both 0.35 T and 1.5 T. However, coverage on this region was usually not achieved for VMAT without bolus and the 0 T plans. The film measurements on phantoms confirmed the results with the relative error never exceeding the calculated differences between the plans. ConclusionThe present study could demonstrate that the ERE for both commercially available MR-linac variants provides sufficient coverage of the superficial tissue layers in MRgRT-plans for laryngeal carcinoma.

Immunization Gender Inequity in Pakistan: An Analysis of 6.2 Million Children Born from 2019 to 2022 and Enrolled in the Sindh Electronic Immunization Registry

Gender-based inequities in immunization impede the universal coverage of childhood vaccines. Leveraging data from the Government of Sindh's Electronic Immunization Registry (SEIR), we estimated inequalities in immunization for males and females from the 2019-2022 birth cohorts in Pakistan. We computed male-to-female (M:F) and gender inequality ratios (GIR) Tfor enrollment, vaccine coverage, and timeliness. We also explored the inequities by maternal literacy, geographic location, mode of vaccination delivery, and gender of vaccinators. Between 1 January 2019, and 31 December 2022, 6,235,305 children were enrolled in the SEIR, 52.2% males and 47.8% females. We observed a median M:F ratio of 1.03 at enrollment and at Penta-1, Penta-3, and Measles-1 vaccinations, indicating more males were enrolled in the immunization system than females. Once enrolled, a median GIR of 1.00 indicated similar coverage for females and males over time; however, females experienced a delay in their vaccination timeliness. Low maternal education; residing in remote-rural, rural, and slum regions; and receiving vaccines at fixed sites, as compared to outreach, were associated with fewer females being vaccinated, as compared to males. Our findings suggeste the need to tailor and implement gender-sensitive policies and strategies for improving equity in immunization, especially in vulnerable geographies with persistently high inequalities.

Ayo, Bisexual Check

Ayo, Bisexual Check

Wall conditioning effects and boron migration during boron powder injection in ASDEX Upgrade

The efficacy of boron powder injection as a wall conditioning tool method in terms of its ability to create a sufficiently uniform boron layer on plasma-facing surfaces has been studied in ASDEX Upgrade. Boron powder was injected in two series of dedicated plasma discharges at varied injection rates and total amount injected. The resulting boron deposition was determined quantitatively by exposure of witness samples followed by ex-situ surface analysis of the retrieved samples. In both experiments, isotopically enriched boron was used to distinguish the deposition of the newly injected material from the residual boron fraction in the machine originating from previous glow discharge boronisations. It could be confirmed that the injected boron is migrating and re-deposited across plasma-facing wall surfaces already within one discharge. At erosion dominated divertor areas, the boron influx from the main chamber results in formation of a mixed tungsten-boron surface layer with a boron area density of O(1nm) whereas at deposition dominated areas closed boron layers grow with ongoing boron injection to a thickness of up to O(1μm). Extrapolating the radial boron deposition profile on the samples exposed in the main chamber to the limiter front yields a similar boron coverage of O(1μm), which is about ten times higher than typical values for glow discharge boronisation. Together with the observed reduction of oxygen level and improved wall pumping, the surface analysis results demonstrate that boron powder injection provides a suitable means to refresh the wall conditioning effect of a preceding glow discharge boronisation.

Advances in retrieving XCH4 and XCO from Sentinel-5 Precursor: improvements in the scientific TROPOMI/WFMD algorithm

Abstract. The TROPOspheric Monitoring Instrument (TROPOMI) on board the Sentinel-5 Precursor satellite enables the accurate determination of atmospheric methane (CH4) and carbon monoxide (CO) abundances at high spatial resolution and global daily sampling. Due to its wide swath and sampling, the global distribution of both gases can be determined in unprecedented detail. The scientific retrieval algorithm Weighting Function Modified Differential Optical Absorption Spectroscopy (WFMD) has proven valuable in simultaneously retrieving the atmospheric column-averaged dry-air mole fractions XCH4 and XCO from TROPOMI's radiance measurements in the shortwave infrared (SWIR) spectral range. Here we present recent improvements of the algorithm which have been incorporated into the current version (v1.8) of the TROPOMI/WFMD product. This includes processing adjustments such as increasing the polynomial degree to 3 in the fitting procedure to better account for possible spectral albedo variations within the fitting window and updating the digital elevation model to minimise topography-related biases. In the post-processing, the machine-learning-based quality filter has been refined using additional data when training the random forest classifier to further reduce scenes with residual cloudiness that are incorrectly classified as good. In particular, the cloud filtering over the Arctic ocean is considerably improved. Furthermore, the machine learning calibration, addressing systematic errors due to simplifications in the forward model or instrumental issues, has been optimised. By including an additional feature associated with the fitted polynomial when training the corresponding random forest regressor, spectral albedo variations are better accounted for. To remove vertical stripes in the XCH4 and XCO data, an efficient orbit-wise destriping filter based on combined wavelet–Fourier filtering has been implemented, while optimally preserving the original spatial trace gas features. The temporal coverage of the data records has been extended to the end of April 2022, covering a total length of 4.5 years since the start of the mission, and will be further extended in the future. Validation with the ground-based Total Carbon Column Observing Network (TCCON) demonstrates that the implemented improvements reduce the pseudo-noise component of the products, resulting in an improved random error. The XCH4 and XCO products have similar spatial coverage from year to year including high latitudes and the oceans. The analysis of annual growth rates reveals accelerated growth of atmospheric methane during the covered period, in line with observations at marine surface sites of the Global Monitoring Division of NOAA's Earth System Research Laboratory, which reported consecutive annual record increases over the past 2 years of 2020 and 2021.

ASAP─Automated Sonication-Free Acid-Assisted Proteomes─from Cells and FFPE Tissues.

Formalin-fixed, paraffin-embedded (FFPE) tissues are an invaluable resource for retrospective studies, but protein extraction and subsequent sample processing steps have been shown to be challenging for mass spectrometry (MS) analysis. Streamlined high-throughput sample preparation workflows are essential for efficient peptide extraction from complex clinical specimens such as fresh frozen tissues or FFPE. Overall, proteome analysis has gained significant improvements in the instrumentation, acquisition methods, sample preparation workflows, and analysis pipelines, yet even the most recent FFPE workflows remain complex and are not readily scalable. Here, we present an optimized workflow for automated sonication-free acid-assisted proteome (ASAP) extraction from FFPE sections. ASAP enables efficient protein extraction from FFPE specimens, achieving similar proteome coverage as established methods using expensive sonicators, resulting in reduced sample processing time. The broad applicability of ASAP on archived pediatric tumor FFPE specimens resulted in high-quality data with increased proteome coverage and quantitative reproducibility. Our study demonstrates the practicality and superiority of the ASAP workflow as a streamlined, time- and cost-effective pipeline for high-throughput FFPE proteomics of clinical specimens.

Effect of Intelligent Multi-Association in Civil Aircraft-Augmented SAGIN

Although 5G networks have gradually commercialized, many scenarios like emergency areas and remote regions still exist with vast communication problems. In this paper, we provide a detailed analysis of civil-aircraft augmented space-air-ground integrated networks (CAA-SAGIN), where the user’s association strategy can be determined intelligently. First, we discuss the influence of the spatial distribution of civil aircrafts (CAs) and satellites on the Rician factor. Then, we provide a novel and simple expression of moment-generating functions related to small-fading variables. With massive visible access points (APs), we combine two user-centric connectivity methods, i.e., multiple resource blocks in a single AP (MRB-SA) and collaborative connectivity in multiple APs (CC-MA), and each segment’s ergodic capacity and coverage probability are investigated respectively. The numerical results demonstrate that CA networks can provide similar coverage and capacity performance as satellite networks in the given range. The advantages of introducing CAs to the satellite-terrestrial integrated networks are significant under the combined connectivity methods. This paper quantitatively proves CA networks’ benefits in capacity and coverage and lays a theoretical foundation for CAA-SAGIN.

Operations research contribution to totally automated radiotherapy treatment planning: A noncoplanar beam angle and fluence map optimization engine based on optimization models and algorithms

The planning of radiotherapy treatments is based on the use of mathematical optimization models and algorithms. A treatment plan will correspond to an admissible solution to a problem that is defined by the medical prescription. The medical prescription defines the constraints that have to be satisfied, and that are patient dependent. To find a treatment plan complying with all the defined constraints, an objective function is built, having a set of parameters that can be tuned. In the clinical practice, the objective function parameters are tuned through a trial-and-error procedure. One common way of defining this objective function is to consider as parameters weights that are related with the importance of the corresponding structures of interest (volumes to treat and organs to spare), as well as upper and lower bounds that are related with the constraints defined by the medical prescription. Some treatment options, like the set of irradiation directions (beam angles), are usually defined beforehand by the planner, considering previous experiences with similar cases. This trial-and-error process is lengthy, since it can take up to several hours to calculate an admissible treatment plan for a single patient. There have been some research efforts to automate the treatment planning procedure, releasing the planner for other important tasks in the radiotherapy treatment workflow and guaranteeing the consistent calculation of high-quality plans. In this work derivative-free optimization algorithms are integrated with fuzzy inference systems that automatically tune the objective function parameters so that an admissible solution is found. This fully automated approach was tested and assessed considering six head-and-neck cancer cases already treated at the Portuguese Institute of Oncology at Coimbra (IPOC). For the clinical cases tested, comparisons between different treatment plans clearly favor the proposed approach. For a similar tumor coverage, it was possible to improve the sparing of the spinal cord, brainstem and parotids. Automating radiotherapy treatment planning can contribute to improved treatment plans in a consistent way.

Different meaning of the mean heart dose between 3D-CRT and IMRT for breast cancer radiotherapy.

Previous studies in 2D and in 3D conformal radiotherapy concludes that the maximal heart distance and the mean heart dose (MHD) are considered predictive of late cardiac toxicities. As the use of inverse-planned intensity modulated radiation therapy (IMRT) is increasing worldwide, we hypothesized that this 3D MHD might not be representative of heart exposure after IMRT for breast cancer (BC). Patients with left-sided BC and unfavorable cardiac anatomy received IMRT. Their treatment plan was compared to a virtual treatment plan for 3D conformal radiotherapy with similar target volume coverage (study A). Then, a second 3D conformal treatment plan was generated to achieve equivalent individual MHD obtained by IMRT. Then the heart and left anterior descending (LAD) coronary artery exposures were analyzed (study B). Last, the relationship between MHD and the heart volume or LAD coronary artery volume receiving at least 30Gy, 40Gy and 45Gy in function of each additional 1Gy to the MHD was assessed (study C). A significant decrease of heart and LAD coronary artery exposure to high dose was observed with the IMRT compared with the 3D conformal radiotherapy plans that both ensured adequate target coverage (study A). The results of study B and C showed that 3D MHD was not representative of similar heart substructure exposure with IMRT, especially in the case of high dose exposure. The mean heart dose is not a representative dosimetric parameter to assess heart exposure following IMRT. Equivalent MHD values following IMRT and 3DRT BC treatment do not represent the same dose distribution leading to extreme caution when using this parameter for IMRT plan validation.

Proton minibeam radiation therapy for treating metastases: A treatment plan study.

Proton minibeam radiation therapy (pMBRT) is a new radiotherapy approach that has shown a significant increase in the therapeutic window in glioma-bearing rats compared to conventional proton therapy. Such preclinical results encourage the preparation of clinical trials. In this study, the potential of pMBRT for treating clinical indications candidates for the first clinical trials (i.e., brain, lung, and liver metastases) was evaluated. Four clinical cases, initially treated with stereotactic radiotherapy (SRT), were selected for this study. pMBRT, SRT, and conventional proton therapy (PT) dose distributions were compared by using three main criteria: (i) the tumor coverage, (ii) the mean dose to organs-at-risk, and (iii) the possible adverse effects in normal tissues by considering valley doses as the responsible for tissue sparing. pMBRT plans consisted of one fraction and one-two fields. Dose calculations were computed by means of Monte Carlo simulations. pMBRT treatments provide a similar or superior target coverage than SRT, even using fewer fields. pMBRT also significantly reduces the biologically effective dose (BED) to organs-at-risk. In addition, valley and mean doses to normal tissues remain below tolerance limits when treatments are delivered in a single fraction, contrary to PT treatments. This work provides a first insight into the possibility of treating metastases with pMBRT. More favorable dose distributions and treatment delivery regimes may be expected from this new approach than SRT. The advantages of pMBRT would need to be confirmed by means of Phase I clinical trials.

Evaluation of Two Simultaneous Metabolomic and Proteomic Extraction Protocols Assessed by Ultra-High-Performance Liquid Chromatography Tandem Mass Spectrometry.

Untargeted multi-omics analysis of plasma is an emerging tool for the identification of novel biomarkers for evaluating disease prognosis, and for developing a better understanding of molecular mechanisms underlying human disease. The successful application of metabolomic and proteomic approaches relies on reproducibly quantifying a wide range of metabolites and proteins. Herein, we report the results of untargeted metabolomic and proteomic analyses from blood plasma samples following analyte extraction by two frequently-used solvent systems: chloroform/methanol and methanol-only. Whole blood samples were collected from participants (n = 6) at University Hospital Sharjah (UHS) hospital, then plasma was separated and extracted by two methods: (i) methanol precipitation and (ii) 4:3 methanol:chloroform extraction. The coverage and reproducibility of the two methods were assessed by ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS). The study revealed that metabolite extraction by methanol-only showed greater reproducibility for both metabolomic and proteomic quantifications than did methanol/chloroform, while yielding similar peptide coverage. However, coverage of extracted metabolites was higher with the methanol/chloroform precipitation.

PS-BPB06-5: URINARY CELL TRANSCRIPTOMICS: A NON-INVASIVE EXPRESSION READOUT OF KIDNEY GENES OF RELEVANCE TO HYPERTENSION

Objective: Hypertension affects 35% of the global adult population and is the leading preventable risk factor for premature death globally. The kidney is the key organ of blood pressure regulation in the body. Here, we compare the gene expression profile from renal cells shed naturally into the urine and kidney tissue to determine if urine can provide a non-invasive readout of kidney gene expression and whether hypertension-associated genes can be quantified in urine. Design and Method: Urinary cell and kidney tissue samples were collected from 33 human participants and were both profiled by poly-A RNA-sequencing, generating an average of 30 million paired reads per sample. These were quantified using the standard Genotype Tissue Expression (GTEx) project pipeline and were compared against 43 different human tissues and other bodily fluids using transcriptomic correlation. RNA-sequencing quality metrics were calculated by RNA-SeQC software. Gene set overrepresentation analysis for Gene Ontology (GO) terms and Kyoto Encyclopaedia of Genes and Genomes (KEGG) employed Fishers exact test. Enriched and enhanced kidney genes were collected from the Human Protein Atlas (HPA). Results: Our RNA-sequencing metric analysis revealed that urinary cells can generate robust data of comparable or superior quality to that of saliva at similar read coverage. The top one hundred most highly expressed urinary cell genes show an enrichment for biological themes shared with the renal transcriptome, including immunity (P = 1.2x10–7), glucose metabolism (P = 1.3x10–5) and renal mineral reabsorption (P = 9.8x10–4). In an analysis all protein-coding genes across 43 human tissues/cell-types, urinary cells showed the highest level of transcriptomic correlation with kidney cortex (r2 = 0.65) and kidney medulla (r2 = 0.64). This correlation between urinary cells and kidney tissue was particularly strong (r2 = 0.72) in an analysis restricted to highly specific kidney genes (including uromodulin and the Na-K-Cl cotransporter NKCC2 [loop diuretic target]). 98% (176 out of 179) of kidney genes with a known causal association to blood pressure were expressed in urinary cells. Their urinary expression demonstrated strong correlation with their abundance in kidney cortex (r2 = 0.68) and medulla (r2 = 0.64). Conclusions: Standard poly-A RNA-sequencing of cells harvested from urinary sediments produces robust gene expression profiles. These profiles provide a non-invasive insight into transcriptome of the kidney and permit measuring expression of kidney genes of relevance to BP regulation and hypertension.

Are active dwell positions always necessary in the ring/ovoids channel of the cervical applicator in the intracavitary-interstitial brachytherapy of cervical cancer?

To compare dosimetric parameters of brachytherapy (BT) treatment plans made with or without active source positions of the ring/ovoid (R/O) applicator in locally advanced cervical cancer patients. Sixty patients with cervical cancer without vaginal involvement were selected for the study, who received intra-cavitary/interstitial BT. For each patient, two plans with and without active source dwell positions in R/O were created, using the same dose-volume constraints. EQD2 total doses from external beam and BT of target volumes and organs at risk (OARs) between the competing plans were compared. There was no significant difference in the dose of high-risk clinical target volume (HR-CTV) and gross tumor volume (GTV) between the plans with inactive vs. active R/O. The mean D98 of intermediate-risk clinical target volume (IR-CTV) was significantly lower with inactive R/O; however, the GEC-ESTRO (EMBRACE II study) and ABS criteria were fulfilled in 96% in both plans. There was no difference in dose homogeneity, but conformity of the plans with inactive R/O was higher. Doses to all OARs were significantly lower in plans without R/O activation. While all the plans without R/O activation fulfilled the recommended dose criteria for OARs, it was less achievable with R/O activation. Inactivation of R/O applicator results in similar dose coverage of the target volumes with lower doses to all OARs, as activation of R/O in cervix cancer patients when HR-CTV does not extend to R/O applicator. The use of active source positions in R/O shows worse performance regarding the fulfilment of the recommended criteria for OARs.

Dosimetric case study of 3-D FiF vs. VMAT techniques in the treatment of H/N tumour

Abstract A case study comparing three-dimensional conformal radiation therapy with field-in-field (FiF) technique and volumetric-modulated arc therapy (VMAT) for head/neck (H/N) irradiation, evaluating the differences in the treatment techniques and low doses to critical structures. Compared to VMAT plan, 3D FIF plan offers similar planning target volume coverage and acceptable organs at risk dose. Therefore, 3D FIF is still a feasible alternative for some centres unqualified for IMRT/VMAT worldwide.

Vertebral artery sparing volumetric modulated arc therapy in nasopharyngeal carcinoma.

Vascular stenosis is a late radiation complication that develops in long-term survivors of nasopharyngeal carcinoma. Vertebral arteries (VAs) are major vessels responsible for posterior circulation. In this study, we evaluated the feasibility of VA-sparing volumetric modulated arc therapy (VMAT) techniques. A total of 20 patients with nasopharyngeal carcinoma treated by a TrueBeam linear accelerator were enrolled in this study. The original VMAT plan was designed without the contouring of VAs as organs at risk (OARs). The same image set of the original VMAT plan was used to contour the VAs for each patient. A new VA-sparing VMAT plan was developed by avoiding VAs as OARs. Finally, a paired t-test was used to compare the dosimetric differences. The VA-sparing VMAT plan had similar target coverage and dose to those of other OARs. The VA-sparing plan yielded a significantly low VA dose from 53 to 40 Gy, with V35Gy changing from 97% to 56%, V50Gy changing from 67% to 35%, and V63Gy changing from 15% to approximately 7%-10% (p < 0.001 for all comparisons). VAs should be correctly identified as OARs. Photon VMAT with VA sparing can help substantially decrease the VA dose.

656. Comparative Activity of Newer β-Lactam/β-Lactamase Inhibitor Combinations against Pseudomonas aeruginosa isolates from United States Medical Centers (2020-2021)

Abstract Background P. aeruginosa (PSA) is one of the most common Gram-negative organisms causing infections in hospitalized patients. Prompt administration of an effective antimicrobial is crucial for patients with systemic PSA infection. We evaluated the in vitro activity of ceftazidime-avibactam (CAZ-AVI), ceftolozane-tazobactam (C-T), meropenem-vaborbactam (MEM-VAB), imipenem-relebactam (IMI-REL), and many comparator agents against contemporary PSA isolates from US hospitals. Methods 3,184 isolates were consecutively collected from 71 US medical centers in 2020-2021 and susceptibility tested by reference broth microdilution methods in a monitoring laboratory (JMI Laboratories). US FDA and CLSI breakpoints were applied. Results CAZ-AVI (97.0% susceptible [S]), C-T (98.0%S), IMI-REL (97.3%S), and tobramycin (TOB; 96.4%S) were the most active agents against the aggregate PSA isolate collection and retained good activity against piperacillin-tazobactam- (PIP-TAZ) nonsusceptible (NS), MEM-NS, and multidrug-resistant (MDR) isolates (Table 1). All other antimicrobials tested showed limited activity against PIP-TAZ-NS, MEM-NS, and MDR isolates. The most common infection types were pneumonia (45.9%), skin and skin structure infections (19.0%), urinary tract infections (UTI; 17.0%), and bloodstream infections (11.7%); CAZ-AVI, C-T, and IMI-REL showed consistent activity against isolates from these infection types. Susceptibility to PIP-TAZ and MEM were lower among isolates from pneumonia compared to other infection types (Table 2). CAZ-AVI remained active against 31.7% and 52.5% of C-T-NS and IMI-REL-NS isolates, respectively. C-T remained active against 54.7% and 68.9% of CAZ-AVI-NS and IMI-REL-NS isolates, respectively, and IMI-REL remained active against 64.2% and 64.8% of isolates NS to CAZ-AVI and C-T, respectively. Conclusion CAZ-AVI, C-T, and IMI-REL were highly active and exhibited similar coverage against a large contemporary collection of PSA isolates from US hospitals. Cross resistance among these new β-lactamase inhibitor combinations varied markedly, indicating that all 3 should be tested in the clinical laboratory. These 3 agents represent valuable therapeutic options for PSA infection treatment. Disclosures Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support SJ Ryan Arends, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

Glycoproteomic Analyses of Influenza A Viruses Using timsTOF Pro MS.

N-Linked glycosylation in hemagglutinin and neuraminidase glycoproteins of influenza viruses affects antigenic and receptor binding properties, and precise analyses of site-specific glycoforms in these proteins are critical in understanding the antigenic and immunogenic properties of influenza viruses. In this study, we developed a glycoproteomic approach by using a timsTOF Pro mass spectrometer (MS) to determine the abundance and heterogeneity of site-specific glycosylation for influenza glycoproteins. Compared with a Q Exactive HF MS, the timsTOF Pro MS method without the hydrophilic interaction liquid chromatography column enrichment achieved similar glycopeptide coverage and quantities but was more effective in identifying low-abundance glycopeptides. We quantified the distributions of intact site-specific glycopeptides in hemagglutinin of A/chicken/Wuxi/0405005/2013 (H7N9) and A/mute swan/Rhode Island/A00325125/2008 (H7N3). Results showed that hemagglutinin for both viruses had complex N-glycans at N22, N38, N240, and N483 but only high-mannose glycans at N411 and, however, that the type and quantities of glycans were distinct between these viruses. Collisional cross section (CCS) provided by the ion mobility spectrometry from the timsTOF Pro MS data differentiated sialylation linkages of the glycopeptides. In summary, timsTOF Pro MS method can quantify intact site-specific glycans for influenza glycoproteins without enrichment and thus facilitate influenza vaccine development and production.

Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma

Ependymomas are the third most-frequent pediatric brain tumors. To prevent local recurrence, the resection site should be irradiated. Compared to photon radiation treatment, proton therapy often achieves even better results regarding target coverage and organ-sparing. Due to their physical properties, helium ions could further reduce side effects, providing better protection of healthy tissue despite similar target coverage. In our in silico study, 15 pediatric ependymoma patients were considered. All patients underwent adjuvant radiotherapeutic treatment with active-scanned protons at Heidelberg Ion Beam Therapy Center (HIT). Both helium ion and highly conformal IMRT plans were calculated to evaluate the potential dosimetric advantage of ion beam therapy compared to the current state-of-the-art photon-based treatments. To estimate the potential clinical benefit of helium ions, normal tissue complication probabilities (NTCP) were calculated. Target coverage was comparable in all three modalities. As expected, the integral dose absorbed by healthy brain tissue could be significantly reduced with protons by up to -48% vs. IMRT. Even compared to actively scanned protons, relative dose reductions for critical neuronal structures of up to another -39% were achieved when using helium ions. The dose distribution of helium ions is significantly superior when compared to proton therapy and IMRT due to the improved sparing of OAR. In fact, previous studies could clearly demonstrate that the dosimetric advantage of protons translates into a measurable clinical benefit for pediatric patients with brain tumors. Given the dose-response relationship of critical organs at risk combined with NTCP calculation, the results of our study provide a strong rationale that the use of helium ions has the potential to even further reduce the risk for treatment related sequelae.