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INTRODUCTION: Opioid dependence represents a public health crisis and can be observed after outpatient urologic procedures. The purpose of this study was to evaluate the risk of persistent opioid usage after radical orchiectomy for testicular cancer. MATERIALS AND METHODS: The TriNetX Research network database was queried for men between 15 and 45 years undergoing radical orchiectomy for a diagnosis of testicular cancer. All patients with N+ or M+ disease, prior opioid use, and patients who underwent chemotherapy, radiotherapy, or retroperitoneal lymph node dissection were excluded. Patients were stratified whether they were prescribed opioids or not at time of orchiectomy. The incidence of new, persistent opioid use, defined as a prescription for opioids between 3 and 15 months after orchiectomy, was evaluated. RESULTS: A total of 2,911 men underwent radical orchiectomy for testicular cancer, of which 89.8% were prescribed opioids at time of orchiectomy. After propensity score matching for age, race, and history of psychiatric diagnosis, 592 patients were included (296 received opioids, 296 did not). Overall, 0% of patients who did not receive postoperative opioids developed new persistent opioid use, whereas 10.5% of patients who received postoperative opioids developed new persistent opioid use. Patients prescribed postoperative opioids for orchiectomy had statistically higher risk difference of developing new persistent opioid use (Risk Difference: 10.5%; 95% CI: 7.0-14.0; Z: 5.7; P < 0.01). CONCLUSIONS: Postoperative opioid prescription following radical orchiectomy is significantly associated with developing new persistent opioid use, with 1 in 10 young men who received postoperative opioids obtaining a new prescription for opioids well beyond the postoperative period. Future efforts should emphasize nonopioid pathways for pain control following this generally minor procedure.
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Reconstructing the tree of life and understanding the relationships of taxa are core questions in evolutionary and systematic biology. The main advances in this field in the last decades were derived from molecular phylogenetics; however, for most species, molecular data are not available. Here, we explore the applicability of two deep learning methods - supervised classification approaches and unsupervised similarity learning - to infer organism relationships from specimen images. As a basis, we assembled an image dataset covering 4144 bivalve species belonging to 74 families across all orders and subclasses of the extant Bivalvia, with molecular phylogenetic data being available for all families and a complete taxonomic hierarchy for all species. The suitability of this dataset for deep learning experiments was evidenced by an ablation study resulting in almost 80% accuracy for identifications on the species level. Three sets of experiments were performed using our dataset. First, we included taxonomic hierarchy and genetic distances in a supervised learning approach to obtain predictions on several taxonomic levels simultaneously. Here, we stimulated the model to consider features shared between closely related taxa to be more critical for their classification than features shared with distantly related taxa, imprinting phylogenetic and taxonomic affinities into the architecture and training procedure. Second, we used transfer learning and similarity learning approaches for zero-shot experiments to identify the higher-level taxonomic affinities of test species that the models had not been trained on. The models assigned the unknown species to their respective genera with approximately 48% and 67% accuracy. Lastly, we used unsupervised similarity learning to infer the relatedness of the images without prior knowledge of their taxonomic or phylogenetic affinities. The results clearly showed similarities between visual appearance and genetic relationships at the higher taxonomic levels. The correlation was 0.6 for the most species-rich subclass (Imparidentia), ranging from 0.5 to 0.7 for the orders with the most images. Overall, the correlation between visual similarity and genetic distances at the family level was 0.78. However, fine-grained reconstructions based on these observed correlations, such as sister-taxa relationships, require further work. Overall, our results broaden the applicability of automated taxon identification systems and provide a new avenue for estimating phylogenetic relationships from specimen images.
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PURPOSE: This study investigated the magnitude, direction, and temporal aspects of the force applied during instrumentation with a piezoelectric ultrasonic periodontal scaler, compared this force with recommendations in the literature, and assessed the influence of the profession (dentist or dental hygienist) and calculus hardness. MATERIALS AND METHODS: The force applied by ten dental hygienists and six dentists during debridement of comparatively soft and hard artificial dental calculus with a piezoelectric ultrasonic scaler was recorded in-vitro. The total force and its components in three axes were statistically analysed. RESULTS: During debridement of soft artificial dental calculus, the mean total force applied by dental hygienists was 0.34 N (± 0.18 N, range: 0.13 N to 0.59 N) and by dentists 0.28 N (± 0.33 N, range: 0.06 N to 0.95 N), and the total force exceeded 0.5 N approximately 23% and 14% of the time for dental hygienists and dentists, respectively. During debridement of hard artificial dental calculus, the mean total force applied by dental hygienists was 0.63 N (± 0.40 N, range: 0.28 N to 1.64 N) and by dentists 0.57 N (± 0.17 N, range: 0.34 N to 0.76 N); the total force exceeded 0.5 N more than half of the time for both professions. On average, dental hygienists applied 1.85x (p = 0.04) and dentists 2.04x (p = 0.06) higher force on hard than on soft artificial calculus. However, dental hygienists and dentists used similar forces during the debridement of both hard (p = 1.00) and soft (p = 0.26) calculus. CONCLUSION: The force applied during the debridement of hard artificial dental calculus was statistically significantly higher than during the debridement of soft artificial dental calculus. No statistically significant difference between dentists and dental hygienists was found. The force applied by both groups on soft and hard artificial dental calculus frequently exceeded recommended values.
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Cálculos Dentários , Higienistas Dentários , Raspagem Dentária , Desbridamento Periodontal , Cálculos Dentários/terapia , Humanos , Raspagem Dentária/instrumentação , Desbridamento Periodontal/métodos , Desbridamento Periodontal/instrumentação , Odontólogos , Dureza , Técnicas In Vitro , Terapia por Ultrassom/instrumentaçãoRESUMO
Although species are central units for biological research, recent findings in genomics are raising awareness that what we call species can be ill-founded entities due to solely morphology-based, regional species descriptions. This particularly applies to groups characterized by intricate evolutionary processes such as hybridization, polyploidy, or asexuality. Here, challenges of current integrative taxonomy (genetics/genomics + morphology + ecology, etc.) become apparent: different favored species concepts, lack of universal characters/markers, missing appropriate analytical tools for intricate evolutionary processes, and highly subjective ranking and fusion of datasets. Now, integrative taxonomy combined with artificial intelligence under a unified species concept can enable automated feature learning and data integration, and thus reduce subjectivity in species delimitation. This approach will likely accelerate revising and unraveling eukaryotic biodiversity.
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Inteligência Artificial , Classificação , Classificação/métodos , Biodiversidade , GenômicaRESUMO
OBJECTIVES: To compare ultrasonic scaler prototypes based on a planar piezoelectric transducer with different working frequencies featuring a titanium (Ti-20, Ti-28, and Ti-40) or stainless steel (SS-28) instrument, with a commercially available scaler (com-29) in terms of biofilm removal and reformation, dentine surface roughness and adhesion of periodontal fibroblasts. MATERIALS AND METHODS: A periodontal multi-species biofilm was formed on specimens with dentine slices. Thereafter specimens were instrumented with scalers in a periodontal pocket model or left untreated (control). The remaining biofilms were quantified and allowed to reform on instrumented dentine slices. In addition, fibroblasts were seeded for attachment evaluation after 72 h of incubation. Dentine surface roughness was analyzed before and after instrumentation. RESULTS: All tested instruments reduced the colony-forming unit (cfu) counts by about 3 to 4 log10 and the biofilm quantity (each p < 0.01 vs. control), but with no statistically significant difference between the instrumented groups. After 24-hour biofilm reformation, no differences in cfu counts were observed between any groups, but the biofilm quantity was about 50% in all instrumented groups compared to the control. The attachment of fibroblasts on instrumented dentine was significantly higher than on untreated dentine (p < 0.05), with the exception of Ti-20. The dentine surface roughness was not affected by any instrumentation. CONCLUSIONS: The planar piezoelectric scaler prototypes are able to efficiently remove biofilm without dentine surface alterations, regardless of the operating frequency or instrument material. CLINICAL RELEVANCE: Ultrasonic scalers based on a planar piezoelectric transducer might be an alternative to currently available ultrasonic scalers.
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Biofilmes , Raspagem Dentária , Dentina , Fibroblastos , Ligamento Periodontal , Propriedades de Superfície , Titânio , Humanos , Raspagem Dentária/instrumentação , Técnicas In Vitro , Dentina/microbiologia , Ligamento Periodontal/citologia , Transdutores , Adesão Celular , Aço Inoxidável , Desenho de Equipamento , Terapia por Ultrassom/instrumentaçãoRESUMO
Tree growth performance can be partly explained by genetics, while a large proportion of growth variation is thought to be controlled by environmental factors. However, to what extent DNA methylation, a stable epigenetic modification, contributes to phenotypic plasticity in the growth performance of long-lived trees remains unclear. In this study, a comparative analysis of targeted DNA genotyping, DNA methylation and mRNAseq profiling for needles of 44-year-old Douglas-fir trees (Pseudotsuga menziesii (Mirb.) Franco) having contrasting growth characteristics was performed. In total, we identified 195 differentially expressed genes (DEGs) and 115 differentially methylated loci (DML) that are associated with genes involved in fitness-related processes such as growth, stress management, plant development and energy resources. Interestingly, all four intronic DML were identified in mega-sized (between 100 and 180 kbp in length) and highly expressed genes, suggesting specialized regulation mechanisms of these long intron genes in gymnosperms. DNA repetitive sequences mainly comprising long-terminal repeats of retroelements are involved in growth-associated DNA methylation regulation (both hyper- and hypomethylation) of 99 DML (86.1% of total DML). Furthermore, nearly 14% of the DML was not tagged by single nucleotide polymorphisms, suggesting a unique contribution of the epigenetic variation in tree growth.
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Pseudotsuga , Pseudotsuga/genética , Íntrons/genética , Árvores , DNA , Epigênese Genética/genética , MetilaçãoRESUMO
The authors wish to correct the following errors in the original paper [...].
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Peptide human leukocyte antigen (pHLA) targeting therapeutics like T-cell receptor based adoptive cell therapy or bispecific T cell engaging receptor molecules hold great promise for the treatment of cancer. Comprehensive pre-clinical screening of therapeutic candidates is important to ensure patient safety but is challenging because of the size of the potential off-target space. By combining stabilized peptide-receptive HLA molecules with microarray printing and screening, we have developed an ultra-high-throughput screening platform named ValidaTe that enables large scale evaluation of pHLA-binder interactions. We demonstrate its potential by measuring and analyzing over 30.000 binding curves for a high-affinity T cell Engaging Receptor towards a large pHLA library. Compared to a dataset obtained by conventional bio-layer interferometry measurements, we illustrate that a massively increased throughput (over 650 fold) is obtained by our microarray screening, paving the way for use in pre-clinical safety screening of pHLA-targeting drugs.
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Neoplasias , Peptídeos , Humanos , Peptídeos/química , Receptores de Antígenos de Linfócitos T , Biblioteca de PeptídeosRESUMO
OBJECTIVE: Pelvic lymph node metastasis (PLNM) at the time of radical prostatectomy (RP) portends an unfavorable prognosis in prostate cancer patients. Conventional and advanced imaging remains limited in its ability to detect PLNM. We sought to evaluate the combination of a genomic classifier Decipher with Prostate Imaging Reporting and Data System (PI-RADS) scores in improving the detection of PLNM. METHODS: A retrospective review was performed of patients whom underwent RP, Decipher analysis, and pre-operative prostate MRI. Categorical variables were compared using Pearson chi-squareχ2 tests. Quantitative variables were assessed with Wilcoxon rank-sum tests. Multivariable logistic regression was used to identify predictors of PLNM on final pathology. RESULTS: In total, 202 patients were included in the analysis, 23 of whom (11%) had PLNM. Patients with PLNM had higher median Decipher scores (0.73) than those without PLNM (0.61; p = 0.003). Patients with PLNM were more likely to demonstrate PI-RADS scores ≥ 4 (96%) than those without PLNM (74%; p = 0.012). Logistic regression demonstrated an interaction between Decipher score with PI-RADS score ≥4 (OR = 20.41; 95% CI, 2.10-198.74; p = 0.009) The combination demonstrated an area under the curve (AUC) of 0.73 (95% CI, 0.63-0.82; p < 0.001) for predicting PLNM. CONCLUSION: The combination of elevated Decipher genomic score (≥ 0.6) and clinically significant PI-RADS score (≥ 4) is associated with PLNM at the time of RP in a modern high-risk cohort of patients with PCaprostate cancer. ADVANCES IN KNOWLEDGE: Prostate MRI and genomic testing may help identify patients with adverse pathology.
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Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Imageamento por Ressonância Magnética/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Gradação de Tumores , Prostatectomia/métodos , Genômica , Estudos RetrospectivosRESUMO
This paper introduces a titanium-based planar ultrasonic microscalpel. The concept of silicon-based planar ultrasonic transducers has already been proven, but they are not yet suitable for clinical use due to material failure. The main objective of this work was to develop a smaller, lighter, and more cost-effective ultrasonic scalpel that could be used as an alternative or supplementary device to current surgical instruments. Various prototypes were fabricated and characterized, differing in bonding by three epoxy adhesives and two solder pastes as well as three variations in tip design. The instruments were designed to operate in the frequency range of commercial instruments and to generate a longitudinal displacement amplitude. The electro-mechanical characterization through impedance analysis and vibration measurements was complemented by an in vitro cutting trial and an acute in vivo animal experiment in comparison to commercial ultrasonic and electrosurgical devices. The operating frequency was around 40 kHz and 48 kHz depending on whether matched or unmatched operation was used. Unmatched operation turned out to be more suitable, achieving displacement amplitudes of 25.3 µm and associated velocity amplitudes of up to 7.9 m/s at an electrical power of 10.2 W. The cutting ability was demonstrated in vivo by successful dissection even under anticoagulation. The geometry of the instrument tip was found to have a major influence on cutting performance by affecting the resonance behaviour and tissue penetration.
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Terapia por Ultrassom , Ultrassom , Animais , Titânio , Desenho de Equipamento , Instrumentos Cirúrgicos , TransdutoresRESUMO
BACKGROUND: A renal mass in a solitary kidney (RMSK) has traditionally been managed with partial nephrectomy (PN), although radical nephrectomy (RN) is occasionally required. Most RMSK studies have focused on patients for whom PN was achieved. OBJECTIVE: To provide a comprehensive analysis of the management strategies/outcomes for an RMSK and address knowledge deficits regarding this challenging disorder. DESIGN, SETTING, AND PARTICIPANTS: A total of 1024 patients diagnosed with an RMSK (1975-2022) were retrospectively evaluated. Baseline characteristics and pathologic/functional/survival outcomes were analyzed. INTERVENTION: PN/RN/cryoablation (CA)/active surveillance (AS). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Functional outcomes, perioperative morbidity/mortality, and 5-yr recurrence-free survival (RFS) were evaluated. Kruskal-Wallis and chi-square tests were used to compare cohorts, and log-rank test and Cox proportional hazard model were used for survival analysis. RESULTS AND LIMITATIONS: Of 1024 patients, 842 underwent PN (82%), 102 CA (10%), 54 RN (5%), and 26 AS (3%). The median tumor size and RENAL([R]adius [tumor size as maximal diameter], [E]xophytic/endophytic properties of tumor, [N]earness of tumor deepest portion to collecting system or sinus, [A]nterior [a]/posterior [p] descriptor, and [L]ocation relative to polar lines) score were 3.7 cm and 8, respectively. The median follow-up was 53 mo. For PN, 95% were clamped, and the median warm and cold ischemia times were 22 and 45 min, respectively. For PN, the median preoperative glomerular filtration rate (GFR) was 57 ml/min/1.73 m2, and the median new baseline and 5-yr GFRs were 47 and 48 ml/min/1.73 m2, respectively. Dialysis-free survival for PN was 97% at 5 yr. Twenty-two (2.1%) patients with clear-cell renal cell carcinoma and RENAL score ≥10 (median = 11) received tyrosine kinase inhibitors (TKIs) to facilitate PN, leading to 57% median decrease of tumor volume; PN was accomplished in 20 (91%). Forty-one patients had planned RN (4.0%), most often due to severe pre-existing chronic kidney disease (CKD), and 13 were converted from PN to RN (1.5%). Clavien III-V perioperative complications were observed in 80 (8%) patients and 90-d mortality was 0.6%. Five-year RFS for PN, CA, and RN were 83%, 80%, and 72%, respectively (p = 0.03 for PN vs RN). CONCLUSIONS: Nephron-sparing approaches are feasible and successful in most RMSK patients. PN for an RMSK is often challenging but can be facilitated by selective use of TKIs. RN is occasionally required due to severe CKD, over-riding oncologic concerns, or conversion from PN. This is the first large RMSK study to provide a comprehensive analysis of all management strategies/outcomes. PATIENT SUMMARY: Kidney cancer in a solitary kidney is a major challenge for achieving cancer-free status and avoiding dialysis. Although partial nephrectomy is the principal treatment for a renal mass in a solitary kidney, other options are occasionally required to optimize outcomes.
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Carcinoma de Células Renais , Neoplasias Renais , Insuficiência Renal Crônica , Rim Único , Humanos , Rim Único/complicações , Rim Único/cirurgia , Estudos Retrospectivos , Neoplasias Renais/cirurgia , Carcinoma de Células Renais/cirurgia , Rim/patologia , Nefrectomia/métodos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/cirurgiaRESUMO
BACKGROUND: The intensive care unit at Asklepios Klinik Langen started a therapeutic drug monitoring (TDM) project in cooperation with the Aukamm pharmacy in Wiesbaden to measure antibiotic concentrations in the serum of intensive care patients for providing plasma level guided anti-infective therapy. METHODS: The serum levels of the ßlactam antibiotics meropenem, piperacillin, ceftriaxone and ceftazidime as well as the glycylcycline antibiotic tigecycline measured between January 1 and December 31, 2020, were evaluated retrospectively. Quantification by high performance liquid chromatography was carried out by the Aukamm pharmacy. RESULTS: During the observation period 288 serum level measurements were carried out in 131 patients with normal as well as impaired kidney or liver function, an increased volume of distribution as well as in patients with extracorporeal organ replacement therapies. The results of the most frequently measured antibiotic piperacillin/tazobactam showed a range of 1.95-308.50⯵g/ml (median 76.54⯵g/ml). The median serum level for meropenem was 26.46⯵g/ml (0.75-157.36⯵g/ml), for ceftriaxone 33.53⯵g/ml (8.38-236.26⯵g/ml) and for ceftazidime 158.56⯵g/ml (24.09-204.61⯵g/ml). The median trough level for tigecycline was 0.42⯵g/ml (0.25-3.7⯵g/ml) and therefore lower compared to administration via continuous infusion (median 0.88⯵g/ml, 0.26-3.81⯵g/ml). CONCLUSIONS: Therapeutic drug monitoring was successfully implemented in the intensive care unit of the Asklepios Klinik Langen. The serum level measurements showed considerable clinically relevant fluctuations in the antibiotic concentrations. Even an only rough approximation of effective antibiotic serum levels is not possible without TDM.
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Ceftazidima , Ceftriaxona , Humanos , Meropeném/uso terapêutico , Estudos Retrospectivos , Tigeciclina , Monitoramento de Medicamentos/métodos , Antibacterianos/uso terapêutico , Piperacilina/uso terapêutico , Cuidados CríticosRESUMO
Engineered barriers are a key element to enable safe nuclear waste disposal. One method currently under research for their construction is magnesia concrete applied in a shotcrete procedure. In this study, the ultrasonic echo method is evaluated as a means for quality assurance. Imaging of internal structures (backwall, boreholes) and defects, such as delamination, has successfully been achieved in the shotcrete. Additionally, detailed information about the potential cause of selected reflectors are obtained by phase analysis. In several test blocks of various sizes, no consistent concrete section boundaries have been found by ultrasonic imaging, which was verified by subsequent drilling and complementary tests. An experiment with artificial defects imitating cracks, air-filled voids, and material with lower density has been challenging and shows the limitations of the current methods. Although significant defects, such as a large delamination, are reliably identified, several smaller defects are not identified. Generally, ultrasonic imaging provides a suitable base as a mean for quality assurance during and after the construction of sealing structures. However, further developments are required to enhance the reliability of the method and a full validation is still pending. Still, the method has potential to increase the safety of nuclear waste repositories.
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Resíduos Radioativos , Eliminação de Resíduos , Ultrassom , Óxido de Magnésio , Reprodutibilidade dos TestesRESUMO
T cell receptor (TCR)-based immunotherapy has emerged as a promising therapeutic approach for the treatment of patients with solid cancers. Identifying peptide-human leukocyte antigen (pHLA) complexes highly presented on tumors and rarely expressed on healthy tissue in combination with high-affinity TCRs that when introduced into T cells can redirect T cells to eliminate tumor but not healthy tissue is a key requirement for safe and efficacious TCR-based therapies. To discover promising shared tumor antigens that could be targeted via TCR-based adoptive T cell therapy, we employed population-scale immunopeptidomics using quantitative mass spectrometry across ~1500 tumor and normal tissue samples. We identified an HLA-A*02:01-restricted pan-cancer epitope within the collagen type VI α-3 (COL6A3) gene that is highly presented on tumor stroma across multiple solid cancers due to a tumor-specific alternative splicing event that rarely occurs outside the tumor microenvironment. T cells expressing natural COL6A3-specific TCRs demonstrated only modest activity against cells presenting high copy numbers of COL6A3 pHLAs. One of these TCRs was affinity-enhanced, enabling transduced T cells to specifically eliminate tumors in vivo that expressed similar copy numbers of pHLAs as primary tumor specimens. The enhanced TCR variants exhibited a favorable safety profile with no detectable off-target reactivity, paving the way to initiate clinical trials using COL6A3-specific TCRs to target an array of solid tumors.
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Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T , Linfócitos T , Antígenos de Neoplasias , Linhagem Celular Tumoral , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Imunoterapia Adotiva/métodos , Proteômica , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/uso terapêuticoRESUMO
OBJECTIVE: To explore if elevated IsoPSA selects for particular adverse radiographic or histopathologic features among men destined to undergo radical prostatectomy (RP) because of clinically significant prostate cancer identified at biopsy. MATERIALS AND METHODS: Single center, retrospective review of patients who had undergone IsoPSA testing, prostate biopsy and RP at our institution from 2019-2021. A consecutive cohort of patients whom had undergone RP within the same period without pre-operative IsoPSA served as controls. Pre-operative prostate Magnetic Resonance Imaging (MRI) was included in our analysis. Adverse histopathologic and MRI features were compared between both groups. Concordance, downstaging, and upstaging grade group rates (GG) was evaluated. Pearson Chi-Square test was used to compare categorical variables, Wilcoxon-Rank sum test for quantitative variables, and binary logistic regression to identify predictors of upstaging at RP. RESULTS: Eighty-three patients underwent IsoPSA and RP while 44 patients were controls. The IsoPSA group had significantly higher pre-operative PSA (IsoPSA group: 7.8 ng/mL vs Control group: 5.2 ng/mL, P<.001 ). Elevated IsoPSA index (>6.0) did not select for any specific adverse histopathologic features at RP. Excluding PSA density, elevated IsoPSA was not selective for adverse MRI features. There were no differences in concordance, downstaging, and upstaging GG rates from biopsy to RP. IsoPSA testing was not a predictor of GG upstaging (Odds Ratio: 0.63, P .58). CONCLUSION: Elevated IsoPSA is a diagnostic tool that can detect clinically significant prostate at the time of biopsy. In doing so, it does not select for any particular adverse prostate MRI or pathologic feature at RP.
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Prostatectomia , Neoplasias da Próstata , Humanos , Masculino , Gradação de Tumores , Prostatectomia/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/cirurgia , Antígeno Prostático Específico , Próstata/diagnóstico por imagem , Próstata/patologia , Estudos RetrospectivosRESUMO
Bispecific T cell receptor (TCR)-based molecules capable of redirecting and activating T cells towards tumor cells represent a novel and promising class of biotherapeutics for the treatment of cancer. Usage of TCRs allows for targeting of intracellularly expressed and highly selective cancer antigens, but also requires a complex maturation process to increase the naturally low affinity and stability of TCRs. Even though TCR domains can be matured via phage and yeast display, these techniques share the disadvantages of non-human glycosylation patterns and the need for a later reformatting into the final bispecific format. Here, we describe the development and application of a Chinese Hamster Ovary (CHO) display for affinity engineering of TCRs in the context of the final bispecific TCR format. The recombinase-mediated cassette exchange (RCME)-based system allows for stable, single-copy integration of bispecific TCR molecules with high efficiency into a defined genetic locus of CHO cells. We used the system to isolate affinity-increased variants of bispecific T cell engaging receptor (TCER) molecules from a library encoding different CDR variants of a model TCR targeting preferentially expressed antigen in melanoma (PRAME). When expressed as a soluble protein, the selected TCER molecules exhibited strong reactivity against PRAME-positive tumor cells associated with a pronounced cytokine release from activated T cells. The obtained data support the usage of the CHO display-based maturation system for TCR affinity maturation in the context of the final bispecific TCER format.
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Stakeholders of software development projects have various information needs for making rational decisions during their daily work. Satisfying these needs requires substantial knowledge of where and how the relevant information is stored and consumes valuable time that is often not available. Easing the need for this knowledge is an ideal text-to-SQL benchmark problem, a field where public datasets are scarce and needed. We propose the SEOSS-Queries dataset consisting of natural language utterances and accompanying SQL queries extracted from previous studies, software projects, issue tracking tools, and through expert surveys to cover a large variety of information need perspectives. Our dataset consists of 1,162 English utterances translating into 166 SQL queries; each query has four precise utterances and three more general ones. Furthermore, the dataset contains 393,086 labeled utterances extracted from issue tracker comments. We provide pre-trained SQLNet and RatSQL baseline models for benchmark comparisons, a replication package facilitating a seamless application, and discuss various other tasks that may be solved and evaluated using the dataset. The whole dataset with paraphrased natural language utterances and SQL queries is hosted at figshare.com/s/75ed49ef01ac2f83b3e2.
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Polymer hydrogels, water-laden 3D cross-linked networks, find broad application as advanced biomaterials and functional materials because of their biocompatibility, stimuli responsiveness, and affordability. The cross-linking density reports material properties such as elasticity, permeability, and swelling propensity. However, this critical design parameter can be challenging to template locally. Here, we report a continuous processing scheme that uses laminar flow to direct the organization of cross-linking density across a single sample. Dilute and concentrated poly(ethylene glycol) diacrylate solutions are fed into custom serpentine millifluidic devices. These feature a modular sequence of splitting, rotation, and recombination elements, which create patterned streamlines that serve as a template for hierarchical concentration distributions. Poly(acrylic acid) microgels impart viscoplasticity, which stabilizes layered flow during multiplication and ensures reliable advection. The devices produce structured, seamless filaments, which are then arranged into objects using 3D printing, and photopolymerized to secure the heterogeneous distribution. The flow-encoded, multiscale architecture provides mechanical contrast, which is demonstratively exploited to program robust and reversible shape transformations, potentially useful in soft actuator and sensor applications. The unique structures achieved, and the geometrically dictated, chemistry-agnostic operating principles used to achieve them, provides a new means to engineer hydrogels to suit a variety of applications.
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In this paper, the investigation of laser-induced periodic surface structures (LIPSSs) on a polycrystalline diamond substrate using synthetic optical holography (SOH) is demonstrated. While many techniques for LIPSS detection operate with sample contact and/or require preparation or processing of the sample, this novel technique operates entirely non-invasively without any processing of or contact with the LIPSS sample at all. The setup provides holographic amplitude and phase images of the investigated sample with confocally enhanced and diffraction-limited lateral resolution, as well as three-dimensional surface topography images of the periodic structures via phase reconstruction with one single-layer scan only.