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PURPOSE: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials. MATERIALS AND METHODS: Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc). RESULTS: The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature. CONCLUSION: U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.
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Adénocarcinome , Tumeurs de la vessie urinaire , Humains , Tumeurs de la vessie urinaire/génétique , Tumeurs de la vessie urinaire/anatomopathologie , Adénocarcinome/génétique , Adénocarcinome/anatomopathologie , Femelle , Mâle , Adulte d'âge moyen , Sujet âgé , Adulte , Génomique , Sujet âgé de 80 ans ou plus , Analyse de profil d'expression de gènesRÉSUMÉ
BACKGROUND: Recent research has identified six domains of work readiness: Practical Wisdom, Interpersonal Capabilities, Personal Attributes, Organisational Acumen, Profession Specific Knowledge and Skills, and Professionally Relevant Experiences. OBJECTIVE: Using a case study, the aim of this study was to demonstrate the process of curriculum mapping to evaluate the alignment of a university program to the work readiness framework. METHODS: A retrospective audit of curriculum material for one cohort of Macquarie University's Doctor of Physiotherapy (DPT) was undertaken. Curriculum was categorized as declared, delivered, or assessed, mapped to the six work readiness domains through qualitative content analysis, and then quantitatively scored and expressed as percentages of maximum possible scores per unit, and average units scores per semester. RESULTS: Mapping curriculum to a six domain work readiness framework revealed declared, delivered, and assessed curriculum within all six work readiness domains, with varying contributions across the degree. Mapping revealed that the Profession Specific Knowledge and Skills domain had the highest coverage of declared (M = 63%, SD = 12), delivered (M = 88%, SD = 11) and assessed (M = 80%, SD = 7) curriculum, highlighting a strength of the program. The Personal Attributes domain had the lowest coverage of declared (M = 5%, SD = 5), delivered (M = 48%, SD = 24) and assessed (M = 29%, SD = 20) curriculum, highlighting opportunities for development. CONCLUSION: Mapping curriculum to a work readiness framework allows universities to consider alignment, and the strength and opportunities for the improvement of work readiness within its curriculum.
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Due to the hierarchical structure of the tree of life, closely related species often resemble each other more than distantly related species; a pattern termed phylogenetic signal. Numerous univariate statistics have been proposed as measures of phylogenetic signal for single phenotypic traits, but the study of phylogenetic signal for multivariate data, as is common in modern biology, remains challenging. Here we introduce a new method to explore phylogenetic signal in multivariate phenotypes. Our approach decomposes the data into linear combinations with maximal (or minimal) phylogenetic signal, as measured by Blomberg's K. The loading vectors of these phylogenetic components or K-components can be biologically interpreted, and scatterplots of the scores can be used as a low-dimensional ordination of the data that maximally (or minimally) preserves phylogenetic signal. We present algebraic and statistical properties, along with two new summary statistics, KA and KG, of phylogenetic signal in multivariate data. Simulation studies showed that KA and KG have higher statistical power than the previously suggested statistic Kmult, especially if phylogenetic signal is low or concentrated in a few trait dimensions. In two empirical applications to vertebrate cranial shape (crocodyliforms and papionins), we found statistically significant phylogenetic signal concentrated in a few trait dimensions. The finding that phylogenetic signal can be highly variable across the dimensions of multivariate phenotypes has important implications for current maximum likelihood approaches to phylogenetic signal in multivariate data.
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Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology.
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Génomique , Tumeurs , Humains , Génomique/méthodes , Tumeurs/génétique , Tumeurs/classification , Variation génétique , MutationRÉSUMÉ
The Montseny brook newt (Calotriton arnoldi), a glacial relict endemic to a small, isolated massif in northeast Spain, is considered the only Critically Endangered urodele in Europe. Its restricted range is divided by a deep valley that acts as an impassable barrier to dispersal, separating two isolated metapopulations (Western and Eastern) that correspond to independent lineages with different evolutionary trajectories, based on genetic and genomic data. Here, we address the ecological differentiation between lineages and discuss its potential effect on the phenotypic distinctness of each lineage. Based on multiple lines of evidence, we formally describe the Western Montseny brook newt as a new subspecies: Calotriton arnoldi laietanus ssp. nov. Finally, our study underscores the importance of considering taxonomic progress in the conservation policies of endangered species, ensuring appropriate management and protection of the newly described taxa.
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Salamandridae , Espagne , Animaux , Salamandridae/génétique , Espèce en voie de disparition , PhylogenèseRÉSUMÉ
In low-microbial biomass samples such as bovine milk, contaminants can outnumber endogenous bacteria. Because of this, milk microbiome research suffers from a critical knowledge gap, namely, does non-mastitis bovine milk contain a native microbiome? In this study, we sampled external and internal mammary epithelia and stripped and cisternal milk and used numerous negative controls, including air and sampling controls and extraction and library preparation blanks, to identify the potential sources of contamination. Two algorithms were used to mathematically remove contaminants and track the potential movement of microbes among samples. Results suggest that the majority (i.e., >75%) of sequence data generated from bovine milk and mammary epithelium samples represents contaminating DNA. Contaminants in milk samples were primarily sourced from DNA extraction kits and the internal and external skin of the teat, while teat canal and apex samples were mainly contaminated during the sampling process. After decontamination, the milk microbiome displayed a more dispersed, less diverse, and compositionally distinct bacterial profile compared with epithelial samples. Similar microbial compositions were observed between cisternal and stripped milk samples, as well as between teat apex and canal samples. Staphylococcus and Acinetobacter were the predominant genera detected in milk sample sequences, and bacterial culture showed growth of Staphylococcus and Corynebacterium spp. in 50% (7/14) of stripped milk samples and growth of Staphylococcus spp. in 7% (1/14) of cisternal milk samples. Our study suggests that microbiome data generated from milk samples obtained from clinically healthy bovine udders may be heavily biased by contaminants that enter the sample during sample collection and processing workflows.IMPORTANCEObtaining a non-contaminated sample of bovine milk is challenging due to the nature of the sampling environment and the route by which milk is typically extracted from the mammary gland. Furthermore, the very low bacterial biomass of bovine milk exacerbates the impacts of contaminant sequences in downstream analyses, which can lead to severe biases. Our finding showed that bovine milk contains very low bacterial biomass and each contamination event (including sampling procedure and DNA extraction process) introduces bacteria and/or DNA fragments that easily outnumber the native bacterial cells. This finding has important implications for our ability to draw robust conclusions from milk microbiome data, especially if the data have not been subjected to rigorous decontamination procedures. Based on these findings, we strongly urge researchers to include numerous negative controls into their sampling and sample processing workflows and to utilize several complementary methods for identifying potential contaminants within the resulting sequence data. These measures will improve the accuracy, reliability, reproducibility, and interpretability of milk microbiome data and research.
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Microbiote , Lait , Animaux , Bovins , Lait/microbiologie , Microbiote/génétique , Femelle , ADN bactérien/analyse , ADN bactérien/génétique , Bactéries/isolement et purification , Bactéries/génétique , Bactéries/classification , Glandes mammaires animales/microbiologie , Manipulation d'échantillons/méthodes , ARN ribosomique 16S/génétique , ARN ribosomique 16S/analyseRÉSUMÉ
Minimally invasive ablation techniques for renal cancer are becoming more popular due to their low complication rate and rapid recovery period. Despite excellent visualisation, one drawback of the use of computed tomography (CT) in these procedures is the requirement for iodine-based contrast agents, which are associated with adverse reactions and require a higher x-ray dose. The purpose of this work is to examine the use of time information to generate synthetic contrast enhanced images at arbitrary points after contrast agent injection from non-contrast CT images acquired during renal cryoablation cases. To achieve this, we propose a new method of conditioning generative adversarial networks with normalised time stamps and demonstrate that the use of a HyperNetwork is feasible for this task, generating images of competitive quality compared to standard generative modelling techniques. We also show that reducing the receptive field can help tackle challenges in interventional CT data, offering significantly better image quality as well as better performance when generating images for a downstream segmentation task. Lastly, we show that all proposed models are robust enough to perform inference on unseen intra-procedural data, while also improving needle artefacts and generalising contrast enhancement to other clinically relevant regions and features.
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Produits de contraste , Traitement d'image par ordinateur , Tomodensitométrie , Humains , Traitement d'image par ordinateur/méthodes , Facteurs temps , Tumeurs du rein/imagerie diagnostique , Tumeurs du rein/chirurgieRÉSUMÉ
The evolution of miniaturization can result in dramatic alterations of morphology, physiology, and behavior; however, the effects of miniaturization on sexual dimorphism remain largely unknown. Here we investigate how miniaturization influences patterns of sexual size dimorphism (SSD) in geckos. Measuring 1,875 individuals from 131 species, we characterized patterns of SSD relative to body size across two families. We found that miniaturized species were more female biased than non-miniaturized species. Additionally, one family that contained many miniaturized species (Sphaerodactylidae) displayed allometric patterns in SSD with body size, where larger species were male biased and smaller species were more female biased. Smaller species in this lineage also produced proportionally larger eggs. By contrast, another family containing few miniaturized species (Phyllodactylidae) displayed a more isometric trend. Together, these observations are consistent with the hypothesis that selection for increased reproductive success in small species of Sphaerodactylidae results in female-biased SSD in these taxa, which in turn drives the positive SSD allometry observed in this lineage. Thus, selection for increased miniaturization in the clade may be offset by selection on maintaining a female size in smaller taxa that ensures reproductive success.
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Évolution biologique , Mensurations corporelles , Lézards , Caractères sexuels , Animaux , Lézards/anatomie et histologie , Lézards/physiologie , Femelle , MâleRÉSUMÉ
Supervised machine learning-based medical image computing applications necessitate expert label curation, while unlabelled image data might be relatively abundant. Active learning methods aim to prioritise a subset of available image data for expert annotation, for label-efficient model training. We develop a controller neural network that measures priority of images in a sequence of batches, as in batch-mode active learning, for multi-class segmentation tasks. The controller is optimised by rewarding positive task-specific performance gain, within a Markov decision process (MDP) environment that also optimises the task predictor. In this work, the task predictor is a segmentation network. A meta-reinforcement learning algorithm is proposed with multiple MDPs, such that the pre-trained controller can be adapted to a new MDP that contains data from different institutes and/or requires segmentation of different organs or structures within the abdomen. We present experimental results using multiple CT datasets from more than one thousand patients, with segmentation tasks of nine different abdominal organs, to demonstrate the efficacy of the learnt prioritisation controller function and its cross-institute and cross-organ adaptability. We show that the proposed adaptable prioritisation metric yields converging segmentation accuracy for a new kidney segmentation task, unseen in training, using between approximately 40% to 60% of labels otherwise required with other heuristic or random prioritisation metrics. For clinical datasets of limited size, the proposed adaptable prioritisation offers a performance improvement of 22.6% and 10.2% in Dice score, for tasks of kidney and liver vessel segmentation, respectively, compared to random prioritisation and alternative active sampling strategies.
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Algorithmes , Humains , Tomodensitométrie , , Apprentissage machine , Chaines de Markov , Apprentissage machine supervisé , Radiographie abdominale/méthodesRÉSUMÉ
BACKGROUND: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification. OBJECTIVE: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC. PATIENTS AND METHODS: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests. RESULTS: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+. CONCLUSIONS: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.
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Récepteur ErbB-2 , Tumeurs de la vessie urinaire , Humains , Tumeurs de la vessie urinaire/génétique , Tumeurs de la vessie urinaire/anatomopathologie , Récepteur ErbB-2/métabolisme , Femelle , Mâle , Sujet âgé , Mutation , Adulte d'âge moyen , Génomique/méthodes , Sujet âgé de 80 ans ou plusRÉSUMÉ
Glycidyl ethers are prepared from a series of furan-based diols and cured with a diamine to form thermosets. The furan diols demonstrate lower toxicity than bisphenol-A in a prior study. The diglycidyl ethers show improved thermal stability compared to the parent diols. Cured thermosets are prepared at elevated temperature using isophorone diamine (IPDA). Glass transition temperatures are in the range of 30-54 °C and depend on the structure of the furan diol. Coatings are prepared on steel substrates and show very high hardness, good adhesion, and a range of flexibility. Properties compare favorably with a control based on a bisphenol-A epoxy resin. The study demonstrates that epoxy resins based on furan diols, which have been shown to have lower toxicity than bisphenol-A, can form thermosets having properties comparable to a standard epoxy resin system; and thus, are viable as replacements for bisphenol-A epoxy resins.
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Résines époxy , Furanes , Résines époxy/composition chimique , Furanes/composition chimique , Composés benzhydryliques/composition chimique , Température , Structure moléculaire , Composés époxy/composition chimique , Phénols/composition chimiqueRÉSUMÉ
PURPOSE: Magnetic resonance (MR) imaging targeted prostate cancer (PCa) biopsy enables precise sampling of MR-detected lesions, establishing its importance in recommended clinical practice. Planning for the ultrasound-guided procedure involves pre-selecting needle sampling positions. However, performing this procedure is subject to a number of factors, including MR-to-ultrasound registration, intra-procedure patient movement and soft tissue motions. When a fixed pre-procedure planning is carried out without intra-procedure adaptation, these factors will lead to sampling errors which could cause false positives and false negatives. Reinforcement learning (RL) has been proposed for procedure plannings on similar applications such as this one, because intelligent agents can be trained for both pre-procedure and intra-procedure planning. However, it is not clear if RL is beneficial when it comes to addressing these intra-procedure errors. METHODS: In this work, we develop and compare imitation learning (IL), supervised by demonstrations of predefined sampling strategy, and RL approaches, under varying degrees of intra-procedure motion and registration error, to represent sources of targeting errors likely to occur in an intra-operative procedure. RESULTS: Based on results using imaging data from 567 PCa patients, we demonstrate the efficacy and value in adopting RL algorithms to provide intelligent intra-procedure action suggestions, compared to IL-based planning supervised by commonly adopted policies. CONCLUSIONS: The improvement in biopsy sampling performance for intra-procedure planning has not been observed in experiments with only pre-procedure planning. These findings suggest a strong role for RL in future prospective studies which adopt intra-procedure planning. Our open source code implementation is available here .
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Biopsie guidée par l'image , Tumeurs de la prostate , Humains , Mâle , Tumeurs de la prostate/imagerie diagnostique , Tumeurs de la prostate/anatomopathologie , Tumeurs de la prostate/chirurgie , Biopsie guidée par l'image/méthodes , Imagerie par résonance magnétique/méthodes , Prostate/imagerie diagnostique , Prostate/anatomopathologie , Prostate/chirurgie , Échographie interventionnelle/méthodes , Apprentissage machineRÉSUMÉ
Limitations in electrochemical performance as well as supply chain challenges have rendered positive electrode materials a critical bottleneck for Li-ion batteries. State-of-the-art Li-ion batteries fall short of accessing theoretical capacities. As such, there is intense interest in the design of strategies that enable the more effective utilization of active intercalation materials. Pre-intercalation with alkali-metal ions has attracted interest as a means of accessing higher reversible capacity and improved rate performance. However, the structural basis for improvements in electrochemical performance remains mostly unexplored. Here we use topochemical single-crystal-to-single-crystal transformations in a tunnel-structured ζ-V2O5 positive electrode to illustrate the effect of pre-intercalation in modifying the host lattice and altering diffusion pathways. Furthermore, operando synchrotron X-ray diffraction is used to map Li-ion site preferences and occupancies as a function of the depth of discharge in pre-intercalated materials. Na- and K-ion intercalation 'props open' the one-dimensional tunnel, reduces electrostatic repulsions between inserted Li ions and entirely modifies diffusion pathways, enabling orders of magnitude higher Li-ion diffusivities and accessing higher capacities. Deciphering the atomistic origins of improved performance in pre-intercalated materials on the basis of single-crystal-to-single-crystal topochemical transformation and operando diffraction studies paves the way to site-selective modification approaches for positive electrode design.
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The primary objective of this study was to identify associations between the prepartum teat apex microbiome and the presence of Staphylococcus aureus intramammary infections (IMI) in primiparous cows during the first 5 weeks after calving. We performed a case-control study using shotgun metagenomics of the teat apex and culture-based milk data collected longitudinally from 710 primiparous cows on five organic dairy farms. Cases had higher odds of having S. aureus metagenomic DNA on the teat apex prior to parturition compared to controls (OR = 38.9, 95% CI: 14.84-102.21). Differential abundance analysis confirmed this association, with cases having a 23.8 higher log fold change (LFC) in the abundance of S. aureus in their samples compared to controls. Of the most prevalent microorganisms in controls, those associated with a lower risk of post-calving S. aureus IMI included Microbacterium phage Min 1 (OR = 0.37, 95% CI: 0.25-0.53), Corynebacterium efficiens (OR = 0.53, 95% CI: 0.30-0.94), Kocuria polaris (OR = 0.54, 95% CI: 0.35-0.82), Micrococcus terreus (OR = 0.64, 95% CI: 0.44-0.93), and Dietzia alimentaria (OR = 0.45, 95% CI: 0.26-0.75). Genes encoding for Microcin B17 AMPs were the most prevalent on the teat apex of cases and controls (99.7% in both groups). The predicted abundance of genes encoding for Microcin B17 was also higher in cases compared to controls (LFC 0.26). IMPORTANCE: Intramammary infections (IMI) caused by Staphylococcus aureus remain an important problem for the dairy industry. The microbiome on the external skin of the teat apex may play a role in mitigating S. aureus IMI risk, in particular the production of antimicrobial peptides (AMPs) by commensal microbes. However, current studies of the teat apex microbiome utilize a 16S approach, which precludes the detection of genomic features such as genes that encode for AMPs. Therefore, further research using a shotgun metagenomic approach is needed to understand what role prepartum teat apex microbiome dynamics play in IMI risk.
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Mammite bovine , Infections à staphylocoques , Femelle , Bovins , Animaux , Staphylococcus aureus/génétique , Métagénome , Études cas-témoins , Mammite bovine/épidémiologie , Mammite bovine/microbiologie , Infections à staphylocoques/épidémiologie , Infections à staphylocoques/médecine vétérinaire , Infections à staphylocoques/microbiologie , Lait/microbiologie , Glandes mammaires animales/microbiologieRÉSUMÉ
BACKGROUND: The purpose of this study is to systematically review the evidence in the literature to ascertain the functional outcomes, recurrence rates, and subsequent revision rates following type V superior labrum anterior to posterior (SLAP) repair. METHODS: Two independent reviewers performed a literature search based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, utilizing the EMBASE, MEDLINE, and the Cochrane Library Databases. Studies were included if they had clinical outcomes on the patients undergoing type V SLAP repair. Statistical analysis was performed using SPSS (IBM, Armonk, NY, USA). A P value of <.05 was considered to be statistically significant. RESULTS: Our review found 13 studies, including 451 shoulders meeting our inclusion criteria. The majority of patients were males (89.3%), with an average age of 25.9 years (range 15-58) and a mean follow-up of 53.8 months. The Rowe score was the most utilized functional outcome score, with a weighted mean of 88.5. Additionally, the mean Constant score was 91.0, the mean American Shoulder and Elbow Surgeons score was 88.3, the mean subjective shoulder value score was 85.5%, and the mean visual analog scale pain score was 1.2. The overall rate of return to play was 84.8%, with 80.2% returning to the same level of play. The overall reoperation rate was 6.1%, with a recurrent dislocation rate of 8.2%. In the studies comparing type V SLAP and isolated Bankart repair, there were statistically insignificant differences in visual analog scale pain scores (mean difference; 0.15, 95% confidence interval, -0.13 to 0.44, I2 = 0%, P = .29) and recurrence rates (risk ratio; 1.38, 95% confidence interval, 0.88-2.15, I2 = 0%, P = .16). CONCLUSION: Arthroscopic repair of type V SLAP tears results in excellent functional outcomes, with high return to play rates in athletes. There are low rates of reoperations and recurrent dislocations. Additionally, in comparison to an isolated Bankart repair, SLAP repair does not increase recurrence rates or postoperative pain.
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Articulation glénohumérale , Humains , Articulation glénohumérale/chirurgie , Lésions de l'épaule/chirurgie , Arthroscopie/méthodes , Réintervention/statistiques et données numériques , RécidiveRÉSUMÉ
Tumour hypoxia promotes poor patient outcomes, with particularly strong evidence for head and neck squamous cell carcinoma (HNSCC). To effectively target hypoxia, therapies require selection biomarkers and preclinical models that can accurately model tumour hypoxia. We established 20 patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models of HNSCC that we characterised for their fidelity to represent clinical HNSCC in gene expression, hypoxia status and proliferation and that were evaluated for their sensitivity to hypoxia-activated prodrugs (HAPs). PDX models showed greater fidelity in gene expression to clinical HNSCC than cell lines, as did CDX models relative to their paired cell lines. PDX models were significantly more hypoxic than CDX models, as assessed by hypoxia gene signatures and pimonidazole immunohistochemistry, and showed similar hypoxia gene expression to clinical HNSCC tumours. Hypoxia or proliferation status alone could not determine HAP sensitivity across our 20 HNSCC and two non-HNSCC tumour models by either tumour growth inhibition or killing of hypoxia cells in an ex vivo clonogenic assay. In summary, our tumour models provide clinically relevant HNSCC models that are suitable for evaluating hypoxia-targeting therapies; however, additional biomarkers to hypoxia are required to accurately predict drug sensitivity.
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Marqueurs biologiques tumoraux , Tumeurs de la tête et du cou , Carcinome épidermoïde de la tête et du cou , Tests d'activité antitumorale sur modèle de xénogreffe , Animaux , Humains , Souris , Marqueurs biologiques tumoraux/métabolisme , Hypoxie cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Pertinence clinique , Tumeurs de la tête et du cou/métabolisme , Tumeurs de la tête et du cou/anatomopathologie , Tumeurs de la tête et du cou/traitement médicamenteux , Tumeurs de la tête et du cou/génétique , Nitroimidazoles/pharmacologie , Promédicaments/pharmacologie , Promédicaments/usage thérapeutique , Carcinome épidermoïde de la tête et du cou/métabolisme , Carcinome épidermoïde de la tête et du cou/anatomopathologie , Carcinome épidermoïde de la tête et du cou/génétique , Carcinome épidermoïde de la tête et du cou/traitement médicamenteux , Hypoxie tumoraleRÉSUMÉ
BACKGROUND: One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker. MATERIALS AND METHODS: We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI cancers. We compared the clinical outcomes of patients with GI cancer harboring MTAP-loss and MTAP-intact tumors in a retrospective study. RESULTS: The prevalence of MTAP-loss in GI cancers is 8.30%. MTAP-loss was most prevalent in pancreatic ductal adenocarcinoma (PDAC) at 21.7% and least in colorectal carcinoma (CRC) at 1.1%. MTAP-loss tumors were more prevalent in East Asian patients with PDAC (4.4% vs 3.2%, Pâ =â .005) or intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, Pâ =â .036). Significant differences in the prevalence of potentially targetable genomic alterations (ATM, BRAF, BRCA2, ERBB2, IDH1, PIK3CA, and PTEN) were observed in MTAP-loss tumors and varied according to tumor type. MTAP-loss PDAC, IHCC, and CRC had a lower prevalence of microsatellite instability or elevated tumor mutational burden. Positive PD-L1 tumor cell expression was less frequent among MTAP-loss versus MTAP-intact IHCC tumors (23.2% vs 31.2%, Pâ =â .017). CONCLUSION: In GI cancers, MTAP-loss occurs as part of 9p21 loss and has an overall prevalence of 8%. MTAP-loss occurs in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC and is not mutually exclusive with other targetable mutations.
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Tumeurs gastro-intestinales , Purine nucleoside phosphorylase , Humains , Purine nucleoside phosphorylase/génétique , Mâle , Femelle , Tumeurs gastro-intestinales/génétique , Tumeurs gastro-intestinales/anatomopathologie , Adulte d'âge moyen , Sujet âgé , Études rétrospectives , Marqueurs biologiques tumoraux/génétique , Adulte , Pronostic , Génomique/méthodesRÉSUMÉ
Pyrazinoic acid is the active form of pyrazinamide, a first-line antibiotic used to treat Mycobacterium tuberculosis infections. However, the mechanism of action of pyrazinoic acid remains a subject of debate, and alternatives to pyrazinamide in cases of resistance are not available. The work presented here demonstrates that pyrazinoic acid and known protonophores including salicylic acid, benzoic acid, and carbonyl cyanide m-chlorophenyl hydrazone all exhibit pH-dependent inhibition of mycobacterial growth activity over a physiologically relevant range of pH values. Other anti-tubercular drugs, including rifampin, isoniazid, bedaquiline, and p-aminosalicylic acid, do not exhibit similar pH-dependent growth-inhibitory activities. The growth inhibition curves of pyrazinoic, salicylic, benzoic, and picolinic acids, as well as carbonyl cyanide m-chlorophenyl hydrazone, all fit a quantitative structure-activity relationship (QSAR) derived from acid-base equilibria with R2 values > 0.95. The QSAR model indicates that growth inhibition relies solely on the concentration of the protonated forms of these weak acids (rather than the deprotonated forms). Moreover, pyrazinoic acid, salicylic acid, and carbonyl cyanide m-chlorophenyl hydrazone all caused acidification of the mycobacterial cytoplasm at concentrations that inhibit bacterial growth. Thus, it is concluded that pyrazinoic acid acts as an uncoupler of oxidative phosphorylation and that disruption of proton motive force is the primary mechanism of action of pyrazinoic acid rather than the inhibition of a classic enzyme activity.
RÉSUMÉ
A 51-year-old male with a history of Cacchi-Ricci disease and long-standing infection with various species of Borrelia, Babesia, and Bartonella presented with recurrent symptoms of right-sided flank pain. Numerous renal calculi were identified on imaging. The etiology of the calculi had not been previously elucidated. Symptoms intermittently date back to 2002 when uric acid stones were identified. Subsequent calculi analysis revealed calcium oxalate stones. Despite the commonality of nephrolithiasis in patients with Cacchi-Ricci disease, the extreme number of calculi and recurrent presentation of symptoms persisted despite a plethora of medical evaluations, dietary changes, and hereditary testing. This case raises questions of etiology including possible immune deficiency and whether his uncommon microbial history contributes to recurrent stone formation.
Sujet(s)
Calculs rénaux , Rein en éponge , Maladies transmises par les tiques , Mâle , Humains , Adulte d'âge moyen , Calculs rénaux/complications , Calculs rénaux/diagnostic , Rein , Rein en éponge/complications , Maladies transmises par les tiques/complications , Maladies transmises par les tiques/diagnosticRÉSUMÉ
The bottom-up prediction of thermodynamic and mechanical behaviors of polymeric materials based on molecular dynamics (MD) simulation is of critical importance in polymer physics. Although the atomistically informed coarse-grained (CG) model can access greater spatiotemporal scales and retain essential chemical specificity, the temperature-transferable CG model is still a big challenge and hinders widespread application of this technique. Herein, we use a silicone polymer, i.e., polydimethylsiloxane (PDMS), having an incredibly low chain rigidity as a model system, combined with an energy-renormalization (ER) approach, to systematically develop a temperature-transferable CG model. Specifically, by introducing temperature-dependent ER factors to renormalize the effective distance and cohesive energy parameters, the developed CG model faithfully preserved the dynamics, mechanical and conformational behaviors compared with the target all-atomistic (AA) model from glassy to melt regimes, which was further validated by experimental data. With the developed CG model featuring tremendously improved computational efficiency, we systematically explored the influences of cohesive interaction strength and temperature on the dynamical heterogeneity and mechanical response of polymers, where we observed consistent trends with other linear polymers with varying chain rigidity and monomeric structures. This study serves as an extension of our proposed ER approach of developing temperature transferable CG models with diverse segmental structures, highlighting the critical role of cohesive interaction strength on CG modeling of polymer dynamics and thermomechanical behaviors.