Discovery of CRBN-dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While Cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-01 derivatives that target casein kinase 1 alpha (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and a rationale for the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists.

We report a blueprint for the rational design of G protein coupled receptor (GPCR) ligands with a tailored functional response. The present study discloses the structure-based design of cannabinoid receptor type 2 (CB2R) selective inverse agonists (S)-1 and (R)-1, which were derived from privileged agonist HU-308 by introduction of a phenyl group at the gem-dimethylheptyl side chain. Epimer (R)-1 exhibits high affinity for CB2R with Kd = 39.1 nM and serves as a platform for the synthesis of a wide variety of probes. Notably, for the first time these fluorescent probes retain their inverse agonist functionality, high affinity, and selectivity for CB2R independent of linker and fluorophore substitution. Ligands (S)-1, (R)-1, and their derivatives act as inverse agonists in CB2R-mediated cAMP as well as G protein recruitment assays and do not trigger ß-arrestin-receptor association. Furthermore, no receptor activation was detected in live cell ERK1/2 phosphorylation and Ca2+-release assays. Confocal fluorescence imaging experiments with (R)-7 (Alexa488) and (R)-9 (Alexa647) probes employing BV-2 microglial cells visualized CB2R expressed at endogenous levels. Finally, molecular dynamics simulations corroborate the initial docking data in which inverse agonists restrict movement of toggle switch Trp2586.48 and thereby stabilize CB2R in its inactive state.

Multimodal artificial intelligence-based pathogenomics improves survival prediction in oral squamous cell carcinoma.

In this study, we aimed to develop a novel prognostic algorithm for oral squamous cell carcinoma (OSCC) using a combination of pathogenomics and AI-based techniques. We collected comprehensive clinical, genomic, and pathology data from a cohort of OSCC patients in the TCGA dataset and used machine learning and deep learning algorithms to identify relevant features that are predictive of survival outcomes. Our analyses included 406 OSCC patients. Initial analyses involved gene expression analyses, principal component analyses, gene enrichment analyses, and feature importance analyses. These insights were foundational for subsequent model development. Furthermore, we applied five machine learning/deep learning algorithms (Random Survival Forest, Gradient Boosting Survival Analysis, Cox PH, Fast Survival SVM, and DeepSurv) for survival prediction. Our initial analyses revealed relevant gene expression variations and biological pathways, laying the groundwork for robust feature selection in model building. The results showed that the multimodal model outperformed the unimodal models across all methods, with c-index values of 0.722 for RSF, 0.633 for GBSA, 0.625 for FastSVM, 0.633 for CoxPH, and 0.515 for DeepSurv. When considering only important features, the multimodal model continued to outperform the unimodal models, with c-index values of 0.834 for RSF, 0.747 for GBSA, 0.718 for FastSVM, 0.742 for CoxPH, and 0.635 for DeepSurv. Our results demonstrate the potential of pathogenomics and AI-based techniques in improving the accuracy of prognostic prediction in OSCC, which may ultimately aid in the development of personalized treatment strategies for patients with this devastating disease.

Performance of cone-beam computed tomography (CBCT) in comparison to conventional computed tomography (CT) and magnetic resonance imaging (MRI) for the detection of bone invasion in oral squamous cell cancer (OSCC): a prospective study.

BACKGROUND: Oral squamous carcinoma (OSCC) is often diagnosed at late stages and bone erosion or invasion of the jawbone is frequently present. Computed tomography (CT) and magnetic resonance imaging (MRI) are known to have high diagnostic sensitivities, specificities, and accuracies in detecting these bone affections in patients suffering from OSCC. To date, the existing data regarding the impact of cone-beam computed tomography (CBCT) have been weak. Therefore, this study aimed to investigate whether CBCT is a suitable tool to detect bone erosion or invasion in patients with OSCC. METHODS: We investigated in a prospective trial the impact of CBCT in the diagnosis of bone erosion or invasion in patients with OSCC who underwent surgery. Every participant received a CBCT, CT, and MRI scan during staging. Imaging modalities were evaluated by two specialists in oral and maxillofacial surgery (CBCT) and two specialists in radiology (CT and MRI) in a blinded way, to determine whether a bone affection was present or not. Reporting used the following 3-point system: no bony destruction ("0"), cortical bone erosion ("1"), or medullary bone invasion ("2"). Histological examination or a follow-up served to calculate the sensitivities, specificities, and accuracies of the imaging modalities. RESULTS: Our results revealed high diagnostic sensitivities (95.6%, 84.4%, and 88.9%), specificities (87.0%, 91.7%, and 91.7%), and accuracies (89.5%, 89.5%, and 90.8%) for CBCT, CT, and MRI. A pairwise comparison found no statistical difference between CBCT, CT, and MRI. CONCLUSION: Our data support the routine use of CBCT in the diagnosis of bone erosion and invasion in patients with OSCC as diagnostic accuracy is equal to CT and MRI, the procedure is cost-effective, and it can be performed during initial contact with the patient.

EELS: Autonomous snake-like robot with task and motion planning capabilities for ice world exploration.

Ice worlds are at the forefront of astrobiological interest because of the evidence of subsurface oceans. Enceladus in particular is unique among the icy moons because there are known vent systems that are likely connected to a subsurface ocean, through which the ocean water is ejected to space. An existing study has shown that sending small robots into the vents and directly sampling the ocean water is likely possible. To enable such a mission, NASA's Jet Propulsion Laboratory is developing a snake-like robot called Exobiology Extant Life Surveyor (EELS) that can navigate Enceladus' extreme surface and descend an erupting vent to capture unaltered liquid samples and potentially reach the ocean. However, navigating to and through Enceladus' environment is challenging: Because of the limitations of existing orbital reconnaissance, there is substantial uncertainty with respect to its geometry and the physical properties of the surface/vents; communication is limited, which requires highly autonomous robots to execute the mission with limited human supervision. Here, we provide an overview of the EELS project and its development effort to create a risk-aware autonomous robot to navigate these extreme ice terrains/environments. We describe the robot's architecture and the technical challenges to navigate and sense the icy environment safely and effectively. We focus on the challenges related to surface mobility, task and motion planning under uncertainty, and risk quantification. We provide initial results on mobility and risk-aware task and motion planning from field tests and simulated scenarios.

Investigation of clindamycin concentrations in human plasma and jawbone tissue in patients with osteonecrosis of the jaw: A prospective trial.

The aim of this study was to investigate the jawbone concentration of clindamycin (CLI) in patients with an osteonecrosis of the jaw (ONJ). Patients with medication-related ONJ (MRONJ) and osteoradionecrosis (ORN) with an antibiotic treatment with CLI were included. Plasma, vital and necrotic bone samples were collected. Plasma and jawbone samples were analyzed by liquid chromatography-tandem mass spectrometry. Patients with MRONJ exhibited a mean plasma CLI concentration of 9.6 µg/mL (SD ± 3.6 µg/mL) and mean concentrations of 2.3 µg/g CLI (SD ± 1.4 µg/g) and 2.1 µg/g CLI (SD ± 2.4 µg/g) in vital and necrotic bone samples, without statistical significance (p = 0.79). In patients with ORN, mean concentration in plasma was 12.0 µg/mL (SD ± 2.6 µg/mL), in vital bone 2.1 µg/g (SD ± 1.5 µg/g), and in necrotic bone 1.7 µg/g (SD ± 1.2 µg/g). Vital and necrotic bone concentrations did not differ significantly (p = 0.88). The results demonstrate that CLI concentrations are considerably lower than in plasma, but sufficient for most bacteria present in ONJ. Within the limitations of the study, it seems that CLI is a relevant alternative to other antibiotics in the treatment of ONJ because it reaches adequate concentrations in jawbone.

Federated Learning for Decentralized Artificial Intelligence in Melanoma Diagnostics.

Importance: The development of artificial intelligence (AI)-based melanoma classifiers typically calls for large, centralized datasets, requiring hospitals to give away their patient data, which raises serious privacy concerns. To address this concern, decentralized federated learning has been proposed, where classifier development is distributed across hospitals. Objective: To investigate whether a more privacy-preserving federated learning approach can achieve comparable diagnostic performance to a classical centralized (ie, single-model) and ensemble learning approach for AI-based melanoma diagnostics. Design, Setting, and Participants: This multicentric, single-arm diagnostic study developed a federated model for melanoma-nevus classification using histopathological whole-slide images prospectively acquired at 6 German university hospitals between April 2021 and February 2023 and benchmarked it using both a holdout and an external test dataset. Data analysis was performed from February to April 2023. Exposures: All whole-slide images were retrospectively analyzed by an AI-based classifier without influencing routine clinical care. Main Outcomes and Measures: The area under the receiver operating characteristic curve (AUROC) served as the primary end point for evaluating the diagnostic performance. Secondary end points included balanced accuracy, sensitivity, and specificity. Results: The study included 1025 whole-slide images of clinically melanoma-suspicious skin lesions from 923 patients, consisting of 388 histopathologically confirmed invasive melanomas and 637 nevi. The median (range) age at diagnosis was 58 (18-95) years for the training set, 57 (18-93) years for the holdout test dataset, and 61 (18-95) years for the external test dataset; the median (range) Breslow thickness was 0.70 (0.10-34.00) mm, 0.70 (0.20-14.40) mm, and 0.80 (0.30-20.00) mm, respectively. The federated approach (0.8579; 95% CI, 0.7693-0.9299) performed significantly worse than the classical centralized approach (0.9024; 95% CI, 0.8379-0.9565) in terms of AUROC on a holdout test dataset (pairwise Wilcoxon signed-rank, P < .001) but performed significantly better (0.9126; 95% CI, 0.8810-0.9412) than the classical centralized approach (0.9045; 95% CI, 0.8701-0.9331) on an external test dataset (pairwise Wilcoxon signed-rank, P < .001). Notably, the federated approach performed significantly worse than the ensemble approach on both the holdout (0.8867; 95% CI, 0.8103-0.9481) and external test dataset (0.9227; 95% CI, 0.8941-0.9479). Conclusions and Relevance: The findings of this diagnostic study suggest that federated learning is a viable approach for the binary classification of invasive melanomas and nevi on a clinically representative distributed dataset. Federated learning can improve privacy protection in AI-based melanoma diagnostics while simultaneously promoting collaboration across institutions and countries. Moreover, it may have the potential to be extended to other image classification tasks in digital cancer histopathology and beyond.

Successful microvascular surgery in patients with thrombophilia in head and neck surgery: a case series.

BACKGROUND: In this case series, a perioperative anticoagulation protocol for microvascular head and neck surgery in patients with thrombophilia is presented. Microvascular free-flap surgery is a standard procedure in head and neck surgery with high success rates. Nevertheless, flap loss-which is most often caused by thrombosis-can occur and has far-reaching consequences, such as functional impairment, prolonged hospitalization, and increased costs. The risk of flap loss owing to thrombosis is significantly increased in patients with thrombophilia. Therefore, perioperative anticoagulation is mandatory. To date, no perioperative anticoagulation protocol exists for these high-risk patients. CASE PRESENTATION: We present three exemplary male Caucasian patients aged 53-57 years with free flap loss owing to an underlying, hidden thrombophilia. CONCLUSION: We present a modified anticoagulation protocol for microvascular surgery in these high-risk patients, enabling successful microsurgical reconstruction.

Artroscopia de cadera como tratamiento del choque femoroacetabular con seguimiento mínimo de 10 años / Hip arthroscopy for femoroacetabular impingement with 10-year minimum follow-up

Objetivo: Valorar los resultados de la artroscopia de cadera (CAC) como tratamiento del choque femoroacetabular (CFA) con seguimiento mínimo de 10 años, y determinar las variables predictoras de reintervención quirúrgica. Material y métodos: Estudio retrospectivo de una base de datos prospectiva de pacientes intervenidos mediante CAC entre enero de 2010 y diciembre de 2011. Las lesiones del reborde acetabular se evaluaron según la clasificación ALAD. Se realizó valoración clínica y radiológica. La supervivencia de la técnica quirúrgica se calculó con la prueba de Kaplan-Meier y la prueba de regresión de Cox. Resultados: Se incluyeron en el estudio 74 pacientes con un seguimiento medio de 132 meses. La puntuación media en las escalas de valoración mejoró significativamente al final del seguimiento. Diecisiete pacientes (23,9%) fueron reintervenidos. El odds ratio de reintervención en un paciente mayor de 40 años fue de 8,08; en un paciente Tönnis 2-3 de 7,57; y en un paciente con lesión cartilaginosa ALAD 2-3 de 4,25. La supervivencia de la CAC en el CFA a 10 años fue del 77,8%, con un 45,4% en los pacientes con grado de Tönnis mayor de 1 frente al 85,2% en los pacientes con grado de Tönnis de 1 o menor (p<0,001). La variable predictora asociada a la necesidad de reintervención quirúrgica fue la degeneración articular radiológica preoperatoria (p=0,02). Conclusiones: La supervivencia de la CAC en el tratamiento del CFA a 10 años fue del 45,4% en los pacientes con grado de Tönnis mayor de 1 frente al 85,2% en los pacientes con grado de Tönnis 1 o menor. La edad, la lesión cartilaginosa y la degeneración articular incrementarían el riesgo de reintervención quirúrgica.(AU)

Purpose: To determine outcomes after hip arthroscopy (HA) for femoroacetabular impingement (FAI) at a minimun 10-year follow up and identified risk factors for revision surgery. Methods: Retrospective study of a prospective database of patients undergoing HA between January 2010 and December 2011. Rim chondral injuries were evaluated using the acetabular labral articular disruptions system (ALAD). Clinical and radiological data was obtained. Cumulative survival was estimated by Kaplan–Meier and a multivariate Cox proportional hazards model. Results: Seventy-four patients were included in the study. Mean follow-up was 132 months. There was statistically significant improvement from preoperative PROs at latest follow-up. Seventeen patients (23.9%) underwent revision surgery. Odds ratio for revision surgery was 8.08 in a patient above 40 years old, 7.57 in a patient Tönnis greater than 1, and 4.25 in a patient ALAD 2-3. Cumulative survivorship rate at 10 years was 77.8%, with a 45.4% for patients with Tönnis grade greater than 1 in front of 85.2% for patients with Tönnis grade of 1 or less (P<.001). Risk factor for revision surgery was preoperative degree of osteoarthrosis (P=.02). Conclusion: Cumulative survivorship rate at 10 years was 45.4% for patients with Tönnis grade greater than 1 in front of 85.2% for patients with Tönnis grade of 1 or less (P<.001). Age, chondral injuries, and degree of osteoarthrosis would increase the risk for revision surgery.(AU)

[Translated article] Hip arthroscopy for femoroacetabular impingement with 10-year minimum follow-up / Artroscopia de cadera como tratamiento del choque femoroacetabular con seguimiento mínimo de 10 años

Objetivo: Valorar los resultados de la artroscopia de cadera (CAC) como tratamiento del choque femoroacetabular (CFA) con seguimiento mínimo de 10 años, y determinar las variables predictoras de reintervención quirúrgica. Material y métodos: Estudio retrospectivo de una base de datos prospectiva de pacientes intervenidos mediante CAC entre enero de 2010 y diciembre de 2011. Las lesiones del reborde acetabular se evaluaron según la clasificación ALAD. Se realizó valoración clínica y radiológica. La supervivencia de la técnica quirúrgica se calculó con la prueba de Kaplan-Meier y la prueba de regresión de Cox. Resultados: Se incluyeron en el estudio 74 pacientes con un seguimiento medio de 132 meses. La puntuación media en las escalas de valoración mejoró significativamente al final del seguimiento. Diecisiete pacientes (23,9%) fueron reintervenidos. El odds ratio de reintervención en un paciente mayor de 40 años fue de 8,08; en un paciente Tönnis 2-3 de 7,57; y en un paciente con lesión cartilaginosa ALAD 2-3 de 4,25. La supervivencia de la CAC en el CFA a 10 años fue del 77,8%, con un 45,4% en los pacientes con grado de Tönnis mayor de 1 frente al 85,2% en los pacientes con grado de Tönnis de 1 o menor (p<0,001). La variable predictora asociada a la necesidad de reintervención quirúrgica fue la degeneración articular radiológica preoperatoria (p=0,02). Conclusiones: La supervivencia de la CAC en el tratamiento del CFA a 10 años fue del 45,4% en los pacientes con grado de Tönnis mayor de 1 frente al 85,2% en los pacientes con grado de Tönnis 1 o menor. La edad, la lesión cartilaginosa y la degeneración articular incrementarían el riesgo de reintervención quirúrgica.(AU)

Purpose: To determine outcomes after hip arthroscopy (HA) for femoroacetabular impingement (FAI) at a minimun 10-year follow up and identified risk factors for revision surgery. Methods: Retrospective study of a prospective database of patients undergoing HA between January 2010 and December 2011. Rim chondral injuries were evaluated using the acetabular labral articular disruptions system (ALAD). Clinical and radiological data was obtained. Cumulative survival was estimated by Kaplan–Meier and a multivariate Cox proportional hazards model. Results: Seventy-four patients were included in the study. Mean follow-up was 132 months. There was statistically significant improvement from preoperative PROs at latest follow-up. Seventeen patients (23.9%) underwent revision surgery. Odds ratio for revision surgery was 8.08 in a patient above 40 years old, 7.57 in a patient Tönnis greater than 1, and 4.25 in a patient ALAD 2-3. Cumulative survivorship rate at 10 years was 77.8%, with a 45.4% for patients with Tönnis grade greater than 1 in front of 85.2% for patients with Tönnis grade of 1 or less (P<.001). Risk factor for revision surgery was preoperative degree of osteoarthrosis (P=.02). Conclusion: Cumulative survivorship rate at 10 years was 45.4% for patients with Tönnis grade greater than 1 in front of 85.2% for patients with Tönnis grade of 1 or less (P<.001). Age, chondral injuries, and degree of osteoarthrosis would increase the risk for revision surgery.(AU)

Hip arthroscopy for femoroacetabular impingement with 10-year minimum follow-up. / Artroscopia de cadera como tratamiento del choque femoroacetabular con seguimiento mínimo de 10 años.

PURPOSE: To determine outcomes after hip arthroscopy (HA) for femoroacetabular impingement (FAI) at a minimun 10-year follow up and identified risk factors for revision surgery. METHODS: Retrospective study of a prospective database of patients undergoing HA between January 2010 and December 2011. Rim chondral injuries were evaluated using the acetabular labral articular disruptions system (ALAD). Clinical and radiological data was obtained. Cumulative survival was estimated by Kaplan-Meier and a multivariate Cox proportional hazards model. RESULTS: Seventy-four patients were included in the study. Mean follow-up was 132 months. There was statistically significant improvement from preoperative PROs at latest follow-up. Seventeen patients (23.9%) underwent revision surgery. Odds ratio for revision surgery was 8.08 in a patient above 40 years old, 7.57 in a patient Tönnis greater than 1, and 4.25 in a patient ALAD 2-3. Cumulative survivorship rate at 10 years was 77.8%, with a 45.4% for patients with Tönnis grade greater than 1 in front of 85.2% for patients with Tönnis grade of 1 or less (P<.001). Risk factor for revision surgery was preoperative degree of osteoarthrosis (P=.02). CONCLUSION: Cumulative survivorship rate at 10 years was 45.4% for patients with Tönnis grade greater than 1 in front of 85.2% for patients with Tönnis grade of 1 or less (P<.001). Age, chondral injuries, and degree of osteoarthrosis would increase the risk for revision surgery.

[Translated article] Hip arthroscopy for femoroacetabular impingement with 10-year minimum follow-up.

PURPOSE: To determine outcomes after hip arthroscopy (HA) for femoroacetabular impingement (FAI) at a minimun 10-year follow up and identified risk factors for revision surgery. METHODS: Retrospective study of a prospective database of patients undergoing HA between January 2010 and December 2011. Rim chondral injuries were evaluated using the acetabular labral articular disruptions system (ALAD). Clinical and radiological data was obtained. Cumulative survival was estimated by Kaplan-Meier and a multivariate Cox proportional hazards model. RESULTS: Seventy-four patients were included in the study. Mean follow-up was 132 months. There was statistically significant improvement from preoperative PROs at latest follow-up. Seventeen patients (23.9%) underwent revision surgery. Odds ratio for revision surgery was 8.08 in a patient above 40 years old, 7.57 in a patient Tönnis greater than 1, and 4.25 in a patient ALAD 2-3. Cumulative survivorship rate at 10 years was 77.8%, with a 45.4% for patients with Tönnis grade greater than 1 in front of 85.2% for patients with Tönnis grade of 1 or less (p<.001). Risk factor for revision surgery was preoperative degree of osteoarthrosis (p=.02). CONCLUSION: Cumulative survivorship rate at 10 years was 45.4% for patients with Tönnis grade greater than 1 in front of 85.2% for patients with Tönnis grade of 1 or less (p<.001). Age, chondral injuries, and degree of osteoarthrosis would increase the risk for revision surgery.

Impact of aminopenicillin administration routes on antimicrobial effects of platelet-rich fibrin: An in-vitro investigation.

INTRODUCTION: The aim of the study was to investigate the impact of different aminopenicillin administration routes on the antimicrobial effects of platelet-rich fibrin (PRF). METHODS: We enrolled patients undergoing treatment with amoxicillin/clavulanic acid (AMC) orally or ampicillin/sulbactam (SAM) intravenously. AMC was applied in a single oral dose (875/125 mg), or in a double oral dose (1750/250 mg), and SAM in a dose of 2000/1000 mg. Blood was obtained one hour after the intake of AMC or 15 min after the infusion of SAM ended. Antimicrobial effects were investigated in agar diffusion tests with fresh PRF, PRF stored for 24, and PRF stored for 48 h. Agar diffusion tests were performed with Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Porphyromonas gingivalis. Inhibition zones (IZs) around a 6 mm PRF disc were measured after 24 h. RESULTS: IZs for fresh PRF and the single oral dose of AMC were 0.0, 4.7, 15.2, 2.3, and 0.9 mm (E. coli, S. aureus, S. pneumoniae, H. influenzae, and P. gingivalis, respectively). For the double oral dose, these values were 0.0, 11.4, 20.0, 8.1, and 7.4 mm. IZs for SAM were 11.9, 18.2, 24.7, 20.3, and 22.1 mm. Differences between parenteral and oral application as well as between different oral doses were significant (p<0.0001, one-way ANOVA). DISCUSSION: The results of our study demonstrate that oral administration is a suitable route to load PRF with these drugs. This could expand the scope of PRF application to prevent infections at the surgical site, especially in an outpatient setting in which drugs are normally applied orally.

Performance of artificial intelligence-based algorithms to predict prolonged length of stay after head and neck cancer surgery.

Background: Medical resource management can be improved by assessing the likelihood of prolonged length of stay (LOS) for head and neck cancer surgery patients. The objective of this study was to develop predictive models that could be used to determine whether a patient's LOS after cancer surgery falls within the normal range of the cohort. Methods: We conducted a retrospective analysis of a dataset consisting of 300 consecutive patients who underwent head and neck cancer surgery between 2017 and 2022 at a single university medical center. Prolonged LOS was defined as LOS exceeding the 75th percentile of the cohort. Feature importance analysis was performed to evaluate the most important predictors for prolonged LOS. We then constructed 7 machine learning and deep learning algorithms for the prediction modeling of prolonged LOS. Results: The algorithms reached accuracy values of 75.40 (radial basis function neural network) to 97.92 (Random Trees) for the training set and 64.90 (multilayer perceptron neural network) to 84.14 (Random Trees) for the testing set. The leading parameters predicting prolonged LOS were operation time, ischemia time, the graft used, the ASA score, the intensive care stay, and the pathological stages. The results revealed that patients who had a higher number of harvested lymph nodes (LN) had a lower probability of recurrence but also a greater LOS. However, patients with prolonged LOS were also at greater risk of recurrence, particularly when fewer (LN) were extracted. Further, LOS was more strongly correlated with the overall number of extracted lymph nodes than with the number of positive lymph nodes or the ratio of positive to overall extracted lymph nodes, indicating that particularly unnecessary lymph node extraction might be associated with prolonged LOS. Conclusions: The results emphasize the need for a closer follow-up of patients who experience prolonged LOS. Prospective trials are warranted to validate the present results.

Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry.

Targeted protein degradation relies on small molecules that induce new protein-protein interactions between targets and the cellular protein degradation machinery. Most of these small molecules feature specific ligands for ubiquitin ligases. Recently, the attachment of cysteine-reactive chemical groups to pre-existing small molecule inhibitors has been shown to drive specific target degradation. We demonstrate here that different cysteine-reactive groups can specify target degradation via distinct ubiquitin ligases. By focusing on the bromodomain ligand JQ1, we identify cysteine-reactive functional groups that drive BRD4 degradation by either DCAF16 or DCAF11. Unlike proteolysis-targeting chimeric molecules (PROTACs), the new compounds use a single small molecule ligand with a well-positioned cysteine-reactive group to induce protein degradation. The finding that nearly identical compounds can engage multiple ubiquitination pathways suggests that targeting cellular pathways that search for and eliminate chemically reactive proteins is a feasible avenue for converting existing small molecule drugs into protein degrader molecules.

Bony Regrowth and New Spur Formation as Possible Causes of Failed Distal Clavicle Excision-Mid-Term Outcomes after Revision Surgery in a Matched-Pair Analysis.

BACKGROUND: Despite high rates of successful outcomes after open and arthroscopic distal clavicle excision (DCE) for symptomatic acromioclavicular joint (ACJ) degeneration, some patients present with persistent symptoms and disabilities after surgical intervention. This study aims to compare radiological, functional, and subjective outcomes of open revision surgery after failed arthroscopic DCE to primary successful arthroscopic DCE. METHODS: In this retrospective case-control study, 10 patients who underwent open DCE revision were age- and gender-matched with 10 patients who did not require revision surgery after DCE. Radiographic evaluation included presence of acromioclavicular spurs and acromioclavicular joint distance. Functional and subjective outcomes were assessed using the CS, SSV, SST, VAS for pain, patient's satisfaction, ASES and quick DASH score. RESULTS: At the latest postoperative follow-up (case: 57.3 ± 19.2 months; control: 63.5 ± 16.3 months), spur formation was detected in twice as many cases in the revision group, while acromioclavicular distance showed no significant difference. However, a significant bony regrowth was noticed in the revision group between revision surgery and latest follow-up, with a decrease of the acromioclavicular distance from 9.2 ± 1.6 mm to 5.9 ± 4.6 mm (p = 0.026) and a development of new spur formations in 30% of cases. There were no significant differences in overall CS between the revision and control group (p = 0.174) at final follow-up, but the control group scored significantly higher in the CS subgroups pain (p = 0.012) and internal rotation (p = 0.016). Mean SSV was significantly lower in the revision (65.5 ± 22.3%) compared to the control group (85.9 ± 16.4%; p = 0.031). CONCLUSIONS: Bony regrowth at the distal clavicle presenting as postoperative AC-distance narrowing and new spur formation was observed more distinctly in the revision group. Despite a slight increase in postoperative outcomes after revision surgery, subjective satisfaction and recalcitrant pain remain a concern. LEVEL OF EVIDENCE: Therapeutic Level III, retrospective case-control study.

Cobalt-Catalyzed Aerobic Aminocyclization of Unsaturated Amides for the Synthesis of Functionalized γ- and δ-Lactams.

We report the cobalt-catalyzed aminocyclization of unsaturated N-acyl sulfonamides in the presence of oxygen to provide γ- and δ-lactam aldehydes. Use of an optically active cobalt catalyst resulted in the formation of enantiomerically enriched γ-and δ-lactam alcohols. The γ-lactam aldehydes and alcohols obtained were elaborated into useful building blocks.

Investigation of three common centrifugation protocols for platelet-rich fibrin (PRF) as a bio-carrier for ampicillin/sulbactam: a prospective trial.

OBJECTIVES: Different platelet-rich fibrin (PRF) protocols exist and are known to differ in resulting mechanical and bioactive properties. Centrifugation parameters may also influence drug release, in particular antibiotics, when using PRF as a bio-carrier. We thus evaluated three common protocols regarding effects on the bio-carrier properties. MATERIALS AND METHODS: In a prospective trial comprising 33 patients, we compared different protocols for PRF as a bio-carrier for ampicillin/sulbactam (SAM). Blood samples were taken shortly after a single dose of ampicillin/sulbactam (2 g/1 g) was administered to patients intravenously. PRF was obtained by centrifugation and three protocols were used: protocol A (1300 rpm, 8 min, RCF-max = 208 g), B (2300 rpm, 12 min, RCF-max = 652 g), and C (1500 rpm, 14 min, RCF-max = 276 g). The antibacterial activity of PRF was investigated against five oral species in vitro, based on agar diffusion methodology. RESULTS: The study demonstrates that a single dose of SAM is sufficient to reach high concentrations in PRF in all protocols (150 µg/ml), which is comparable to the plasma SAM concentration. Antibacterial activity was inferred from the diameter of inhibition zones seen in agar diffusion tests using PRF discs. Protocol B resulted in the largest inhibition zones. One-way ANOVA revealed statistically improved results for protocol B for some bacteria. CONCLUSIONS: The study provides valuable data on PRF antibiotic enrichment, notably SAM. A single dose of SAM is sufficient to reach clinically relevant concentrations in PRF. CLINICAL RELEVANCE: These findings potentially extend the application of PRF, for example in patients with osteonecrosis of the jaw or in oral surgery (e.g., stick bone).