Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies.

Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and mitogen-activated protein kinase (MAPK) pathway activation. The high specificity of the designed agonists reveals distinct roles for two FGFR splice variants in driving arterial endothelium and perivascular cell fates during early vascular development. Our designed modular assemblies should be broadly useful for unraveling the complexities of signaling in key developmental transitions and for developing future therapeutic applications.

Recent advances in implantable sensors and electronics using printable materials for advanced healthcare.

This review article focuses on the recent printing technological progress in healthcare, underscoring the significant potential of implantable devices across diverse applications. Printing technologies have widespread use in developing health monitoring devices, diagnostic systems, and surgical devices. Recent years have witnessed remarkable progress in fabricating low-profile implantable devices, driven by advancements in printing technologies and nanomaterials. The importance of implantable biosensors and bioelectronics is highlighted, specifically exploring printing tools using bio-printable inks for practical applications, including a detailed examination of fabrication processes and essential parameters. This review also justifies the need for mechanical and electrical compatibility between bioelectronics and biological tissues. In addition to technological aspects, this article delves into the importance of appropriate packaging methods to enhance implantable devices' performance, compatibility, and longevity, which are made possible by integrating cutting-edge printing technology. Collectively, we aim to shed light on the holistic landscape of implantable biosensors and bioelectronics, showcasing their evolving role in advancing healthcare through innovative printing technologies.

Variability of the femoral mechanical-anatomical axis angle and its implications in primary and revision total knee arthroplasty.

Aims: Distal femoral resection in conventional total knee arthroplasty (TKA) utilizes an intramedullary guide to determine coronal alignment, commonly planned for 5° of valgus. However, a standard 5° resection angle may contribute to malalignment in patients with variability in the femoral anatomical and mechanical axis angle. The purpose of the study was to leverage deep learning (DL) to measure the femoral mechanical-anatomical axis angle (FMAA) in a heterogeneous cohort. Methods: Patients with full-limb radiographs from the Osteoarthritis Initiative were included. A DL workflow was created to measure the FMAA and validated against human measurements. To reflect potential intramedullary guide placement during manual TKA, two different FMAAs were calculated either using a line approximating the entire diaphyseal shaft, and a line connecting the apex of the femoral intercondylar sulcus to the centre of the diaphysis. The proportion of FMAAs outside a range of 5.0° (SD 2.0°) was calculated for both definitions, and FMAA was compared using univariate analyses across sex, BMI, knee alignment, and femur length. Results: The algorithm measured 1,078 radiographs at a rate of 12.6 s/image (2,156 unique measurements in 3.8 hours). There was no significant difference or bias between reader and algorithm measurements for the FMAA (p = 0.130 to 0.563). The FMAA was 6.3° (SD 1.0°; 25% outside range of 5.0° (SD 2.0°)) using definition one and 4.6° (SD 1.3°; 13% outside range of 5.0° (SD 2.0°)) using definition two. Differences between males and females were observed using definition two (males more valgus; p < 0.001). Conclusion: We developed a rapid and accurate DL tool to quantify the FMAA. Considerable variation with different measurement approaches for the FMAA supports that patient-specific anatomy and surgeon-dependent technique must be accounted for when correcting for the FMAA using an intramedullary guide. The angle between the mechanical and anatomical axes of the femur fell outside the range of 5.0° (SD 2.0°) for nearly a quarter of patients.

Immunohistochemical evaluation of keratins and involucrin in differentiating between palmoplantar pustulosis and pompholyx.

BACKGROUND: Palmoplantar pustulosis (PPP) and pompholyx are chronic diseases characterized by pustules and vesicles on the palms and soles. These disorders often have similar clinicopathological features, which lead to diagnostic difficulties. We aimed to investigate the expression patterns of keratins and involucrin in PPP and pompholyx using immunohistochemical staining. METHODS: Skin biopsies from patients with PPP (n = 40) and pompholyx (n = 22) were immunohistochemically analyzed for Keratin 5, 9, 14, and involucrin expression. RESULTS: K5 expression was higher in PPP than in pompholyx, with diffusely positive expression in the basal, spinous, and granular layers. K14 expression did not differ between groups. K9 expression was observed near the pompholyx vesicle (P = 0.014) and stratum spinosum (P < 0.001) but was almost absent around PPP pustules. Involucrin expression was diffused around the PPP pustules and partially around the pompholyx vesicles, but without statistical significance (P = 0.123). Involucrin expression was elevated in the basal layer of the PPP compared with that in the pompholyx (P = 0.023). CONCLUSION: PPP and pompholyx exhibited distinctive differentiation in the expression of K5, K9, and involucrin.

Deep-Learning Automation of Preoperative Radiographic Parameters Associated With Early Periprosthetic Femur Fracture After Total Hip Arthroplasty.

BACKGROUND: The radiographic assessment of bone morphology impacts implant selection and fixation type in total hip arthroplasty (THA) and is important to minimize the risk of periprosthetic femur fracture (PFF). We utilized a deep-learning algorithm to automate femoral radiographic parameters and determined which automated parameters were associated with early PFF. METHODS: Radiographs from a publicly available database and from patients undergoing primary cementless THA at a high-volume institution (2016 to 2020) were obtained. A U-Net algorithm was trained to segment femoral landmarks for bone morphology parameter automation. Automated parameters were compared against that of a fellowship-trained surgeon and compared in an independent cohort of 100 patients who underwent THA (50 with early PFF and 50 controls matched by femoral component, age, sex, body mass index, and surgical approach). RESULTS: On the independent cohort, the algorithm generated 1,710 unique measurements for 95 images (5% lesser trochanter identification failure) in 22 minutes. Medullary canal width, femoral cortex width, canal flare index, morphological cortical index, canal bone ratio, and canal calcar ratio had good-to-excellent correlation with surgeon measurements (Pearson's correlation coefficient: 0.76 to 0.96). Canal calcar ratios (0.43 ± 0.08 versus 0.40 ± 0.07) and canal bone ratios (0.39 ± 0.06 versus 0.36 ± 0.06) were higher (P < .05) in the PFF cohort when comparing the automated parameters. CONCLUSIONS: Deep-learning automated parameters demonstrated differences in patients who had and did not have early PFF after cementless primary THA. This algorithm has the potential to complement and improve patient-specific PFF risk-prediction tools.

What's all the chatter about?

The OpenAI chatbot ChatGPT is an artificial intelligence (AI) application that uses state-of-the-art language processing AI. It can perform a vast number of tasks, from writing poetry and explaining complex quantum mechanics, to translating language and writing research articles with a human-like understanding and legitimacy. Since its initial release to the public in November 2022, ChatGPT has garnered considerable attention due to its ability to mimic the patterns of human language, and it has attracted billion-dollar investments from Microsoft and PricewaterhouseCoopers. The scope of ChatGPT and other large language models appears infinite, but there are several important limitations. This editorial provides an introduction to the basic functionality of ChatGPT and other large language models, their current applications and limitations, and the associated implications for clinical practice and research.

Complication Rate After Primary Total Hip Arthroplasty Using the Posterior Approach and Enabling Technology: A Consecutive Series of 2,888 Hips.

BACKGROUND: Total hip arthroplasty (THA) is a safe and effective procedure; however, complications such as dislocation, fracture, and infection still occur. It is still unclear whether the dislocation rate via the posterior approach (PA) is better, equal, or worse than the direct anterior approach. Our aim was to report the primary THA dislocation rate via the PA using enabling technology in a large consecutive series of patients. METHODS: A retrospective cohort of 2,888 primary THAs were reviewed at a single, high-volume, academic institution from January 2018 to September 2021. All patients underwent a THA by 4 fellowship-trained orthopaedic surgeons through the PA with enabling technology. Overall dislocation and readmission rates within 90 days and up to 3 years were analyzed. RESULTS: Of the 2,888 procedures, a total of 39 patients had complications related to the surgery during the 3-year follow-up period. There were 10 patients (0.35%) who experienced a dislocation, with half undergoing surgical revision. Of the 39 patients who experienced complications, 37 (1.3%) were readmitted and 2 underwent revision during their hospital stay. Postoperative periprosthetic fractures were the most common cause for readmission and reoperation at a rate of 0.52% and 0.52%, respectively. CONCLUSION: The dislocation rate of 0.35% is one of the lowest reported rates via the PA at a mean follow up of 2.1 years and is comparable to previously published rates using alternate approaches. Using contemporary THA with enabling technology, the PA is a reliable approach with respect to dislocation and complication rates after primary THA.

Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies.

Growth factors and cytokines signal by binding to the extracellular domains of their receptors and drive association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affects signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo designed fibroblast growth-factor receptor (FGFR) binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and MAPK pathway activation. The high specificity of the designed agonists reveal distinct roles for two FGFR splice variants in driving endothelial and mesenchymal cell fates during early vascular development. The ability to incorporate receptor binding domains and repeat extensions in a modular fashion makes our designed scaffolds broadly useful for probing and manipulating cellular signaling pathways.

Geographic Variation in Knee Phenotypes Based on the Coronal Plane Alignment of the Knee Classification: A Systematic Review.

BACKGROUND: The extent of geographic variation in knee phenotypes remains unclear. The Coronal Plane Alignment of the Knee (CPAK) Classification proposes 9 coronal plane phenotypes based on constitutional limb alignment and joint line obliquity. This systematic review aims to examine differences in the distributions of CPAK types across geographic regions. METHODS: A systematic review of the literature was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies reporting distributions of knee phenotypes according to the CPAK classification for healthy and/or arthritic knees were included. RESULTS: There were 7 studies included, accounting for 5,964 knees in 3,917 subjects. Among healthy knees (n = 1,214), CPAK type II was the most common type in Belgium (39.2%), Taiwan (39.3%), and India (25.6%). Among arthritic knees (n = 2,804), CPAK type I was the most common in France (33.4%), India (58.8%), and Japan (53.8%), whereas CPAK type II was the most common in Australia (32.8%). The proportion of CPAK type I and II knees varied significantly across geographic regions among healthy (P < .01) and arthritic knees (P < .01). CONCLUSION: Significant variation in CPAK distributions exists between countries. Further work is needed to delineate racial and sexual differences in CPAK types, which were not explored in this article. A better understanding of population-level variability in knee phenotypes may enable orthopaedic surgeons to offer a more personalized approach to knee arthroplasty.

Heparin is essential for optimal cell signaling by FGF21 and for regulation of ßKlotho cellular stability.

While important insights were gained about how FGF21 and other endocrine fibroblast growth factors (FGFs) bind to Klotho proteins, the exact mechanism of Klotho/FGF receptor assembly that drives receptor dimerization and activation has not been elucidated. The prevailing dogma is that Klotho proteins substitute for the loss of heparan sulfate proteoglycan (HSPG) binding to endocrine FGFs by high-affinity binding of endocrine FGF molecules to Klotho receptors. To explore a potential role of HSPG in FGF21 signaling, we have analyzed the dynamic properties of FGF21-induced FGF21-ßKlotho-FGFR1c complexes on the surface of living wild-type (WT) or HSPG-deficient Chinese hamster ovary (CHO) cells by employing quantitative single-molecule fluorescence imaging analyses. Moreover, detailed analyses of FGF21 and FGF1 stimulation of cellular signaling pathways activated in WT or in HSPG-deficient CHO cells are also analyzed and compared. These experiments demonstrate that heparin is required for the formation of FGF21-ßKlotho-FGFR1c complexes on the cell membrane and that binding of heparin or HSPG to FGFR1c is essential for optimal FGF21 stimulation of FGFR1c activation, mitogen-activated protein kinase responses, and intracellular Ca2+ release. It is also shown that FGF1 binding stimulates assembly of ßKlotho and FGFR1c on cell membranes, resulting in endocytosis and degradation of ßKlotho. We conclude that heparin or HSPG is essential for FGF21 signaling and for regulation of ßKlotho cellular stability by acting as a coligand of FGFR1c.

Genome-wide screening reveals the genetic basis of mammalian embryonic eye development.

BACKGROUND: Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. RESULTS: Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. CONCLUSIONS: Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

A practical guide to the development and deployment of deep learning models for the orthopedic surgeon: part II.

Deep learning has the potential to be one of the most transformative technologies to impact orthopedic surgery. Substantial innovation in this area has occurred over the past 5 years, but clinically meaningful advancements remain limited by a disconnect between clinical and technical experts. That is, it is likely that few orthopedic surgeons possess both the clinical knowledge necessary to identify orthopedic problems, and the technical knowledge needed to implement deep learning-based solutions. To maximize the utilization of rapidly advancing technologies derived from deep learning models, orthopedic surgeons should understand the steps needed to design, organize, implement, and evaluate a deep learning project and its workflow. Equipping surgeons with this knowledge is the objective of this three-part editorial review. Part I described the processes involved in defining the problem, team building, data acquisition, curation, labeling, and establishing the ground truth. Building on that, this review (Part II) provides guidance on pre-processing and augmenting the data, making use of open-source libraries/toolkits, and selecting the required hardware to implement the pipeline. Special considerations regarding model training and evaluation unique to deep learning models relative to "shallow" machine learning models are also reviewed. Finally, guidance pertaining to the clinical deployment of deep learning models in the real world is provided. As in Part I, the focus is on applications of deep learning for computer vision and imaging.

Standardized Fixation Zones and Cone Assessments for Revision Total Knee Arthroplasty Using Deep Learning.

BACKGROUND: Achieving adequate implant fixation is critical to optimize survivorship and postoperative outcomes after revision total knee arthroplasty (rTKA). Three anatomical zones (ie, epiphysis, metaphysis, and diaphysis) have been proposed to assess fixation, but are not well-defined. The purpose of the study was to develop a deep learning workflow capable of automatically delineating rTKA zones and cone placements in a standardized way on postoperative radiographs. METHODS: A total of 235 patients who underwent rTKA were randomly partitioned (6:2:2 training, validation, and testing split), and a U-Net segmentation workflow was developed to delineate rTKA fixation zones and assess revision cone placement on anteroposterior radiographs. Algorithm performance for zone delineation and cone placement were compared against ground truths from a fellowship-trained arthroplasty surgeon using the dice segmentation coefficient and accuracy metrics. RESULTS: On the testing cohort, the algorithm defined zones in 98% of images (8 seconds/image) using anatomical landmarks. The dice segmentation coefficient between the model and surgeon was 0.89 ± 0.08 (interquartile range [IQR]:0.88-0.94) for femoral zones, 0.91 ± 0.08 (IQR: 0.91-0.95) for tibial zones, and 0.90 ± 0.05 (IQR:0.88-0.94) for all zones. Cone identification and zonal cone placement accuracy were 98% and 96%, respectively, for the femur and 96% and 89%, respectively, for the tibia. CONCLUSION: A deep learning algorithm was developed to automatically delineate revision zones and cone placements on postoperative rTKA radiographs in an objective, standardized manner. The performance of the algorithm was validated against a trained surgeon, suggesting that the algorithm demonstrated excellent predictive capabilities in accordance with relevant anatomical landmarks used by arthroplasty surgeons in practice.

The Impact of Varying Femoral Head Length on Hip External Rotation During Posterior-approach Total Hip Arthroplasty.

Background: Prior investigations of total hip arthroplasty (THA) have studied the effects of prosthetic femoral head size and stem offset on hip range of motion (ROM), impingement risk, and overall hip stability to optimize the return to activities of daily living. However, the relationship between femoral head length and hip ROM, specifically external rotation (ER), has not been evaluated. The aim of our study was to intraoperatively assess how femoral head length affects hip ROM during a posterior approach THA. Methods: Thirty-two patients undergoing a primary elective THA through a posterior approach were prospectively included. After final femoral stem insertion, femoral head trials were performed using the targeted head length, followed by the shorter (-3.0 to -3.5 mm) and longer (+3.0 to +4.0 mm) head length configurations. At each length, hip ER was measured using an intraoperative goniometer from an imageless navigation system. ER values across the three head lengths were compared using a repeated-measures analysis of variance and paired t-tests. Results: Varying femoral head lengths demonstrated a statically significant and reproducible effect on intraoperative ER range (analysis of variance; P < .001) in each patient. An increased femoral head length (mean 3.4 mm) significantly decreased (P < .001) ER range by 10.8 ± 3.3° while a shortened femoral head length (mean 3.5 mm) significantly increased (P < .001) the ER ROM by 6.0 ± 3.8°. Conclusions: The results of this study demonstrate the sensitivity of hip ROM to incremental changes in femoral head length. As ER is important for activities of daily living, inadvertent lengthening should be avoided.

The modern Burch-Schneider antiprotrusio cage for the treatment of acetabular defects: is it still an option? A systematic review.

BACKGROUND: A number of papers have been published about the clinical performance of modern rough-blasted titanium Burch-Schneider antiprotrusio cages (BS-APCs) for the treatment of acetabular bone defects. However, no systematic review of the literature has been published to date. METHODS: The US National Library of Medicine (PubMed/MEDLINE), EMBASE, and the Cochrane Database of Systematic Reviews were queried for publications using keywords pertinent to Burch-Schneider antiprotrusio cage, revision THA, and clinical outcomes. RESULTS: 8 articles were found to be suitable for inclusion in the present study in which 374 cases (370 patients) had been treated with modern BS-APCs. Most acetabular bone defects were type 3 according to the Paprosky classification (type 2C: 18.1%, 3A: 51%, and 3B: 28.9%). The overall re-revision rate for the 374 acetabular reconstructions with modern BS-APCs was 11.5% (43 cases). The short-term survival rate of the modern BS-APC construct was 90.6% (339 out of 374 cases), while the mid-term survival rate was 85.6% (320 out of 374 cases), and the long-term survival rate 62% (54 out of 87 cases). The most common reasons for revision were aseptic loosening (5.6%), periprosthetic joint infection (3.8%), dislocation (2.7%), and acetabular periprosthetic fracture (1.9%). CONCLUSIONS: There was moderate quality evidence to show that the use of modern rough blasted titanium BS-APCs in cases of acetabular bone loss has an unacceptably high failure rate (38%). Given that antiprotrusio cages do not provide any biological fixation, we would not recommend the routine use of modern BS-APCs in complex revision THA cases. By contrast, the satisfactory short- to mid-term outcome of modern BS-APCs in combination with their low cost compared to highly porous acetabular implants, make us feel that BS-APCs might still be used in selected elderly or low-demand patients without severe superomedial acetabular bone loss.

Periodontitis is associated with the development of fungal sinusitis: A nationwide 12-year follow-up study.

AIM: The incidence of fungal sinusitis is increasing; however, its pathophysiology has not been investigated previously. We investigate the effect of periodontitis on the incidence of fungal sinusitis over a 12-year follow-up period using nationwide population-based data. MATERIALS AND METHODS: The periodontitis group was randomly selected from the National Health Insurance Service database. The non-periodontitis group was obtained by propensity score matching considering several variables. The primary end point was the diagnosis of sinonasal fungal balls (SFBs) and invasive fungal sinusitis (IFS). RESULTS: The periodontitis and non-periodontitis groups included 12,442 and 12,442 individuals, respectively. The overall adjusted hazard ratio (aHR) for SFBs in the periodontitis group was 1.46 (p = .002). In subgroup analysis, the aHR for SFBs was 1.59 (p = 0.008) for those with underlying chronic kidney disease (CKD), 1.58 (p = .022) for those with underlying atopic dermatitis, 1.48 (p = .019) for those with chronic obstructive pulmonary disease (COPD), and 1.36 (p = .030) for those with diabetes mellitus (DM), but these values are applicable only when considering the relationship between periodontitis and SFB. The aHR for IFS in the periodontitis group was higher than in the non-periodontitis group (2.80; p = .004). CONCLUSIONS: The risk of SFBs and IFS increased after diagnosis of periodontitis. This trend is often more severe in patients with DM, COPD, or CKD, but this association with underlying diseases is applicable only when considering the association between periodontitis and fungal sinusitis.

Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes.

We searched a database of single-gene knockout (KO) mice produced by the International Mouse Phenotyping Consortium (IMPC) to identify candidate ciliopathy genes. We first screened for phenotypes in mouse lines with both ocular and renal or reproductive trait abnormalities. The STRING protein interaction tool was used to identify interactions between known cilia gene products and those encoded by the genes in individual knockout mouse strains in order to generate a list of "candidate ciliopathy genes." From this list, 32 genes encoded proteins predicted to interact with known ciliopathy proteins. Of these, 25 had no previously described roles in ciliary pathobiology. Histological and morphological evidence of phenotypes found in ciliopathies in knockout mouse lines are presented as examples (genes Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1). Phenotyping data and descriptions generated on IMPC mouse line are useful for mechanistic studies, target discovery, rare disease diagnosis, and preclinical therapeutic development trials. Here we demonstrate the effective use of the IMPC phenotype data to uncover genes with no previous role in ciliary biology, which may be clinically relevant for identification of novel disease genes implicated in ciliopathies.

Regulation of EGF-stimulated activation of the PI-3K/AKT pathway by exocyst-mediated exocytosis.

The phosphoinositide-3 kinase (PI-3K)/AKT cell survival pathway is an important pathway activated by EGFR signaling. Here we show, that in addition to previously described critical components of this pathway, i.e., the docking protein Gab1, the PI-3K/AKT pathway in epithelial cells is regulated by the exocyst complex, which is a vesicle tether that is essential for exocytosis. Using live-cell imaging, we demonstrate that PI(3,4,5)P3 levels fluctuate at the membrane on a minutes time scale and that these fluctuations are associated with local PI(3,4,5)P3 increases at sites where recycling vesicles undergo exocytic fusion. Supporting a role for exocytosis in PI(3,4,5)P3 generation, acute promotion of exocytosis by optogenetically driving exocyst-mediated vesicle tethering up-regulates PI(3,4,5)P3 production and AKT activation. Conversely, acute inhibition of exocytosis using Endosidin2, a small-molecule inhibitor of the exocyst subunit Exo70 (also designated EXOC7), or inhibition of exocyst function by siRNA-mediated knockdown of the exocyst subunit Sec15 (EXOC6), impairs PI(3,4,5)P3 production and AKT activation induced by EGF stimulation of epithelial cells. Moreover, prolonged inhibition of EGF signaling by EGFR tyrosine kinase inhibitors results in spontaneous reactivation of AKT without a concomitant relief of EGFR inhibition. However, this reactivation can be negated by acutely inhibiting the exocyst. These experiments demonstrate that exocyst-mediated exocytosis-by regulating PI(3,4,5)P3 levels at the plasma membrane-subserves activation of the PI-3K/AKT pathway by EGFR in epithelial cells.

A predictive model based on site-specific risk factors of recurrence regions in endometrial cancer patients.

OBJECTIVE: This study investigated site-specific differences in clinical factors for recurrence in patients who were newly diagnosed and treated for endometrial cancer. A model for predicting recurrence sites was generated. METHODS: Electronic medical records' data were retrieved from January 2006 to December 2018 for patients who were diagnosed with endometrial cancer at the National cancer center in Korea. Recurrence sites were classified as local, regional, or distant. We used multinomial logistic regression models that modeled the log-odds for the three recurrence sites relative to non-recurrence as a linear combination of possible risk factors for the recurrence of endometrial cancer. RESULTS: The data of 611 patients were selected for analysis; there were 20, 12, and 25 cases of local, regional, and distant recurrence, respectively, and 554 patients had no recurrence. High-grade disease was associated with local recurrence; non-endometrioid histology and parametrial invasion were risk factors for regional recurrence; additionally, parametrial invasion and no lymphadenectomy were associated with distant metastasis. CONCLUSION: We identified different risk factors specific for each type of recurrence site. Using these risk factors, we suggest that individually tailored adjuvant treatments be introduced for patients.

Validating the use of 3D biplanar radiography versus CT when measuring femoral anteversion after total hip arthroplasty : a comparative study.

AIMS: Although CT is considered the benchmark to measure femoral version, 3D biplanar radiography (hipEOS) has recently emerged as a possible alternative with reduced exposure to ionizing radiation and shorter examination time. The aim of our study was to evaluate femoral stem version in postoperative total hip arthroplasty (THA) patients and compare the accuracy of hipEOS to CT. We hypothesize that there will be no significant difference in calculated femoral stem version measurements between the two imaging methods. METHODS: In this study, 45 patients who underwent THA between February 2016 and February 2020 and had both a postoperative CT and EOS scan were included for evaluation. A fellowship-trained musculoskeletal radiologist and radiological technician measured femoral version for CT and 3D EOS, respectively. Comparison of values for each imaging modality were assessed for statistical significance. RESULTS: Comparison of the mean postoperative femoral stem version measurements between CT and 3D hipEOS showed no significant difference (p = 0.862). In addition, the two version measurements were strongly correlated (r = 0.95; p < 0.001), and the mean paired difference in postoperative femoral version for CT scan and 3D biplanar radiography was -0.09° (95% confidence interval -1.09 to 0.91). Only three stem measurements (6.7%) were considered outliers with a > 5° difference. CONCLUSION: Our study supports the use of low-dose biplanar radiography for the postoperative assessment of femoral stem version after THA, demonstrating high correlation with CT. We found no significant difference for postoperative femoral version when comparing CT to 3D EOS. We believe 3D EOS is a reliable option to measure postoperative femoral version given its advantages of lower radiation dosage and shorter examination time.Cite this article: Bone Joint J 2022;104-B(11):1196-1201.