Identification of KU-55933 as an anti-atherosclerosis compound by using a hemodynamic-based high-throughput drug screening platform.

Several compounds have been used for atherosclerosis treatment, including clinical trials; however, no anti-atherosclerotic drugs based on hemodynamic force-mediated atherogenesis have been discovered. Our previous studies demonstrated that "small mothers against decapentaplegic homolog 1/5" (Smad1/5) is a convergent signaling molecule for chemical [e.g., bone morphogenetic proteins (BMPs)] and mechanical (e.g., disturbed flow) stimulations and hence may serve as a promising hemodynamic-based target for anti-atherosclerosis drug development. The goal of this study was to develop a high-throughput screening (HTS) platform to identify potential compounds that can inhibit disturbed flow- and BMP-induced Smad1/5 activation and atherosclerosis. Through HTS using a Smad1/5 downstream target inhibitor of DNA binding 1 (Id-1) as a luciferase reporter, we demonstrated that KU-55933 and Apicidin suppressed Id-1 expression in AD-293 cells. KU-55933 (10 µM), Apicidin (10 µM), and the combination of half doses of each [1/2(K + A)] inhibited disturbed flow- and BMP4-induced Smad1/5 activation in human vascular endothelial cells (ECs). KU-55933, Apicidin, and 1/2(K + A) treatments caused 50.6%, 47.4%, and 73.3% inhibitions of EC proliferation induced by disturbed flow, respectively, whereas EC inflammation was only suppressed by KU-55933 and 1/2(K + A), but not Apicidin alone. Administrations of KU-55933 and 1/2(K + A) to apolipoprotein E-deficient mice inhibited Smad1/5 activation in ECs in athero-susceptible regions, thereby suppressing endothelial proliferation and inflammation, with the attenuation of atherosclerotic lesions in these mice. A unique drug screening platform has been developed to demonstrate that KU-55933 and its combination with Apicidin are promising therapeutic compounds for atherosclerosis based on hemodynamic considerations.

Development of a generalized pharmacokinetic model to characterize clinical pharmacokinetics of monomethyl auristatin E-based antibody-drug conjugates.

AIMS: This study aims to develop a generalized pharmacokinetic (PK) model for monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) that can simultaneously capture the PK of multiple ADC analytes commonly measured in the clinic. METHODS: A comprehensive literature review was conducted to collect PK data on MMAE-based ADCs from clinical trials. From each study, PK profiles of total antibody, the ADC, conjugated MMAE, and unconjugated MMAE, were extracted. These data were pooled and dose-normalized to evaluate the generalizability of PK across various ADCs and dose levels. Upon confirming PK generalizability, a generalized PK model for MMAE-based ADCs was developed using the entire dataset. Furthermore, exposure metrics ( C max and AUC) reported across the range of doses were combined to establish linear relationships between dose and exposure metrics for MMAE-based ADCs. RESULTS: A total of 109 PK profiles from 18 distinct MMAE-based ADCs were gathered. The dose-normalized PK profiles supported the generalizability of PK for MMAE-based ADCs. A generalized PK model was developed, which enabled capturing the PK data for 4 ADC analytes across all collected MMAE-based ADCs. A linear relationship between dose and PK exposure metrics was established, enabling the prediction of typical exposure values across different doses for MMAE-based ADCs. CONCLUSIONS: This study comprehensively analysed clinical PK data from different valine-citrulline (vc)-MMAE-based ADCs. The generalized PK model developed here serves as an important tool for a priori prediction of the PK for multiple ADC analytes in clinical settings and lays the foundation for establishing generalized exposure-response and exposure-toxicity correlations for MMAE-based ADCs.

Evolving from Didactic to Dialogic: How to Improve Faculty Development and Support Faculty Developers by Using Action Research.

Problem: Since competency-based medical education has gained widespread acceptance to guide curricular reforms, faculty development has been regarded as an indispensable element to make these programs successful. Faculty developers have striven to design and deliver myriad of programs or workshops to better prepare faculty members for fulfilling their teaching roles. However, how faculty developers can improve workshop delivery by researching their teaching practices remains underexplored. Intervention: Action research aims to understand real world practices and advocates for formulation of doable plans through cycles of investigations, and ultimately contributes to claims of knowledge and a progression toward the goal of practice improvement. This methodology aligns with the aim of this study to understand how I could improve a faculty development workshop by researching my teaching practices. Context: In 2016, we conducted four cycles of action research in the context of mini-Clinical Evaluation Exercise (mini-CEX) workshops within a faculty development program aiming for developing teaching and assessment competence in faculty members. We collected multiple sources of qualitative data for thematic analysis, including my reflective journal, field notes taken by a researcher-observer, and post-workshop written reflection and feedback in portfolio from fourteen workshop attendees aiming to develop faculty teaching and assessment competence. Impact: By doing action research, I scrutinized each step as an opportunity for change, enacted adaptive practice and reflection on my teaching practices, and formulated action plans to transform a workshop design through each cycle. In so doing, my workshop evolved from didactic to dialogic with continuous improvement on enhanced engagement, focused discussion and participant empowerment through a collaborative inquiry into feedback practice. Moreover, these processes of action research also supported my growth as a faculty developer. Lessons Learned: The systematic approach of action research serves as a vehicle to enable faculty developers to investigate individual teaching practices as a self-reflective inquiry, to examine, rectify, and transform processes of program delivery, and ultimately introduce themselves as agents for change and improvement.

Striving to thrive or striving to survive: Professional identity constructions of medical trainees in clinical assessment activities.

CONTEXT: Assessment plays a key role in competence development and the shaping of future professionals. Despite its presumed positive impacts on learning, unintended consequences of assessment have drawn increasing attention in the literature. Considering professional identities and how these can be dynamically constructed through social interactions, as in assessment contexts, our study sought to understand how assessment influences the construction of professional identities in medical trainees. METHODS: Within social constructionism, we adopted a discursive, narrative approach to investigate the different positions trainees narrate for themselves and their assessors in clinical assessment contexts and the impact of these positions on their constructed identities. We purposively recruited 28 medical trainees (23 students and five postgraduate trainees), who took part in entry, follow-up and exit interviews of this study and submitted longitudinal audio/written diaries across nine-months of their training programs. Thematic framework and positioning analyses (focusing on how characters are linguistically positioned in narratives) were applied using an interdisciplinary teamwork approach. RESULTS: We identified two key narrative plotlines, striving to thrive and striving to survive, across trainees' assessment narratives from 60 interviews and 133 diaries. Elements of growth, development, and improvement were identified as trainees narrated striving to thrive in assessment. Neglect, oppression and perfunctory narratives were elaborated as trainees narrated striving to survive from assessment. Nine main character tropes adopted by trainees with six key assessor character tropes were identified. Bringing these together we present our analysis of two exemplary narratives with elaboration of their wider social implications. CONCLUSION: Adopting a discursive approach enabled us to better understand not only what identities are constructed by trainees in assessment contexts but also how they are constructed in relation to broader medical education discourses. The findings are informative for educators to reflect on, rectify and reconstruct assessment practices for better facilitating trainee identity construction.

Cervical disc arthroplasty for magnetic resonance-evident cervical spondylotic myelopathy: comparison with anterior cervical discectomy and fusion.

OBJECTIVE: Anterior cervical discectomy and fusion (ACDF) is a standard surgical approach for cervical spondylotic myelopathy (CSM) caused by disc herniations. Although cervical disc arthroplasty (CDA) has become, in the past decade, a viable alternative to ACDF in selected patients, the differences among patients with CSM treated with CDA and ACDF remain elusive. The effectiveness of motion preservation devices in CSM is also unclear. METHODS: Adult patients who underwent 1- or 2-level CDA or ACDF between 2007 and 2021 were retrospectively reviewed. Patients whose preoperative T2-weighted MRI demonstrated increased intramedullary signal intensity (IISI) were included and analyzed for the following: comparison of the length of IISI on pre- and postoperative MR images as well as range of motion (ROM) at the indexed levels between the CDA and ACDF groups. Measurement for clinical outcomes included the visual analog scale (VAS) of the arm and neck, the Neck Disability Index, and modified Japanese Orthopaedic Association scores. Perioperative clinical data were also compared between the two groups. RESULTS: A total of 122 patients were allocated to the CDA group and 108 to the ACDF group, with mean follow-ups of 46.6 and 39.0 months, respectively. Patients in the CDA group were younger than those in the ACDF group (47.64 ± 12.40 vs 61.73 ± 12.25 years, p < 0.001) (mean ± SD). The ACDF group had more 2-level surgery compared to the CDA group (p = 0.002). Both groups had significant regression of IISI on postoperative MRI compared to that of preoperative imaging (CDA: 1.23 ± 0.84 to 0.28 ± 0.39 cm; ACDF: 1.07 ± 0.60 to 0.37 ± 0.42 cm; both p < 0.001). The decrease in the length of IISI was similar between the two groups (p = 0.058). The postoperative ROM was well preserved in the CDA group (superior to ACDF, which yielded minimal ROM postoperatively). Both the CDA and ACDF groups demonstrated improvement in Neck Disability Index and modified Japanese Orthopaedic Association scores at 24 months postoperatively. The CDA group had significant improvements on VAS scores, whereas the improvement did not reach significance for the ACDF group at 24 months postoperatively. CONCLUSIONS: Significant shortening of IISI on T2-weighted MRI was demonstrated after both CDA and ACDF. At 24 months postoperatively, all clinical outcomes demonstrated improvement after both strategies, except that the VAS score was not significantly improved for ACDF. Therefore, CDA is a safe and effective option for patients with MR-evident CSM.

Self-reported cognitive impairments and quality of life in patients with gastrointestinal stromal tumor: Results of a multinational survey.

BACKGROUND: Cancer-related cognitive impairment (CRCI) has long-term effects on survivor quality of life, but CRCI research on patients with gastrointestinal stromal tumor (GIST) is lacking. The aims of this study were to investigate CRCI and concomitant quality of life among patients with GIST. METHODS: An online survey was used to assess CRCI in adult patients with GIST using the validated Functional Assessment of Cancer Therapy-Cognitive-v.3. Age, education, demographically indexed IQ, general health, and quality of life factors (e.g., fatigue, emotional distress) were also assessed. The online survey was administered through five international GIST and sarcoma support organizations. RESULTS: Over the 3-month recruitment period, the survey was completed by 485 participants: mean age, 57.80 (SD, 11.51), median 5 years after diagnosis. A majority (63.91%) reported experiencing cognitive symptoms with a significant negative quality of life impact. Controlling for age, patients with GIST ≥5 years after diagnosis reported worse cognitive function than those <5 years after diagnosis (p < .05) but did not differ in educational level or IQ. Whereas longer term survivors were more likely to have been treated with tyrosine kinase inhibitor (TKI) therapies, there was no observed association of TKI therapy with self-reported cognitive impairments. CONCLUSIONS: A majority of GIST patients report cognitive symptoms that have a negative impact on quality of life, with longer term survivors (≥5 years) tending to report more cognitive impairments. Given the success of TKI therapy to substantially increase overall survival of patients with GIST, addressing CRCI in clinical practice may improve long-term GIST survivor function and quality of life.

A dated molecular phylogeny and biogeographical analysis reveals the evolutionary history of the trans-pacifically disjunct tropical tree genus Ormosia (Fabaceae).

The papilionoid legume genus Ormosia (Fabaceae) comprises about 150 species of trees and exhibits a striking disjunct geographical distribution between the New World- and Asian and Australasian wet tropics and subtropics. Modern classifications of Ormosia are not grounded on a well-substantiated phylogenetic hypothesis and have been limited to just portions of the geographical range of the genus. The lack of an evolutionarily-based foundation for systematic studies has hindered taxonomic work on the genus and prevented the testing of biogeographical hypotheses related to the origin of the Old World/New World disjunction and the individual dispersal histories within both areas. Here, we present the most comprehensively sampled molecular phylogeny of Ormosia to date, based on analysis of both nuclear (ITS) and plastid (matK and trnL-F) DNA sequences from 82 species of the genus. Phylogenetically-based divergence times and ancestral range estimations are employed to test hypotheses related to the biogeographical history of the genus. We find strong support for the monophyly of Ormosia and the grouping of all sampled Asian species of the genus into two comparably sized clades, one of which is sister to another large clade containing all sampled New World species. Within the New World clade, additional resolution supports the grouping of most species into three mutually exclusive subordinate clades. The remaining New World species form a fourth well-supported clade in the analyses of plastid sequences, but that result is contradicted by the analysis of ITS. With few exceptions the supported clades have not been previously recognized as taxonomic groups. The biogeographical analysis suggests that Ormosia originated in continental Asia and dispersed to the New World in the Oligocene or early Miocene via long-distance trans-oceanic dispersal. We reject the hypothesis that the inter-hemispheric disjunction in Ormosia resulted from fragmentation of a more continuous "Boreotropical" distribution since the dispersal post-dates Eocene climatic maxima. Both of the Old World clades appear to have originated in mainland Asia and subsequently dispersed into the Malay Archipelago and beyond, at least two lineages dispersing across Wallace's Line as far as the Solomon Islands and northeastern Australia. In the New World, the major clades all originated in Amazonia. Dispersal from Amazonia into peripheral areas in Central America, the Caribbean, and Extra-Amazonian Brazil occurred multiple times over varying time scales, the earliest beginning in the late Miocene. In a few cases, these dispersals were followed by local diversification, but not by reverse migration back to Amazonia. Within each of the two main areas of distribution, multiple modest bouts of oceanic dispersal were required to achieve the modern distributions.

Miniaturization and image optimization of a full-color holographic display system using a vibrating light guide.

In this study, a miniaturized full-color holographic reconstruction system that uses a single spatial light modulator to achieve full-color image reconstruction was developed. The reconstruction system uses a single light guide for light combination and is therefore less voluminous than conventional reconstruction systems. The experimental results demonstrated that the system had a full-color display, corrected light combination, and eliminated zero-order light. The vibrations of the light guide disrupted the temporal coherence of the laser beam, thus ensuring that the speckle in the reconstructed image was almost imperceptible to the human eye.

A population physiologically-based pharmacokinetic model to characterize antibody disposition in pediatrics and evaluation of the model using infliximab.

AIMS: In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in paediatric patients, there is a need to develop systems PK models that integrate ontogeny-related changes in human physiological parameters. METHODS: A population-based physiological-based PK (PBPK) model to characterize antibody PK in paediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs. age and dose-exposure relationships for infliximab. RESULTS: By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two paediatric cohorts (n = 141, 4-19 years) reasonably well. Model simulations demonstrated that only 50% of children reached desired trough concentrations when receiving FDA-labelled dosing regimen for infliximab, suggesting that higher doses and/or more frequent dosing are needed to achieve target trough concentrations of this antibody. CONCLUSION: The paediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in paediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.

Development of a Physiologically-Based Pharmacokinetic Model for Whole-Body Disposition of MMAE Containing Antibody-Drug Conjugate in Mice.

PURPOSE: To quantitate and mathematically characterize the whole-body pharmacokinetics (PK) of different ADC analytes following administration of an MMAE-conjugated ADC in tumor-bearing mice. METHODS: The PK of different ADC analytes (total antibody, total drug, unconjugated drug) was measured following administration of an MMAE-conjugated ADC in tumor-bearing mice. The PK of ADC analytes was compared with the whole-body PK of the antibody and drug obtained following administration of these molecules alone. An ADC PBPK model was developed by linking antibody PBPK model with small-molecule PBPK model, where the drug was assumed to deconjugate in DAR-dependent manner. RESULTS: Comparison of antibody biodistribution coefficient (ABC) values for total antibody suggests that conjugation of drug did not significantly affect the PK of antibody. Comparison of tissue:plasma AUC ratio (T/P) for the conjugated drug and total antibody suggests that in certain tissues (e.g., spleen) ADC may demonstrate higher deconjugation. It was observed that the tissue distribution profile of the drug can be altered following its conjugation to antibody. For example, MMAE distribution to the liver was found to increase while its distribution to the heart was found to decrease upon conjugation to antibody. MMAE exposure in the tumor was found to increase by ~20-fold following administration as conjugate (i.e., ADC). The PBPK model was able to a priori predict the PK of all three ADC analytes in plasma, tissues, and tumor reasonably well. CONCLUSIONS: The ADC PBPK model developed here serves as a platform for translational and clinical investigations of MMAE containing ADCs.

Hyperspectral sensing of heavy metals in soil by integrating AI and UAV technology.

Given the limitation of conventional soil pollution monitoring through mapping which is a costly, time-consuming work, the study aims to establish an image recognition model to identify the source of pollution automatically. The study choses a contaminated land and then use a non-destructive instrument that can quickly and effectively measure the content of heavy metals. A two concentration prediction models of Ni, Cu, Zn, Cr, Pb, As, Cd, and Hg using hyperspectral imaging were developed, Decision Tree and Back Propagation Neural Network, in combination of particle swarm optimization employed for optimization algorithm. As a result, random forest is more accurate than the forecast result of back propagation neural network. This study has established an excellent Cu and Cr model, which can accurately capture the pollution source. In addition, through aerial photographs, we also found that there were also high pollution reactions on the banks of the river. The developed model is beneficial for high pollution areas which can be quickly found, thereby following investigation and remediation work can be carried out with less time and cost consuming comparing with the conventional soil monitoring.

Two-pore physiologically based pharmacokinetic model validation using whole-body biodistribution of trastuzumab and different-size fragments in mice.

In the past, our lab proposed a two-pore PBPK model for different-size protein therapeutics using de novo derived parameters and the model was validated using plasma PK data of different-size antibody fragments digitized from the literature (Li Z, Shah DK, J Pharmacokinet Pharmacodynam 46(3):305-318, 2009). To further validate the model using tissue distribution data, whole-body biodistribution study of 6 different-size proteins in mice were conducted. Studied molecules covered a wide MW range (13-150 kDa). Plasma PK and tissue distribution profiles is 9 tissues were measured, including heart, lung, liver, spleen, kidney, skin, muscle, small intestine, large intestine. Tumor exposure of different-size proteins were also evaluated. The PBPK model was validated by comparing percentage predictive errors (%PE) between observed and model predicted results for each type of molecule in each tissue. Model validation showed that the two-pore PBPK model was able to predict plasma, tissues and tumor PK of all studied molecules relatively well. This model could serve as a platform for developing a generic PBPK model for protein therapeutics in the future.

Understanding the lived experiences of medical learners in a narrative medicine course: a phenomenological study.

BACKGROUND: Reflection and various approaches to foster reflection have been regarded as an indispensable element in enhancing professional practice across different disciplines. With its inherent potential to engage learners in reflection and improvement, narrative medicine has been adopted in various settings. However, the relevance and effectiveness of reflection remains underexplored in the context of narrative medicine, specifically in regard to the concern about variability of learner acceptance and the way learners really make sense of these reflective activities. This study aimed to explore what medical learners experience through narrative medicine and the meanings they ascribe to the phenomenon of this narrative-based learning. METHODS: Using a transcendental phenomenology approach, twenty medical learners were interviewed about their lived experiences of taking a narrative medicine course during their internal medicine clerkship rotation. Moustakas' phenomenological analysis procedures were applied to review the interview data. RESULTS: Six themes were identified: feeling hesitation, seeking guidance, shifting roles in narratives, questioning relationships, experiencing transformation, and requesting a safe learning environment. These themes shaped the essence of the phenomenon and illustrated what and how medical learners set out on a reflective journey in narrative medicine. These findings elucidate fundamental elements for educators to consider how narrative approaches can be effectively used to engage learners in reflective learning and practice. CONCLUSION: Adopting Moustakas' transcendental phenomenology approach, a better understanding about the lived experiences of medical learners regarding learning in narrative medicine was identified. Learner hesitancy should be tackled with care by educators so as to support learners with strategies that address guidance, relationship, and learning environment. In so doing, medical learners can be facilitated to develop reflective capabilities for professional and personal growth.

Natural History of Acromegaly: Incidences, Re-operations, Cancers, and Mortality Rates in a National Cohort.

BACKGROUND: Acromegaly is so rare that its natural history, including incidence, risk of cancers, and mortality rates, remains elusive. This natural study utilized a nationwide database to provide a better understanding of acromegaly's disease course. METHODS: A cohort of 1,195 acromegaly patients were identified and followed-up from 1997 to 2013. Incidence, operation, and re-operation rates were calculated. Excessive mortality and cancer risk related to acromegaly were estimated by standardized mortality ratio (SMR) and standardized incidence ratio (SIR). RESULTS: The incidence was 2.78 per million-person-years, with little gender predominance (female vs. male, 49.5 vs. 50.5%, respectively). There was female predominance only among 50 and 60 year-olds (incidence rate ratio: 1.37 and 1.43, p < 0.001 and p = 0.002). Among them, 673 (56.3%) had hypophysectomy surgery, and the young-onset (<40 years) patients had more re-operations (15.5%, p = 0.01). The overall mortality rate was 22.3 per 1,000 person-years, with a median survival of 4.67 years (with no gender differences, p = 0.38). The overall SMR of acromegaly patients was 1.41, and the onset-age-specific SMRs of the early- and middle-onset patients were higher than for those with late-onset. There were 87 newly diagnosed cancers in the cohort, with an incidence rate of 10.6 per 1,000 person-years (median 5.4 years). The overall SIR of cancers was 1.91, and there were no differences among gender, onset-age, and disease duration (all SIR >1, approximately 2). CONCLUSION: Acromegaly is associated with an excessive risk of mortality and two-fold higher risk of cancers. Patients with acromegaly should be managed appropriately after the diagnosis.

Minimally invasive dynamic screw stabilization using cortical bone trajectory.

BACKGROUND: The conventional pedicle-screw-based dynamic stabilization process involves dissection of the Wiltse plane to cannulate the pedicles, which cannot be undertaken with minimal surgical invasion. Despite some reports having demonstrated satisfactory outcomes of dynamic stabilization in the management of low-grade spondylolisthesis, the extensive soft tissue dissection involved during pedicle screw insertion substantially compromises the designed rationale of motion (muscular) preservation. The authors report on a novel method for minimally invasive insertion of dynamic screws and a mini case series. METHODS: The authors describe innovations for inserting dynamic screws via the cortical bone trajectory (CBT) under spinal navigation. All the detailed surgical procedures and clinical data are demonstrated. RESULTS: A total of four (2 females) patients (mean age 64.75 years) with spinal stenosis at L4-5 were included. By a combination of microscopic decompression and image-guided CBT screw insertion, laminectomy and dynamic screw stabilization were achieved via one small skin incision (less than 3 cm). These patients' back and leg pain improved significantly after the surgery. CONCLUSION: This innovative dynamic screw stabilization via the CBT involved no discectomy (or removal of sequestrated fragment only), no interbody fusion, and little muscle dissection (not even of the Wiltse plane). As a minimally invasive surgery, CBT appeared to be a viable alternative to the conventional pedicle-screw-based dynamic stabilization approach.

Effect of Size on Solid Tumor Disposition of Protein Therapeutics.

In this study, we evaluated the effect of size on tumor disposition of protein therapeutics, including the plasma and tumor pharmacokinetics (PK) of trastuzumab (∼150 kDa), FcRn-nonbinding trastuzumab (∼150 kDa), F(ab)2 fragment of trastuzumab (∼100 kDa), Fab fragment of trastuzumab (∼50 kDa), and trastuzumab scFv (∼27 kDa) in both antigen (i.e., HER2)-overexpressing (N87) and antigen-nonexpressing (MDA-MB-468) tumor-bearing mice. The observed data were used to develop the maximum tumor uptake versus molecular weight and tumor-to-plasma area under the curve (AUC) ratio versus molecular weight relationships. Comparison of the PK of different sizes of FcRn nonbinding molecules in target-expressing tumor showed that ∼100 kDa is an optimal size to achieve maximum tumor uptake and ∼50 kDa is an optimal size to achieve maximum tumor-to-plasma exposure ratio of protein therapeutics. The PK data were also used to validate a systems PK model for tumor disposition of different-sized protein therapeutics. The PK model was able to predict a priori the PK of all five molecules in both tumor types reasonably well (within 2- to 3-fold). In addition, the model captured the bell-shaped relationships observed between maximum tumor uptake and molecular weight and between tumor-to-plasma AUC ratio and molecular weight. Our results provide an unprecedented insight into the effect of size and target engagement on the tumor PK of protein therapeutics. Our results also provide further validation of the tumor disposition model, which can be used to support discovery, development, and preclinical-to-clinical translation of different sizes of protein therapeutics. SIGNIFICANCE STATEMENT: This article highlights the importance of molecular size and target engagement on the tumor disposition of protein therapeutics. Our results suggest that ∼100 kDa is an optimal size to achieve maximum tumor uptake and ∼50 kDa is an optimal size to achieve maximum tumor-to-plasma exposure ratio for non-FcRn-binding targeted protein therapeutics. We also demonstrate that a systems pharmacokinetics model developed to characterize tumor disposition of protein therapeutics can predict a priori the disposition of different-sized protein therapeutics in target-expressing and target-nonexpressing solid tumors.

Radiological and clinical outcomes of cervical disc arthroplasty for the elderly: a comparison with young patients.

BACKGROUND: This study aimed to investigate whether cervical disc arthroplasty (CDA) would be equally effective in elderly patients as in the young. The inclusion criteria of published clinical trials for CDA-enrolled patients covered the ages from 18 to 78 years. However, there was a paucity of data addressing the differences of outcomes between older and the younger patients. METHODS: A series of consecutive patients who underwent one- or two-level CDA were retrospectively reviewed. Patients at the two extreme ends of the age distribution (≥65 and ≤ 40 years) were selected for comparison. Clinical outcome parameters included visual analog scale (VAS) of neck and arm pain, neck disability index (NDI), and Japanese Orthopaedic Association (JOA) scores. Radiographic outcomes included range of motion (ROM) at the indexed level and evaluation of heterotopic ossification (HO) by computed tomography (CT). Complication profiles were also investigated. RESULTS: There were 24 patients in the elderly group (≥65 years old) and 47 patients in the young group (≤40 years old) with an overall mean follow-up of 28.0 ± 21.97 months. The elderly group had more two-level CDA, and thus the mean operative time was longer (239 vs. 179 min, p < 0.05) than the young group. Both groups had similarly significant improvement in clinical outcomes at the final follow-up. All the replaced disc segments remained mobile on post-operative lateral flexion and extension radiographs. However, the elderly group had a slight decrease in mean ROM (- 0.32° ± 3.93°) at the index level after CDA when compared to that of pre-operation. In contrast, the young group had an increase in mean ROM (+ 0.68° ± 3.60°). The complication profiles were not different, though a trend toward dysphagia was noted in the elderly group (p = 0.073). The incidence or severity (grading) of HO was similar between the two groups. CONCLUSIONS: During the follow-up of two years, CDA was equally effective for patients over 65 years old and those under 40 years in clinical improvement. Although the elderly group demonstrated a small reduction of mean ROM after CDA, in contrast to the young group which had a small increase, the segmental mobility was well preserved at every indexed level for each group.

Computer-aided diagnosis for identifying and delineating early gastric cancers in magnifying narrow-band imaging.

BACKGROUND AND AIMS: Magnifying narrow-band imaging (M-NBI) is important in the diagnosis of early gastric cancers (EGCs) but requires expertise to master. We developed a computer-aided diagnosis (CADx) system to assist endoscopists in identifying and delineating EGCs. METHODS: We retrospectively collected and randomly selected 66 EGC M-NBI images and 60 non-cancer M-NBI images into a training set and 61 EGC M-NBI images and 20 non-cancer M-NBI images into a test set. After preprocessing and partition, we determined 8 gray-level co-occurrence matrix (GLCM) features for each partitioned 40 × 40 pixel block and calculated a coefficient of variation of 8 GLCM feature vectors. We then trained a support vector machine (SVMLv1) based on variation vectors from the training set and examined in the test set. Furthermore, we collected 2 determined P and Q GLCM feature vectors from cancerous image blocks containing irregular microvessels from the training set, and we trained another SVM (SVMLv2) to delineate cancerous blocks, which were compared with expert-delineated areas for area concordance. RESULTS: The diagnostic performance revealed accuracy of 96.3%, precision (positive predictive value [PPV]) of 98.3%, recall (sensitivity) of 96.7%, and specificity of 95%, at a rate of 0.41 ± 0.01 seconds per image. The performance of area concordance, on a block basis, demonstrated accuracy of 73.8% ± 10.9%, precision (PPV) of 75.3% ± 20.9%, recall (sensitivity) of 65.5% ± 19.9%, and specificity of 80.8% ± 17.1%, at a rate of 0.49 ± 0.04 seconds per image. CONCLUSIONS: This pilot study demonstrates that our CADx system has great potential in real-time diagnosis and delineation of EGCs in M-NBI images.

Astrocytic GAP43 Induced by the TLR4/NF-κB/STAT3 Axis Attenuates Astrogliosis-Mediated Microglial Activation and Neurotoxicity.

Growth-associated protein 43 (GAP43), a protein kinase C (PKC)-activated phosphoprotein, is often implicated in axonal plasticity and regeneration. In this study, we found that GAP43 can be induced by the endotoxin lipopolysaccharide (LPS) in rat brain astrocytes both in vivo and in vitro. The LPS-induced astrocytic GAP43 expression was mediated by Toll-like receptor 4 and nuclear factor-κB (NF-κB)- and interleukin-6/signal transducer and activator of transcription 3 (STAT3)-dependent transcriptional activation. The overexpression of the PKC phosphorylation-mimicking GAP43(S41D) (constitutive active GAP43) in astrocytes mimicked LPS-induced process arborization and elongation, while application of a NF-κB inhibitory peptide TAT-NBD or GAP43(S41A) (dominant-negative GAP43) or knockdown of GAP43 all inhibited astrogliosis responses. Moreover, GAP43 knockdown aggravated astrogliosis-induced microglial activation and expression of proinflammatory cytokines. We also show that astrogliosis-conditioned medium from GAP43 knock-down astrocytes inhibited GAP43 phosphorylation and axonal growth, and increased neuronal damage in cultured rat cortical neurons. These proneurotoxic effects of astrocytic GAP43 knockdown were accompanied by attenuated glutamate uptake and expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in LPS-treated astrocytes. The regulation of EAAT2 expression involves actin polymerization-dependent activation of the transcriptional coactivator megakaryoblastic leukemia 1 (MKL1), which targets the serum response elements in the promoter of rat Slc1a2 gene encoding EAAT2. In sum, the present study suggests that astrocytic GAP43 mediates glial plasticity during astrogliosis, and provides beneficial effects for neuronal plasticity and survival and attenuation of microglial activation. SIGNIFICANCE STATEMENT: Astrogliosis is a complex state in which injury-stimulated astrocytes exert both protective and harmful effects on neuronal survival and plasticity. In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation. Importantly, LPS-induced GAP43 mediates plastic changes of astrocytes while attenuating astrogliosis-induced microglial activation and neurotoxicity. Hence, astrocytic GAP43 upregulation may serve to indicate beneficial astrogliosis after CNS injury.

Image multiplexing and encryption using the nonnegative matrix factorization method adopting digital holography.

In this paper, a joint multiple-image encryption and multiplexing system, which utilizes both the nonnegative matrix factorization (NMF) scheme and digital holography, is proposed. A number of images are transformed into noise-like digital holograms, which are then decomposed into a defined number of basis images and a corresponding weighting matrix using the NMF scheme. The determined basis images are similar to the digital holograms and appear as noise-like patterns, which are then stored as encrypted data and serve as the lock in an encryption system. On the other hand, the column vectors in the weighting matrix serve as the keys for the corresponding plain images or the addresses of the multiplexed images. Both the increased uniformity of the column weighting factors and the parameters used in the digital holography enhance the security of the distributed keys. The experimental results show that the proposed method can successfully perform multiple-image encryption with high-level security.