Selenium-alloyed tellurium oxide for amorphous p-channel transistors.

Compared to polycrystalline semiconductors, amorphous semiconductors offer inherent cost-effective, simple and uniform manufacturing. Traditional amorphous hydrogenated Si falls short in electrical properties, necessitating the exploration of new materials. The creation of high-mobility amorphous n-type metal oxides, such as a-InGaZnO (ref. 1), and their integration into thin-film transistors (TFTs) have propelled advancements in modern large-area electronics and new-generation displays2-8. However, finding comparable p-type counterparts poses notable challenges, impeding the progress of complementary metal-oxide-semiconductor technology and integrated circuits9-11. Here we introduce a pioneering design strategy for amorphous p-type semiconductors, incorporating high-mobility tellurium within an amorphous tellurium suboxide matrix, and demonstrate its use in high-performance, stable p-channel TFTs and complementary circuits. Theoretical analysis unveils a delocalized valence band from tellurium 5p bands with shallow acceptor states, enabling excess hole doping and transport. Selenium alloying suppresses hole concentrations and facilitates the p-orbital connectivity, realizing high-performance p-channel TFTs with an average field-effect hole mobility of around 15 cm2 V-1 s-1 and on/off current ratios of 106-107, along with wafer-scale uniformity and long-term stabilities under bias stress and ambient ageing. This study represents a crucial stride towards establishing commercially viable amorphous p-channel TFT technology and complementary electronics in a low-cost and industry-compatible manner.

Aging in a Dish: iPSC-Derived and Directly Induced Neurons for Studying Brain Aging and Age-Related Neurodegenerative Diseases.

Age-associated neurological diseases represent a profound challenge in biomedical research as we are still struggling to understand the interface between the aging process and the manifestation of disease. Various pathologies in the elderly do not directly result from genetic mutations, toxins, or infectious agents but are primarily driven by the many manifestations of biological aging. Therefore, the generation of appropriate model systems to study human aging in the nervous system demands new concepts that lie beyond transgenic and drug-induced models. Although access to viable human brain specimens is limited and induced pluripotent stem cell models face limitations due to reprogramming-associated cellular rejuvenation, the direct conversion of somatic cells into induced neurons allows for the generation of human neurons that capture many aspects of aging. Here, we review advances in exploring age-associated neurodegenerative diseases using human cell reprogramming models, and we discuss general concepts, promises, and limitations of the field.

Amputation in patients with extremity soft tissue sarcoma: the experience of an East Asian referral center.

BACKGROUND: This study aimed to investigate the characteristics and clinical outcomes in a series of patients with extremity soft tissue sarcoma (STS) who underwent amputation at a large East Asian referral center. PATIENTS AND METHODS: Of the 652 patients who underwent surgery for extremity STS, data of 37 consecutive patients who underwent amputation were reviewed retrospectively. The median follow-up period was 96.0 months (range, 15-216). The patients were classified in to three cohorts. The primary localized (PL) group included patients who underwent amputation as a primary surgical procedure with curative intent. The recurrent localized (RL) group included patients who underwent amputation as a revision procedure after failure of previous limb sparing surgeries. The metastatic group included patients who underwent amputation as a palliative procedure. RESULTS: There were 22 cases of amputation in 596 STS patients and the amputation rate was 3.6% (22/596). Further, 1.8% (9/490) of patients with primary localized STS underwent amputation. Patients with localized STS who underwent amputation had a 5-year disease-specific survival (DSS) rate of 89.9% (95% Confidence Interval (CI), 87.1-92.7%), a local-recurrence-free survival (LRFS) of 84.1% (95% CI, 80.5-87.6%), and a metastasis-free survival (MFS) of 84.6%. (95% CI, 81.1-88.0%) Compared with previous studies, our results showed higher DSS and MFS rates with similar LRFS. CONCLUSIONS: The amputation rate of extremity STS in our institute in East Asia was similar but slightly lower than that reported in Western studies. The oncologic outcome of amputation reported in this study was higher than that indicated in Western studies and oncologic outcome of amputation was not statistically different from those of limb salvage surgery. However, considering the small cohort in single institute study, there is a possibility of selection bias and future multi-center study is necessary. From our results, amputation is still a feasible option for appropriately selected patients unsuitable for limb-conserving surgery.

Enhanced Omicron Variant Neutralization by a Human Antibody Tailored to Wild-Type and Delta-Variant SARS-CoV-2 RBDs.

Given the previous SARS-CoV-2 pandemic and the inherent unpredictability of viral antigenic drift and shift, preemptive development of diverse neutralizing antibodies targeting a broad spectrum of epitopes is essential to ensure immediate therapeutic and prophylactic interventions during emerging outbreaks. In this study, we present a monoclonal antibody engineered for cross-reactivity to both wild-type and Delta RBDs, which, surprisingly, demonstrates enhanced neutralizing activity against the Omicron variant despite a significant number of mutations. Using an Escherichia coli inner membrane display of a human naïve antibody library, we identified antibodies specific to the wild-type SARS-CoV-2 receptor binding domain (RBD). Subsequent directed evolution via yeast surface display yielded JS18.1, an antibody with high binding affinity for both the Delta and Kappa RBDs, as well as enhanced binding to other RBDs (wild-type, Alpha, Beta, Gamma, Kappa, and Mu). Notably, JS18.1 (engineered for wild-type and Delta RBDs) exhibits enhanced neutralizing capability against the Omicron variant and binds to RBDs noncompetitively with ACE2, distinguishing it from other previously reported antibodies. This underscores the potential of pre-existing antibodies to neutralize emerging SARS-CoV-2 strains and offers insights into strategies to combat emerging viruses.

Time-asymmetric loop around an exceptional point over the full optical communications band.

Topological operations around exceptional points1-8-time-varying system configurations associated with non-Hermitian singularities-have been proposed as a robust approach to achieving far-reaching open-system dynamics, as demonstrated in highly dissipative microwave transmission3 and cryogenic optomechanical oscillator4 experiments. In stark contrast to conventional systems based on closed-system Hermitian dynamics, environmental interferences at exceptional points are dynamically engaged with their internal coupling properties to create rotational stimuli in fictitious-parameter domains, resulting in chiral systems that exhibit various anomalous physical phenomena9-16. To achieve new wave properties and concomitant device architectures to control them, realizations of such systems in application-abundant technological areas, including communications and signal processing systems, are the next step. However, it is currently unclear whether non-Hermitian interaction schemes can be configured in robust technological platforms for further device engineering. Here we experimentally demonstrate a robust silicon photonic structure with photonic modes that transmit through time-asymmetric loops around an exceptional point in the optical domain. The proposed structure consists of two coupled silicon-channel waveguides and a slab-waveguide leakage-radiation sink that precisely control the required non-Hermitian Hamiltonian experienced by the photonic modes. The fabricated devices generate time-asymmetric light transmission over an extremely broad spectral band covering the entire optical telecommunications window (wavelengths between 1.26 and 1.675 micrometres). Thus, we take a step towards broadband on-chip optical devices based on non-Hermitian topological dynamics by using a semiconductor platform with controllable optoelectronic properties, and towards several potential practical applications, such as on-chip optical isolators and non-reciprocal mode converters. Our results further suggest the technological relevance of non-Hermitian wave dynamics in various other branches of physics, such as acoustics, condensed-matter physics and quantum mechanics.

Thermodynamically Driven Tilt Grain Boundaries of Monolayer Crystals Using Catalytic Liquid Alloys.

We report a method to precisely control the atomic defects at grain boundaries (GBs) of monolayer MoS2 by vapor-liquid-solid (VLS) growth using sodium molybdate liquid alloys, which serve as growth catalysts to guide the formations of the thermodynamically most stable GB structure. The Mo-rich chemical environment of the alloys results in Mo-polar 5|7 defects with a yield exceeding 95%. The photoluminescence (PL) intensity of VLS-grown polycrystalline MoS2 films markedly exceeds that of the films, exhibiting abundant S 5|7 defects, which are kinetically driven by vapor-solid-solid growths. Density functional theory calculations indicate that the enhanced PL intensity is due to the suppression of nonradiative recombination of charged excitons with donor-type defects of adsorbed Na elements on S 5|7 defects. Catalytic liquid alloys can aid in determining a type of atomic defect even in various polycrystalline 2D films, which accordingly provides a technical clue to engineer their properties.

Engineering bispecific T-cell engagers to deplete eosinophils for the treatment of severe eosinophilic asthma.

Severe eosinophilic asthma (SEA) is characterized by elevated eosinophil counts in the blood and airway mucosa. While monoclonal antibody therapies targeting interleukin-5 (IL-5) and its receptor (IL-5Rα) have improved treatment, some patients remain unresponsive. We propose an alternative approach to eliminate eosinophils using T cells by engineering IL-5Rα × CD3 bispecific T-cell engagers (bsTCEs) that target both IL-5Rα on eosinophils and CD3 on T cells. We designed different formats of IL-5Rα × CD3 bsTCEs, incorporating variations in valency, geometry, and affinity for the target antigen binding. We identified the single-chain variable fragment (scFv)-Fc format with the highest affinity toward the membrane-proximal domain of IL-5Rα in the IL-5Rα-binding arm showed the most potent cytotoxicity against IL-5Rα-expressing peripheral eosinophils by activating autologous primary T cells from healthy donors. This study proposes IL-5Rα × CD3 bsTCEs as potential alternatives for SEA treatment. Importantly, it demonstrates the first application of bsTCEs in eliminating disease-associated cells, including eosinophils, beyond cancer cells.

Does the Clinical Presentation of Secondary Osteosarcoma in Patients Who Survive Retinoblastoma Differ From That of Conventional Osteosarcoma and How Do We Detect Them?

BACKGROUND: Osteosarcoma is the most common secondary malignancy among survivors of retinoblastoma. Most previous reports on secondary malignancy of retinoblastoma included all types of secondary malignancies without a focus on osteosarcoma, owing to its rarity. In addition, there are few studies suggesting tools for regular surveillance for early detection. QUESTIONS/PURPOSES: (1) What are the radiologic and clinical characteristics of secondary osteosarcoma after retinoblastoma? (2) What is the clinical survivorship? (3) Is a radionuclide bone scan a reasonable imaging modality for early detection in patients with retinoblastoma? METHODS: Between February 2000 and December 2019, we treated 540 patients for retinoblastoma. Twelve patients (six male, six female) subsequently developed an osteosarcoma in the extremities; two of these patients had two sites of osteosarcoma (10 femurs, four tibiae) . A Technetium-99m bone scan image was examined annually in all patients for regular surveillance after the treatment of retinoblastoma as per our hospital's policy. All patients were treated with the same strategy as that used for primary conventional osteosarcoma, namely neoadjuvant chemotherapy, wide excision, and adjuvant chemotherapy. The median follow-up period was 12 years (range 8 to 21 years). The median age at the time of diagnosis of osteosarcoma was 9 years (range 5 to 15 years), and the median interval from retinoblastoma diagnosis to osteosarcoma diagnosis was 8 years (range 5 to 15 years). Radiologic characteristics were assessed with plain radiographs and MRI, while clinical characteristics were assessed through a retrospective review of medical records. For clinical survivorship, we evaluated overall survival, local recurrence-free survival, and metastasis-free survival. We reviewed the results of bone scans and clinical symptoms at the time of diagnosis for osteosarcoma after retinoblastoma. RESULTS: In nine of 14 patients, the tumor had a diaphyseal center, and five of the tumors were located at the metaphysis. The femur was the most common site (n = 10), followed by the tibia (n = 4). The median tumor size was 9 cm (range 5 to 13 cm). There was no local recurrence after surgical resection of the osteosarcoma, and the 5-year overall survival rate after the diagnosis of osteosarcoma was 86% (95% CI 68% to 100%). In all 14 tumors, the Technetium bone scan showed increased uptake in the lesions. Ten of 14 tumors were examined in clinic because of patient complaints of pain in the affected limb. Four patients showed no clinical symptoms detected by abnormal uptake on bone scan. CONCLUSION: For unclear reasons, secondary osteosarcomas in patients who were alive after the treatment of retinoblastoma had a slight predilection for the diaphysis of the long bone compared with patients with spontaneous osteosarcoma in other reports. The clinical survivorship of osteosarcoma as a secondary malignancy after retinoblastoma may not be inferior to that of conventional osteosarcoma. Close follow-up with at least yearly clinical assessment and bone scans or other imaging modalities appears to be helpful in detecting secondary osteosarcoma after the treatment of patients with retinoblastoma. Larger multi-institutional studies will be needed to substantiate these observations.Level of Evidenc e Level IV, therapeutic study.

An IoMT-Based Melanoma Lesion Segmentation Using Conditional Generative Adversarial Networks.

Currently, Internet of medical things-based technologies provide a foundation for remote data collection and medical assistance for various diseases. Along with developments in computer vision, the application of Artificial Intelligence and Deep Learning in IOMT devices aids in the design of effective CAD systems for various diseases such as melanoma cancer even in the absence of experts. However, accurate segmentation of melanoma skin lesions from images by CAD systems is necessary to carry out an effective diagnosis. Nevertheless, the visual similarity between normal and melanoma lesions is very high, which leads to less accuracy of various traditional, parametric, and deep learning-based methods. Hence, as a solution to the challenge of accurate segmentation, we propose an advanced generative deep learning model called the Conditional Generative Adversarial Network (cGAN) for lesion segmentation. In the suggested technique, the generation of segmented images is conditional on dermoscopic images of skin lesions to generate accurate segmentation. We assessed the proposed model using three distinct datasets including DermQuest, DermIS, and ISCI2016, and attained optimal segmentation results of 99%, 97%, and 95% performance accuracy, respectively.

Antibody-mediated delivery of a viral MHC-I epitope into the cytosol of target tumor cells repurposes virus-specific CD8+ T cells for cancer immunotherapy.

BACKGROUND: Redirecting pre-existing virus-specific cytotoxic CD8+ T lymphocytes (CTLs) to tumors by simulating a viral infection of the tumor cells has great potential for cancer immunotherapy. However, this strategy is limited by lack of amenable method for viral antigen delivery into the cytosol of target tumors. Here, we addressed the limit by developing a CD8+ T cell epitope-delivering antibody, termed a TEDbody, which was engineered to deliver a viral MHC-I epitope peptide into the cytosol of target tumor cells by fusion with a tumor-specific cytosol-penetrating antibody. METHODS: To direct human cytomegalovirus (CMV)-specific CTLs against tumors, we designed a series of TEDbodies carrying various CMV pp65 antigen-derived peptides. CMV-specific CTLs from blood of CMV-seropositive healthy donors were expanded for use in in vitro and in vivo experiments. Comprehensive cellular assays were performed to determine the presentation mechanism of TEDbody-mediated CMV peptide-MHC-I complex (CMV-pMHCI) on the surface of target tumor cells and the recognition and lysis by CMV-specific CTLs. In vivo CMV-pMHCI presentation and antitumor efficacy of TEDbody were evaluated in immunodeficient mice bearing human tumors. RESULTS: TEDbody delivered the fused epitope peptides into target tumor cells to be intracellularly processed and surface displayed in the form of CMV-pMHCI, leading to disguise target tumor cells as virally infected cells for recognition and lysis by CMV-specific CTLs. When systemically injected into tumor-bearing immunodeficient mice, TEDbody efficiently marked tumor cells with CMV-pMHCI to augment the proliferation and cytotoxic property of tumor-infiltrated CMV-specific CTLs, resulting in significant inhibition of the in vivo tumor growth by redirecting adoptively transferred CMV-specific CTLs. Further, combination of TEDbody with anti-OX40 agonistic antibody substantially enhanced the in vivo antitumor activity. CONCLUSION: Our study offers an effective technology for MHC-I antigen cytosolic delivery. TEDbody may thus have utility as a therapeutic cancer vaccine to redirect pre-existing anti-viral CTLs arising from previously exposed viral infections to attack tumors.

Engineering a U-box of E3 ligase E4B through yeast surface display-based functional screening generates a variant with enhanced ubiquitin ligase activity.

Ubiquitination is the covalent attachment of ubiquitin (Ub) to substrate proteins and regulates several cellular processes, including protein degradation. Ub ligases (E3s) bring a Ub-conjugated enzyme E2 (E2-Ub) and the target protein closer to enable ubiquitination. In this study, we engineered a U-box domain of human U-box-type E3 E4B (E4BU) to enhance its function as a Ub ligase by accelerating the rate of Ub transfer directly from Ub-loaded human E2 UbcH5b (E2(UbcH5b)-Ub) to the proximal substrate. We developed a functional screening system for the E4BU library using a yeast surface display system combined with fluorescence-activated cell sorting (FACS) to isolate functionally improved variants. This phenotypic screening system yielded an E4BU variant, E4BU(#8), which exhibited an approximately 4-fold greater Ub ligase activity rate in the yeast displayed form than that of the E4BU wild-type. When E4BU(#8) was fused to a green fluorescent protein (GFP)-specific nanobody, the fusion protein polyubiquitinated GFP in proportion to the concentration and incubation time, with an approximately 3-fold faster Ub ligase activity rate than the previously isolated E4BU(NT) variant. Importantly, the engineered E4BU(#8) retained endogenous Lys48-linked polyubiquitination activity, which is essential for substrate degradation by the 26S proteasome. Our results indicated that E4BU(#8), which binds to and allosterically stimulates E2(UbcH5b)-Ub to enhance Ub transferase activity to a substrate, may be valuable in designing biological molecules for targeted protein degradation.

The clinical outcome of hemicortical resection in extremity malignant bone tumors.

INTRODUCTION: Hemicortical resection is challenging when a huge fungating tumor is covering the osteotomy site. We report the clinical outcome of hemicortical resection and reconstruction for primary bone tumors, especially with high-grade histology and extensive circumferential involvement. MATERIALS AND METHODS: We retrospectively reviewed 44 patients (males, n = 18; females, n = 26) who underwent hemicortical resection from 2005 to 2014. RESULTS: The median follow-up period was 46.0 (23-178) months. Disease-specific, local recurrence-free, and metastasis-free survival rates of patients in the malignant group at 5 years were 96.6%, 84.5%, and 93.6%, respectively. Among 42 patients, there were local recurrences (n = 6), metastasis (n = 2), and death (n = 1). Surgical margin was an independent prognostic factor for local recurrence (hazard ratio = 5.7; p = 0.038). The recycled autograft and strut allograft groups did not show statistical difference in bone union. Failure rate was 31.8% and local recurrence was the most frequent, followed by infection. CONCLUSION: Hemicortical resection can be a feasible option for extremity malignant bone tumors. Regarding reconstruction, there were no difference between autograft and allograft in bone union rate. Surgical margin was an independent prognostic factor for local recurrence.

Does reverse total shoulder arthroplasty with allograft-prosthesis composite (APC) have surgical benefits over hemiarthroplasty with APC in patients with tumors of the proximal humerus?

BACKGROUND: The research on surgical outcomes of hemiarthroplasty and reverse total shoulder arthroplasty using allograft-prosthesis composites for the proximal humeral oncologic condition is still scarce. Therefore, this study aimed to compare surgical outcomes of shoulder joint reconstruction with hemiarthroplasty and reverse total shoulder arthroplasty using allograft-prosthesis composites for tumors of the proximal humerus. METHODS: Eleven patients underwent hemiarthroplasty or reverse total shoulder arthroplasty using allograft-prosthesis composites for tumors of the proximal humerus between July 2011 and April 2018 were reviewed. Radiographic analysis for bone union of allograft-host bone junction, implant loosening, stress shielding and shoulder dislocation or subluxation was performed. Functional outcomes were evaluated using visual analog scales for pain, range of motion, Simple Shoulder Test score and Musculoskeletal Tumor Society score. Furthermore, oncologic outcome and complications were also assessed, respectively. RESULTS: There were five patients with hemiarthroplasty (mean age, 23.2 years) and six patients with reverse total shoulder arthroplasty (mean age, 46.8 years, P = 0.05). Radiographically, there were no events associated with implant loosening, stress shielding and shoulder dislocation or subluxation in the two groups. There were no differences in functional outcomes between the two groups. There was no local recurrence in entire cohort. In the hemiarthroplasty group, one patient was required revision surgery to reverse total shoulder arthroplasty at postoperative 6 years due to rotator cuff dysfunction. In the reverse total shoulder arthroplasty group, one patient showed the fracture occurred at allograft-host bone junction at postoperative 6 months. CONCLUSIONS: Surgical outcomes of hemiarthroplasty with allograft-prosthesis composites were not inferior to reverse total shoulder arthroplasty when applied in properly selected patients. The authors recommended that hemiarthroplasty with allograft-prosthesis composites could be used for young age patients without glenoid metastasis involvement, and reverse total shoulder arthroplasty with allograft-prosthesis composites could be used for patients with old age or metastatic bone tumors.

Machine Learning-Based Boosted Regression Ensemble Combined with Hyperparameter Tuning for Optimal Adaptive Learning.

Over the past couple of decades, many telecommunication industries have passed through the different facets of the digital revolution by integrating artificial intelligence (AI) techniques into the way they run and define their processes. Relevant data acquisition, analysis, harnessing, and mining are now fully considered vital drivers for business growth in these industries. Machine learning, a subset of artificial intelligence (AI), can assist, particularly in learning patterns in big data chunks, intelligent extrapolative extraction of data and automatic decision-making in predictive learning. Firstly, in this paper, a detailed performance benchmarking of adaptive learning capacities of different key machine-learning-based regression models is provided for extrapolative analysis of throughput data acquired at the different user communication distances to the gNodeB transmitter in 5G new radio networks. Secondly, a random forest (RF)-based machine learning model combined with a least-squares boosting algorithm and Bayesian hyperparameter tuning method for further extrapolative analysis of the acquired throughput data is proposed. The proposed model is herein referred to as the RF-LS-BPT method. While the least-squares boosting algorithm is engaged to turn the possible RF weak learners to form stronger ones, resulting in a single strong prediction model, the Bayesian hyperparameter tuning automatically determines the best RF hyperparameter values, thereby enabling the proposed RF-LS-BPT model to obtain desired optimal prediction performance. The application of the proposed RF-LS-BPT method showed superior prediction accuracy over the ordinary random forest model and six other machine-learning-based regression models on the acquired throughput data. The coefficient of determination (Rsq) and mean absolute error (MAE) values obtained for the throughput prediction at different user locations using the proposed RF-LS-BPT method range from 0.9800 to 0.9999 and 0.42 to 4.24, respectively. The standard RF models attained 0.9644 to 0.9944 Rsq and 5.47 to 12.56 MAE values. The improved throughput prediction accuracy of the proposed RF-LS-BPT method demonstrates the significance of hyperparameter tuning/optimization in developing precise and reliable machine-learning-based regression models. The projected model would find valuable applications in throughput estimation and modeling in 5G and beyond 5G wireless communication systems.

Expanding the Therapeutic Window of EGFR-Targeted PE24 Immunotoxin for EGFR-Overexpressing Cancers by Tailoring the EGFR Binding Affinity.

Immunotoxins (ITs), which are toxin-fused tumor antigen-specific antibody chimeric proteins, have been developed to selectively kill targeted cancer cells. The epidermal growth factor receptor (EGFR) is an attractive target for the development of anti-EGFR ITs against solid tumors due to its overexpression on the cell surface of various solid tumors. However, the low basal level expression of EGFR in normal tissue cells can cause undesirable on-target/off-tumor toxicity and reduce the therapeutic window of anti-EGFR ITs. Here, based on an anti-EGFR monobody with cross-reactivity to both human and murine EGFR, we developed a strategy to tailor the anti-EGFR affinity of the monobody-based ITs carrying a 24-kDa fragment of Pseudomonas exotoxin A (PE24), termed ER-PE24, to distinguish tumors that overexpress EGFR from normal tissues. Five variants of ER-PE24 were generated with different EGFR affinities (KD ≈ 0.24 nM to 104 nM), showing comparable binding activity for both human and murine EGFR. ER/0.2-PE24 with the highest affinity (KD ≈ 0.24 nM) exhibited a narrow therapeutic window of 19 pM to 93 pM, whereas ER/21-PE24 with an intermediate affinity (KD ≈ 21 nM) showed a much broader therapeutic window of 73 pM to 1.5 nM in in vitro cytotoxic assays using tumor model cell lines. In EGFR-overexpressing tumor xenograft mouse models, the maximum tolerated dose (MTD) of intravenous injection of ER/21-PE24 was found to be 0.4 mg/kg, which was fourfold higher than the MTD (0.1 mg/kg) of ER/0.2-PE24. Our study provides a strategy for the development of IT targeting tumor overexpressed antigens with basal expression in broad normal tissues by tailoring tumor antigen affinities.

Metalloendopeptidase ADAM-like Decysin 1 (ADAMDEC1) in Colonic Subepithelial PDGFRα+ Cells Is a New Marker for Inflammatory Bowel Disease.

Metalloendopeptidase ADAM-Like Decysin 1 (ADAMDEC1) is an anti-inflammatory peptidase that is almost exclusively expressed in the gastrointestinal (GI) tract. We have recently found abundant and selective expression of Adamdec1 in colonic mucosal PDGFRα+ cells. However, the cellular origin for this gene expression is controversial as it is also known to be expressed in intestinal macrophages. We found that Adamdec1 mRNAs were selectively expressed in colonic mucosal subepithelial PDGFRα+ cells. ADAMDEC1 protein was mainly released from PDGFRα+ cells and accumulated in the mucosal layer lamina propria space near the epithelial basement membrane. PDGFRα+ cells significantly overexpressed Adamdec1 mRNAs and protein in DSS-induced colitis mice. Adamdec1 was predominantly expressed in CD45- PDGFRα+ cells in DSS-induced colitis mice, with only minimal expression in CD45+ CD64+ macrophages. Additionally, overexpression of both ADAMDEC1 mRNA and protein was consistently observed in PDGFRα+ cells, but not in CD64+ macrophages found in human colonic mucosal tissue affected by Crohn's disease. In summary, PDGFRα+ cells selectively express ADAMDEC1, which is localized to the colon mucosa layer. ADAMDEC1 expression significantly increases in DSS-induced colitis affected mice and Crohn's disease affected human tissue, suggesting that this gene can serve as a diagnostic and/or therapeutic target for intestinal inflammation and Crohn's disease.

Engineering of an EpCAM-targeting cyclic peptide to improve the EpCAM-mediated cellular internalization and tumor accumulation of a peptide-fused antibody.

Fusion of a target-specific peptide to a full-length antibody (Ab) can result in a peptide-Ab fusion protein with additional specificity and enhanced activity. We recently developed an intracellular pan-RAS-targeting cytosol-penetrating antibody, RT22-ep59, in which a tumor-specific targeting ability was achieved via the fusion of an epithelial cell adhesion molecule (EpCAM) targeting cyclic peptide (ep133). Here, the aim was to enhance EpCAM-mediated endocytosis and tumor accumulation of the peptide-fused RAS-targeting Ab. Accordingly, we engineered a cyclic peptide (from ep133) that has stronger affinity for EpCAM by using yeast surface display technology and then rationally designed cyclic peptides in the Ab-fused form to enhance colloidal stability. The finally engineered EpCAM-targeting cyclic peptide (ep6)-fused Ab, ep6Ras37, has ∼10-fold stronger affinity (KD ≈ 1.9 nM) for EpCAM than that of RT22-ep59, without deterioration of biophysical properties. Compared with the parental antibody (RT22-ep59), ep6Ras37 more efficiently reached the cytosol of EpCAM-expressing cells and showed greater preferential tumor homing and accumulation in mice bearing EpCAM-expressing LoVo xenograft tumors. Thus, the high-affinity EpCAM-targeting peptide ensures efficient cellular internalization and better tumor accumulation of the peptide-fused Ab.

Obstructive sleep apnea in airline pilots during daytime sleep following overnight flights.

To identify the vulnerability of recovery sleep, this study investigated the occurrence of obstructive sleep apnea during daytime sleep following overnight flights in healthy airline pilots. We conducted daytime polysomnography following a long-haul night-time flight in 103 pilots. The following variables were assessed: apnea-hypopnea index, respiratory disturbance index and oxygen desaturation index. Moderate-to-severe obstructive sleep apnea was defined as an apnea-hypopnea index ≥15. Seventy-three pilots (70.9%) with no known history of obstructive sleep apnea presented with moderate-to-severe obstructive sleep apnea. Pilots showed high mean apnea-hypopnea, respiratory disturbance and oxygen desaturation indices. The body mass index, Berlin questionnaire score and cumulative flight time contributed to these indices, with both body mass index and cumulative flight time remaining significant at an apnea-hypopnea index ≥15. We found that pilots are vulnerable to obstructive sleep apnea during daytime sleep after night-time flights, which may deteriorate their health, increase fatigue and impair overall flight safety. Further research is needed to ensure flight safety, as daytime recovery sleep is unavoidable for night-time flight pilots. The pilots' normal and recovery sleep patterns should both be studied to develop an effective sleep management protocol.

Impact of the coronavirus disease 2019 pandemic on irritable bowel syndrome.

BACKGROUND AND AIM: Gastrointestinal manifestations of the coronavirus disease 2019 (COVID-19) pandemic may mimic irritable bowel syndrome (IBS), and social distancing measures may affect IBS patients negatively. We aimed to study the impact of COVID-19 on respondents with self-reported IBS. METHODS: We conducted an anonymized survey from May to June 2020 in 33 countries. Knowledge, attitudes, and practices on personal hygiene and social distancing as well as psychological impact of COVID-19 were assessed. Statistical analysis was performed to determine differences in well-being and compliance to social distancing measures between respondents with and without self-reported IBS. Factors associated with improvement or worsening of IBS symptoms were evaluated. RESULTS: Out of 2704 respondents, 2024 (74.9%) did not have IBS, 305 (11.3%) had self-reported IBS, and 374 (13.8%) did not know what IBS was. Self-reported IBS respondents reported significantly worse emotional, social, and psychological well-being compared with non-IBS respondents and were less compliant to social distancing measures (28.2% vs 35.3%, P = 0.029); 61.6% reported no change, 26.6% reported improvement, and 11.8% reported worsening IBS symptoms. Higher proportion of respondents with no change in IBS symptoms were willing to practice social distancing indefinitely versus those who deteriorated (74.9% vs 51.4%, P = 0.016). In multivariate analysis, willingness to continue social distancing for another 2-3 weeks (vs longer period) was significantly associated with higher odds of worsening IBS. CONCLUSION: Our study showed that self-reported IBS respondents had worse well-being and compliance to social distancing measures than non-IBS respondents. Future research will focus on occupational stress and dietary changes during COVID-19 that may influence IBS.

Clinical outcomes of endoprosthetic reconstruction for proximal femoral resection.

INTRODUCTION: The proximal femur is a common site for primary sarcomas and metastatic lesions. Although the early results of tumor prostheses are promising, the long-term results of reconstruction are unknown. The purpose of this study is to evaluate the prognostic factors affecting prosthesis survival and complications after proximal femoral resection and reconstruction. METHODS: We reviewed the results of 68 patients who underwent proximal femoral resection and reconstruction with a modular bipolar-type tumor prosthesis between 2005 and 2017. The mean follow-up was 55.6 months (range 6-172 months). There were 50 male and 18 female patients with a mean age of 41.5 years (range 11-80 years). Cumulative survival analysis was performed to analyze the risk factors of prosthesis survival. We also evaluated the complications after operation. RESULTS: Fourteen (21%) patients required further surgery at a mean 37 months post-operatively (range 5-125 months). There were three cases of infection (4%), six of local recurrence (9%), three of acetabular erosion (4%) and two of stem loosening (3%). The implant survival rates were 83.9% at 5 years and 59.8% at 10 years. Prosthesis survivals did not differ based on fixation method (P = 0.085), age (P = 0.329) or resection length (P = 0.61). Acetabular chondrolysis was identified in 18 (26%) patients and longer resection length (≥20 cm) showed a trend for risk of acetabular wear (P = 0.132). CONCLUSION: The results of proximal femoral resection and reconstruction with a modular bipolar-type prosthesis were found to be acceptable with infection and local recurrence as short-term complications and loosening and acetabular erosion as long-term complications.