Apelin-13 reverses bupivacaine-induced cardiotoxicity: an experimental study.

INTRODUCTION: Cardiac arrest or arrhythmia caused by bupivacaine may be refractory to treatment. Apelin has been reported to directly increase the frequency of spontaneous activation and the propagation of action potentials, ultimately promoting cardiac contractility. This study aimed to investigate the effects of apelin-13 in reversing cardiac suppression induced by bupivacaine in rats. METHODS: A rat model of cardiac suppression was established by a 3-min continuous intravenous infusion of bupivacaine at the rate of 5 mg.kg-1.min-1, and serial doses of apelin-13 (50, 150 and 450 µg.kg-1) were administered to rescue cardiac suppression to identify its dose-response relationship. We used F13A, an inhibitor of Angiotensin Receptor-Like 1 (APJ), and Protein Kinase C (PKC) inhibitor chelerythrine to reverse the effects of apelin-13. Moreover, the protein expressions of PKC, Nav1.5, and APJ in ventricular tissues were measured using Western blotting and immunofluorescence assay. RESULTS: Compared to the control rats, the rats subjected to continuous intravenous administration of bupivacaine had impaired hemodynamic stability. Administration of apelin-13, in a dose-dependent manner, significantly improved hemodynamic parameters in rats with bupivacaine-induced cardiac suppression (p < 0.05), and apelin-13 treatment also significantly upregulated the protein expressions of p-PKC and Nav1.5 (p < 0.05), these effects were abrogated by F13A or chelerythrine (p < 0.05). CONCLUSION: Exogenous apelin-13, at least in part, activates the PKC signaling pathway through the apelin/APJ system to improve cardiac function in a rat model of bupivacaine-induced cardiac suppression.

Optimized multiple-attribute group decision-making through employing probabilistic hesitant fuzzy TODIM and EDAS technique and application to teaching quality evaluation of international Chinese course in higher vocational colleges.

With the construction and development of the "the Belt and Road", the international community has an increasing demand for high-quality technical and skilled talents who both understand Chinese and have an international perspective. Exploring a Chinese curriculum system suitable for the development of international students is conducive to promoting the international development of vocational education, improving the quality of international student training, providing talent support for Chinese and foreign enterprises, and promoting the "going out" of Chinese enterprises and international production capacity cooperation. The training of international students in higher vocational colleges starts late, has little experience, lacks theoretical innovation, and lacks the development characteristics of vocational education. The teaching quality evaluation of international Chinese course in higher vocational colleges is multiple-attributes group decision-making (MAGDM). Recently, the TODIM and EDAS technique has been employed to manage MAGDM. The probabilistic hesitant fuzzy sets (PHFSs) are employed as a useful tool for depicting uncertain information during the teaching quality evaluation of international Chinese course in higher vocational colleges. In this paper, the probabilistic hesitant fuzzy TODIM-EDAS (PHF-TODIM-EDAS) technique is built to manage the MAGDM under PHFSs. Finally, the numerical example for teaching quality evaluation of international Chinese course in higher vocational colleges is employed to show the PHF-TODIM-EDAS technique. The main contribution of this paper is outlined: (1) the TODIM technique based on EDAS technique has been extended to PHFSs based on CRITIC technique; (2) the CRITIC technique is employed to derive weight numbers under PHFSs. (3) the PHF-TODIM-EDAS technique is founded to manage the MAGDM under PHFSs; (4) a numerical case study for teaching quality evaluation of international Chinese course in higher vocational colleges and some comparative analysis is supplied to validate the proposed PHF-TODIM-EDAS technique.

A Comprehensive Investigation of Active Learning Strategies for Conducting Anti-Cancer Drug Screening.

It is well-known that cancers of the same histology type can respond differently to a treatment. Thus, computational drug response prediction is of paramount importance for both preclinical drug screening studies and clinical treatment design. To build drug response prediction models, treatment response data need to be generated through screening experiments and used as input to train the prediction models. In this study, we investigate various active learning strategies of selecting experiments to generate response data for the purposes of (1) improving the performance of drug response prediction models built on the data and (2) identifying effective treatments. Here, we focus on constructing drug-specific response prediction models for cancer cell lines. Various approaches have been designed and applied to select cell lines for screening, including a random, greedy, uncertainty, diversity, combination of greedy and uncertainty, sampling-based hybrid, and iteration-based hybrid approach. All of these approaches are evaluated and compared using two criteria: (1) the number of identified hits that are selected experiments validated to be responsive, and (2) the performance of the response prediction model trained on the data of selected experiments. The analysis was conducted for 57 drugs and the results show a significant improvement on identifying hits using active learning approaches compared with the random and greedy sampling method. Active learning approaches also show an improvement on response prediction performance for some of the drugs and analysis runs compared with the greedy sampling method.

Facilitating Lung Collapse for Thoracoscopic Surgery Utilizing Endobronchial Airway Occlusion Preceded by Pleurotomy and One-minute Suspension of Two-lung Ventilation.

OBJECTIVES: To assess when and whether clamping the double-lumen endobronchial tube (DLT) limb of the non-ventilated lung is more conducive to a rapid and effective lung deflation than simply allowing the open limb of the DLT to communicate with the atmosphere. DESIGN: This was a single-center, single-blind, randomized, controlled trial. SETTING: The trial was performed in a single institutional setting. PARTICIPANTS: The participants were 60 patients undergoing elective video-assisted thoracoscopic surgery. INTERVENTIONS: Patients were randomized to the open-clamp airway technique (OCAT group) or control group. Patients in the control group had one-lung ventilation initiated upon being placed in the lateral decubitus position. The OCAT group had two-lung ventilation maintained until the pleural cavity was opened with the introduction of a planned thoracoscopic access port to allow the operated lung to fall away from the chest wall. Thereafter, ventilation was suspended (temporarily ceased) for 1 minute before the DLT lumen of the isolated lung was clamped. The primary outcome of the trial was the time to complete lung collapse scored as determined from video clips taken during surgery. The secondary outcomes were (1) lung collapse score at 30 minutes after pleural incision, (2) surgeon satisfaction with surgery, and (3) intraoperative hypoxemia. MEASUREMENTS AND MAIN RESULTS: The median time to reach complete lung collapse in the OCAT group was 10 minutes (odds ratio 10.0, 95% CI 6.3-13.7), which was much shorter than that of the control group (25 minutes [odds ratio 25.0, 95% CI 13.6-36.4]). The difference in complete lung collapse at 30 minutes between the 2 groups was significant (p < 0.001). The surgeon's satisfaction with surgery was higher in the OCAT group than in the control group (8.5 ± 0.2 vs 6.8 ± 0.2; p < 0.001). There was no difference regarding intraoperative hypoxemia. CONCLUSIONS: Suspending ventilation of both DLT limbs for 1 minute after pleural cavity opening and then clamping the DLT lumen of the isolated lung resulted in a more rapid deflation of the surgical lung. This open-clamp airway technique is an effective technique for rapid surgical lung collapse during thoracoscopic surgery.

C2H2 Zinc Finger Transcription Factors Associated with Hemoglobinopathies.

In humans, specific aberrations in ß-globin results in sickle cell disease and ß-thalassemia, symptoms of which can be ameliorated by increased expression of fetal globin (HbF). Two recent CRISPR-Cas9 screens, centered on ∼1500 annotated sequence-specific DNA binding proteins and performed in a human erythroid cell line that expresses adult hemoglobin, uncovered four groups of candidate regulators of HbF gene expression. They are (1) members of the nucleosome remodeling and deacetylase (NuRD) complex proteins that are already known for HbF control; (2) seven C2H2 zinc finger (ZF) proteins, including some (ZBTB7A and BCL11A) already known for directly silencing the fetal γ-globin genes in adult human erythroid cells; (3) a few other transcription factors of different structural classes that might indirectly influence HbF gene expression; and (4) DNA methyltransferase 1 (DNMT1) that maintains the DNA methylation marks that attract the MBD2-associated NuRD complex to DNA as well as associated histone H3 lysine 9 methylation. Here we briefly discuss the effects of these regulators, particularly C2H2 ZFs, in inducing HbF expression for treating ß-hemoglobin disorders, together with recent advances in developing safe and effective small-molecule therapeutics for the regulation of this well-conserved hemoglobin switch.

The efficacy of a device-based approach to microorganism disinfection and protein removal for orthokeratology lenses in varied clinical circumstances.

PURPOSE: RigidCare is an electrolysis-based device that recently obtained approval from the US's FDA to sterilise microorganisms and remove proteins for orthokeratology (O-K) lenses. The study was conducted to investigate the device's performance in varied clinical circumstances. METHODS: Trial lenses and private lenses were employed by O-K lens wearers from five hospitals for an evaluation of disinfection and sterilisation and an assessment of protein removal, respectively. Menicon multipurpose solution and protein remover were selected for use with the control group. Following the instructions, pre-cleaning lens samples, post-cleaning lens samples and residual solution samples of trial lenses of the experimental and control groups were collected for microorganism examinations by an experienced third-party testing organisation. The levels of protein deposition for these two approaches were rated by senior O-K experts. Categorical variables were analysed using statistical tests, such as the chi-squared test and Fisher's exact test. RESULTS: The microbial positive rate detected from the pre-cleaning and post-cleaning lens samples and the residual solution of the trial lenses for the experimental and control group was 4/76 vs 1/74 (P = 0.37), 1/76 vs 0/74 (P = 1.00) and 0/76 vs 8/74 (P = 0.006), respectively. Following protein removal, the experimental group exhibited a significantly higher overall proportion of lenses rated as 'clean' or with a 'mild deposit' (96.4 %, 79/82) compared to the control group (85.7 %, 66/77), with a significant difference (P < 0.05). CONCLUSION: This multi-center study demonstrated that RigidCare exhibited superior efficacy in disinfection, sterilisation and protein removal as compared to Menicon multipurpose solution and protein remover.

Sufentanil Improves the Analgesia Effect of Continuous Femoral Nerve Block After Total Knee Arthroplasty.

Purpose: We examined whether the addition of sufentanil to local anesthetics improves the quality of continuous femoral nerve block in patients undergoing total knee arthroplasty (TKA). Patients and Methods: With institutional ethical approval and having obtained written informed consent from each, 35 patients scheduled for elective bilateral TKA with ASA I or II physical status were studied. Bilateral femoral perineural catheters were preoperatively inserted. Both-sided catheters were randomly assigned to receive perineural ropivacaine of 0.2% plus 0.5µg/mL sufentanil deemed as RS group or 0.2% ropivacaine alone deemed as R group at the end of surgery. Visual analogue pain scores (VAS) during activity and at rest of each lower limb were recorded at 6,12,18,24,30,36,42 and 48h after surgery. During the first 48 postoperative hours, the number and reason of patients sleep interruption at night, the number of painful compressions, patient satisfaction and morphine requirements were recorded for each lower limb of patients. Results: Pain scores of RS group on movement were significantly lower than R group, but no difference was noted at rest. When compared to R group, RS group had a lower incidence of sleep interruption at night, fewer painful compressions, higher satisfaction scores and less morphine requirement. Conclusion: The addition of sufentanil to ropivacaine improved analgesia quality of continuous femoral nerve block after arthroplasty.

Oligonucleotide nanoassemblies with allyl bromide scaffold-based small molecules.

The development of oligonucleotide nanoassemblies with small molecules has shown great potential in bio-medical applications. However, the interaction of negatively charged oligonucleotides with halogenated small molecules represents a scientific challenge. Here, we introduced a distinct allyl bromide halogenated scaffold, which exhibits specific interaction with adenine nucleic bases of the oligonucleotides, thus leading to the formation of self-assembled nanostructures.

CholecTriplet2021: A benchmark challenge for surgical action triplet recognition.

Context-aware decision support in the operating room can foster surgical safety and efficiency by leveraging real-time feedback from surgical workflow analysis. Most existing works recognize surgical activities at a coarse-grained level, such as phases, steps or events, leaving out fine-grained interaction details about the surgical activity; yet those are needed for more helpful AI assistance in the operating room. Recognizing surgical actions as triplets of combination delivers more comprehensive details about the activities taking place in surgical videos. This paper presents CholecTriplet2021: an endoscopic vision challenge organized at MICCAI 2021 for the recognition of surgical action triplets in laparoscopic videos. The challenge granted private access to the large-scale CholecT50 dataset, which is annotated with action triplet information. In this paper, we present the challenge setup and the assessment of the state-of-the-art deep learning methods proposed by the participants during the challenge. A total of 4 baseline methods from the challenge organizers and 19 new deep learning algorithms from the competing teams are presented to recognize surgical action triplets directly from surgical videos, achieving mean average precision (mAP) ranging from 4.2% to 38.1%. This study also analyzes the significance of the results obtained by the presented approaches, performs a thorough methodological comparison between them, in-depth result analysis, and proposes a novel ensemble method for enhanced recognition. Our analysis shows that surgical workflow analysis is not yet solved, and also highlights interesting directions for future research on fine-grained surgical activity recognition which is of utmost importance for the development of AI in surgery.

Introducing the Bacterial and Viral Bioinformatics Resource Center (BV-BRC): a resource combining PATRIC, IRD and ViPR.

The National Institute of Allergy and Infectious Diseases (NIAID) established the Bioinformatics Resource Center (BRC) program to assist researchers with analyzing the growing body of genome sequence and other omics-related data. In this report, we describe the merger of the PAThosystems Resource Integration Center (PATRIC), the Influenza Research Database (IRD) and the Virus Pathogen Database and Analysis Resource (ViPR) BRCs to form the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) https://www.bv-brc.org/. The combined BV-BRC leverages the functionality of the bacterial and viral resources to provide a unified data model, enhanced web-based visualization and analysis tools, bioinformatics services, and a powerful suite of command line tools that benefit the bacterial and viral research communities.

Integration of Computational Docking into Anti-Cancer Drug Response Prediction Models.

Cancer is a heterogeneous disease in that tumors of the same histology type can respond differently to a treatment. Anti-cancer drug response prediction is of paramount importance for both drug development and patient treatment design. Although various computational methods and data have been used to develop drug response prediction models, it remains a challenging problem due to the complexities of cancer mechanisms and cancer-drug interactions. To better characterize the interaction between cancer and drugs, we investigate the feasibility of integrating computationally derived features of molecular mechanisms of action into prediction models. Specifically, we add docking scores of drug molecules and target proteins in combination with cancer gene expressions and molecular drug descriptors for building response models. The results demonstrate a marginal improvement in drug response prediction performance when adding docking scores as additional features, through tests on large drug screening data. We discuss the limitations of the current approach and provide the research community with a baseline dataset of the large-scale computational docking for anti-cancer drugs.

TULIP: An RNA-seq-based Primary Tumor Type Prediction Tool Using Convolutional Neural Networks.

Background: With cancer as one of the leading causes of death worldwide, accurate primary tumor type prediction is critical in identifying genetic factors that can inhibit or slow tumor progression. There have been efforts to categorize primary tumor types with gene expression data using machine learning, and more recently with deep learning, in the last several years. Methods: In this paper, we developed four 1-dimensional (1D) Convolutional Neural Network (CNN) models to classify RNA-seq count data as one of 17 highly represented primary tumor types or 32 primary tumor types regardless of imbalanced representation. Additionally, we adapted the models to take as input either all Ensembl genes (60,483) or protein coding genes only (19,758). Unlike previous work, we avoided selection bias by not filtering genes based on expression values. RNA-seq count data expressed as FPKM-UQ of 9,025 and 10,940 samples from The Cancer Genome Atlas (TCGA) were downloaded from the Genomic Data Commons (GDC) corresponding to 17 and 32 primary tumor types respectively for training and validating the models. Results: All 4 1D-CNN models had an overall accuracy of 94.7% to 97.6% on the test dataset. Further evaluation indicates that the models with protein coding genes only as features performed with better accuracy compared to the models with all Ensembl genes for both 17 and 32 primary tumor types. For all models, the accuracy by primary tumor type was above 80% for most primary tumor types. Conclusions: We packaged all 4 models as a Python-based deep learning classification tool called TULIP (TUmor CLassIfication Predictor) for performing quality control on primary tumor samples and characterizing cancer samples of unknown tumor type. Further optimization of the models is needed to improve the accuracy of certain primary tumor types.

2D Ruddlesden-Popper perovskite sensitized SnP2S6 ultraviolet photodetector enabling high responsivity and fast speed.

As the newly developed wide-bandgap semiconductors, two-dimensional layered metal phosphorus chalcogenides (2D LMPCs) exhibit enormous potential applications in ultraviolet (UV) photodetection due to their superior optoelectronic performance. However, 2D LMPC-based UV photodetectors generally suffer from low responsivity and slow response speed, which hinder their practical applications. Here, we present an effective strategy of sensitizing 2D LMPC UV photodetectors with a 2D Ruddlesden-Popper (RP) perovskite to enable high responsivity and fast response speed. As a demonstration, a hybrid heterojunction composed of RP perovskite (PEA)2PbI4 and a 2D SnP2S6 flake is fabricated by spin-coating method. Benefitting from the strong optical absorption of (PEA)2PbI4 and the efficient interfacial charge transfer caused by the favorable type-II energy band alignment, the as-fabricated 2D SnP2S6/(PEA)2PbI4 hybrid heterojunction photodetectors show high responsivity (67.1 A W-1), large detectivity (2.8 × 1011 Jones), fast rise/delay time (30/120 µs) and excellent external quantum efficiency (22825%) at 365 nm. Under field-effect modulation, the responsivity of the heterojunction photodetector can reach up to 239.4 A W-1, which is attributed to the photogating mechanism and reduced Schottky barriers. Owing to the excellent photodetection performance, the heterojunction device further shows superior imaging capability. This work provides an effective strategy for designing high-performance UV photodetectors toward future applications.

The Potential of miR-370-3p and miR-495-3p Serving as Biomarkers for Sepsis-Associated Acute Kidney Injury.

Objective: This study is aimed at evaluating the miR-370-3p and miR-495-3p expression in the urine of patients with sepsis-associated acute kidney injury (SA-AKI) and exploring its diagnosis value in for SA-AKI. Methods: 184 sepsis invalids were collected and divided two groups (non-AKI group or AKI group) according to whether they had acute kidney injury. RT-qPCR was utilized to measure miR-370-3p and miR-495-3p expressions. ROC curve was performed to evaluate the diagnostic value of miR-370-3p and miR-495-3p for SA-AKI. Patients diagnosed with SA-AKI were followed up for 28 days to record survival time. The prognostic performance of miR-370-3p and miR-495-3p for SA-AKI was evaluated by survival curves. Results: Compared with non-AKI invalids, miR-370-3p and miR-495-3p expressions were obviously lower in the urine of AKI invalids. miR-370-3p and miR-495-3p expressions were markedly negatively correlated with biomarkers of renal injury. Furthermore, the area under the curve (AUC) of miR-370-3p and miR-495-3p for diagnosing sepsis SA-AKI was 0.896 and 0.814, respectively. The higher 28 days-survival rate was observed in patients with high miR-370-3p and miR-495-3p expressions. Conclusions: A novel biomarker for the early diagnosis of SA-AKI may be miR-370-3p and miR-495-3p, which was clearly reduced in the urine of SA-AKI patients.

KGF-2 Protects against Lung Ischemia-Reperfusion Injury by Inhibiting Inflammation-Induced Damage to Endothelial Barrier Function.

Lung ischemia-reperfusion injury (LIRI), which has a mortality rate of approximately 50%, is a popular topic in critical care research. Keratinocyte growth factor-2 (KGF-2) is secreted by mesenchymal cells, and it is effective in promoting the proliferation, migration, and differentiation of various epithelial cells. To date, however, only a few reports on KGF-2-related regulators in LIRI have been published. In the current study, an LIRI rat model is constructed, and the upregulation of the fibroblast growth factor receptor 2 (FGFR2) is observed in the LIRI rat model. In addition, LIRI induces NLRP1 inflammasome activation in vivo and in vitro, and KGF-2 inhibits LIRI-induced damage to pulmonary microvascular endothelial cells. Mechanistically, KGF-2 inhibits NLRP1 inflammasome and NF-κB activity. KGF-2 inhibition attenuates LIRI injury-induced damage to endothelial integrity. In conclusion, KGF-2 protects against LIRI by inhibiting inflammation-induced endothelial barrier damage.

Pancytopenia Due to Possible Drug-Drug Interactions Between Low-Dose Methotrexate and Proton Pump Inhibitors.

Methotrexate (MTX) has been widely used with a wide range of doses in the treatment of certain neoplastic diseases, severe psoriasis, and rheumatoid arthritis. At higher dose, monitoring of serum MTX elimination is performed because delayed elimination can result in serious and potentially life-threatening toxicities. A number of medications, including nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, phenylbutazone, phenytoin, sulfonamides, and some oral antibiotics, are known to interact with MTX therapy through various mechanisms. Accumulating evidence suggests that concomitant use of MTX (primarily at high doses) and proton pump inhibitors (PPIs) such as omeprazole, esomeprazole, and pantoprazole may decrease MTX clearance. The majority of the reported cases occurred with the administration of high-dose MTX in patients receiving doses of 300 mg/m2 to 12 g/m2. However, there were also cases of patients taking PPI and experiencing toxicity at doses as low as 10 mg of MTX per week. Although the dosage of MTX is small, the presence of side effect may be delayed and still dangerous. After literature review, it was found that common toxicities associated with low-dose MTX used for inflammatory arthritis include gastrointestinal adverse effects (>10%; ie nausea, stomatitis) and central nervous system toxicity (~20%; ie fatigue, malaise, dizziness, impaired cognition) with weekly administration. Bone marrow suppression (<3%; ie leukopenia, neutropenia, thrombocytopenia) and hepatotoxicity (~15%; ie reversible elevations in transaminases) are less common, and rarely MTX can also cause pulmonary (<1%) and other toxicities. Here, we report two cases who presented with severe pancytopenia 8 and 13 days after taking low-dose MTX and PPI. We highlight that in absence of risk/benefit ratio correctly set, an assessment of appropriateness of PPI prescription before MTX therapy can limit an iatrogenic risk.

Comparison of Two Main Orthokeratology Lens Designs in Efficacy and Safety for Myopia Control.

Purpose: This study aimed to compare the efficacy and safety of corneal refractive therapy (CRT) lenses and vision shaping treatment (VST) lenses for myopia control in children. Methods: Medical records of 1,001 children (2,002 eyes) who had been fitted with orthokeratology lenses for over 1.5 years were retrospectively reviewed. We collected the clinical data of four types of orthokeratology (OK) lenses available: one CRT lens (brand: CRT) and three VST lenses (brands: Euclid, Alpha, and Hiline) over 1.5 years. Results were compared and analyzed using a one-way ANOVA and Pearson's chi-square test. Results: Axial length elongation in the CRT lens group was 0.13 ± 0.02 mm faster than that in the Euclid lens, 0.1 ± 0.02 mm faster in the Alpha lens, and 0.08 ± 0.02 mm faster in the Hiline lens over the 1.5-year period (all P < 0.05). Among the subjects, 37.3% of them using the CRT lens experienced more than 1 D of refractive growth, compared with 20.2-30.8% of subjects wearing the three groups of VST lenses (all P < 0.05). A lower incidence of total adverse events was found with the CRT lenses compared with the VST lenses (P < 0.05), especially corneal staining. No difference was found in axial length elongation, refraction growth, and incidence of adverse events among the three types of VST lenses (all P > 0.05). Conclusions: Compared with the VST lenses, CRT lenses demonstrated a weaker effect on myopia control but with a better safety profile. Different types of VST lenses had similar efficacy and safety in the context of controlling myopia progression.

Self-Assembled Nanoparticles for Tumor-Triggered Targeting Dual-Mode NIRF/MR Imaging and Photodynamic Therapy Applications.

In this study, the self-assembling strategy was used to synthesize a therapeutic and diagnostic nanosystem for tumor-triggered targeting dual-mode near-infrared fluorescence (NIRF)/magnetic resonance (MR) imaging and photodynamic therapy applications. This theranostic nanosystem was synthesized based on the self-assembling of the short peptide (PLGVRGRGDC) and the gadolinium chelator (diethylenetriamine pentaacetic acid) functionalized amphiphilic DSPE-PEG2000, followed by loading with the insoluble photosensitizer therapeutic agent chlorin e6 (Ce6). The formed theranostic nanosystem can accumulate in the matrix metalloproteinase 2 (MMP2) rich tumor sites guided by the enhanced permeability and retention effect and MMP2-substrate peptide (PLGVR) targeting. After PLGVR was hydrolyzed in the tumor microenvironment by MMP2, the nanosystem was actively taken up by tumor cells via Arg-Gly-Asp (RGD) peptide-mediated internalization. With the coexistence of gadolinium and Ce6, the formed nanosystem can be used for both NIRF/MR dual-mode imaging and photodynamic therapy. These tumor-triggered targeting self-assembled nanoparticles with low cytotoxicity and high endocytosis efficiency can efficiently induce A549 cancer cell apoptosis under laser irradiation. Meanwhile, they possessed enhanced tumor-targeted NIRF/MR imaging ability and efficiently inhibited tumor growth with minimal side effects in mice bearing A549 lung cancer. Therefore, these self-assembled theranostic nanoparticles may have great potential for cancer clinical diagnosis and therapy.

Inhibition of IKKß/NF-κB signaling facilitates tendinopathy healing by rejuvenating inflamm-aging induced tendon-derived stem/progenitor cell senescence.

Degenerative rotator cuff tendinopathy (RCT) is a chronic tendon disease caused by degeneration and inflammation, which often affects the elderly population. Mesenchymal stem cell senescence is generally recognized as an important pathophysiological mechanism in many age-related skeletal diseases. Herein, we collected human tendon-derived stem/progenitor cells (TSPCs) from degenerative supraspinatus tendons and found that TSPC senescence is closely related to RCT. We further identified that nuclear factor κB (NF-κB) pathway activation is involved in age-related inflammation (inflamm-aging) of degenerative RCT. Moreover, whole genome RNA sequencing revealed that in vitro inhibition of the I kappa B kinase ß (IKKß)/NF-κB signaling pathway could reverse the aged TSPC phenotype with decreased TSPC senescence and increased tenogenic potential. To achieve effective in vivo inhibition of IKKß/NF-κB signaling, we fabricated IKKß small interfering RNA (siRNA)-loaded gold nanoclusters (AuNC-siRNA) for efficient and convenient intra-articular delivery of IKKß siRNA. We found that AuNC-siRNA prevented inflamm-aging-induced TSPC senescence and dysfunction in a degenerative RCT aged rat model. Together, these data show that inflamm-aging causes degenerative RCT through inducing TSPC senescence, which can be reversed by blocking the IKKß/NF-κB pathway in vivo. Thus, our study provides a promising therapeutic strategy for degenerative RCT via intra-articular delivery of IKKß siRNA using AuNCs.

A cross-study analysis of drug response prediction in cancer cell lines.

To enable personalized cancer treatment, machine learning models have been developed to predict drug response as a function of tumor and drug features. However, most algorithm development efforts have relied on cross-validation within a single study to assess model accuracy. While an essential first step, cross-validation within a biological data set typically provides an overly optimistic estimate of the prediction performance on independent test sets. To provide a more rigorous assessment of model generalizability between different studies, we use machine learning to analyze five publicly available cell line-based data sets: National Cancer Institute 60, ancer Therapeutics Response Portal (CTRP), Genomics of Drug Sensitivity in Cancer, Cancer Cell Line Encyclopedia and Genentech Cell Line Screening Initiative (gCSI). Based on observed experimental variability across studies, we explore estimates of prediction upper bounds. We report performance results of a variety of machine learning models, with a multitasking deep neural network achieving the best cross-study generalizability. By multiple measures, models trained on CTRP yield the most accurate predictions on the remaining testing data, and gCSI is the most predictable among the cell line data sets included in this study. With these experiments and further simulations on partial data, two lessons emerge: (1) differences in viability assays can limit model generalizability across studies and (2) drug diversity, more than tumor diversity, is crucial for raising model generalizability in preclinical screening.