Development and validation of the 5-Dimension Comprehensive Assessment Scale (5DCAS) for assessing physical function and health in axial spondyloarthritis.

OBJECTIVE: To describe the development and validation of a novel patient reported scale, which is a comprehensive assessment of the physical function and health specific for patients with axial spondyloarthritis (axSpA). METHODS: This is a multiphase, mixed methods study. Based on opinion collection and discussions of multidisciplinary consensus meetings and patients, an initial item pool covering all of the ranges of functioning was generated. The item optimization, model fit, response category functioning, differential item functioning, reliability, structure validity, and unidimensionality were tested by confirmatory factor analysis and Rasch measurement theory framework. RESULTS: After the consensus meeting and the two rounds of surveys in patients with axSpA, the initial pool of 135 items was reduced to 25 items formed in five dimensions, which exhibited preferable item reliability, item fit, and person fit to the Rasch model. The Five-Dimensional Comprehensive Assessment Scale (5DCAS) had the best reliability and validity (Kaiser-Meyer-Olkin was 0.919, and the standardized Cronbach's α coefficient was 0.932). The final version of 5DCAS had good unidimensionality, and the Person Separation Index ranged from 0.77 to 0.85. 5DCAS significantly correlated with ASAS-HI, SF-36, BASFI, and disease activity with p values of < 0.001. CONCLUSION: 5DCAS is a novel patient-reported outcome specific to axSpA, and it forms five dimensions providing a linear sum score of 25 items. 5DCAS comprehensively and significantly represents the physical function and health status of patients with axSpA, although its performance needs further validation in future clinical practices. Key Points • The primary goal in the management of axial spondyloarthritis is to maximize health-related quality of life. Except for the current instruments of ASAS-HI, BASFI, or SF-36, the heterogeneous clinical symptoms and rapid updated treat-to-target concept require a new instrument which can comprehensive and significant evaluate the changes of physical function and health-related quality of life due to disease. • 5DCAS is a novel patient-reported outcome specific to axSpA, and it forms five dimensions providing a linear sum score of 25 items, which contained aspect of pain involvement, spine mobility, global body performance and activity, social participation and environment, and mental health. All of the items were set to a 4-point semantic rating scale measuring severity, frequency, or interference from score 0 to 3. Total 5DCAS score ranges from 0 to 75; higher scores represented greater symptom burden and worse physical function. • 5DCAS is a comprehensive, multidisciplinary, and convenient disease outcome measurement specific for axSpA. It provides a new evaluation instrument in clinical trial and treat-to-target clinical remission for patients and physicians, and also provides a sensitive and accurate assessment standard for optimized health benefits.

Gastrointestinal tract organoids as novel tools in drug discovery.

Organoids, characterized by their high physiological attributes, effectively preserve the genetic characteristics, physiological structure, and function of the simulated organs. Since the inception of small intestine organoids, other organoids for organs including the liver, lungs, stomach, and pancreas have subsequently been developed. However, a comprehensive summary and discussion of research findings on gastrointestinal tract (GIT) organoids as disease models and drug screening platforms is currently lacking. Herein, in this review, we address diseases related to GIT organoid simulation and highlight the notable advancements that have been made in drug screening and pharmacokinetics, as well as in disease research and treatment using GIT organoids. Organoids of GIT diseases, including inflammatory bowel disease, irritable bowel syndrome, necrotizing enterocolitis, and Helicobacter pylori infection, have been successfully constructed. These models have facilitated the study of the mechanisms and effects of various drugs, such as metformin, Schisandrin C, and prednisolone, in these diseases. Furthermore, GIT organoids have been used to investigate viruses that elicit GIT reactions, including Norovirus, SARS-CoV-2, and rotavirus. Previous studies by using GIT organoids have shown that dasabuvir, gemcitabine, and imatinib possess the capability to inhibit viral replication. Notably, GIT organoids can mimic GIT responses to therapeutic drugs at the onset of disease. The GIT toxicities of compounds like gefitinib, doxorubicin, and sunset yellow have also been evaluated. Additionally, these organoids are instrumental for the study of immune regulation, post-radiation intestinal epithelial repair, treatment for cystic fibrosis and diabetes, the development of novel drug delivery systems, and research into the GIT microbiome. The recent use of conditioned media as a culture method for replacing recombinant hepatocyte growth factor has significantly reduced the cost associated with human GIT organoid culture. This advancement paves the way for large-scale culture and compound screening of GIT organoids. Despite the ongoing challenges in GIT organoid development (e.g., their inability to exist in pairs, limited cell types, and singular drug exposure mode), these organoids hold considerable potential for drug screening. The use of GIT organoids in this context holds great promises to enhance the precision of medical treatments for patients living with GIT diseases.

Reversal of injury-associated retinal ganglion cell gene expression by a phosphodiesterase anchoring disruptor peptide.

Loss of retinal ganglion cells (RGCs) is central to the pathogenesis of optic neuropathies such as glaucoma. Increased RGC cAMP signaling is neuroprotective. We have shown that displacement of the cAMP-specific phosphodiesterase PDE4D3 from an RGC perinuclear compartment by expression of the modified PDE4D3 N-terminal peptide 4D3(E) increases perinuclear cAMP and protein kinase A activity in cultured neurons and in vivo RGC survival after optic nerve crush (ONC) injury. To explore mechanisms by which PDE4D3 displacement promotes neuroprotection, in this study mice intravitreally injected with an adeno-associated virus to express an mCherry-tagged 4D3(E) peptide were subjected to ONC injury and analyzed by single cell RNA-sequencing (scRNA-seq). 4D3(E)-mCherry expression was associated with an attenuation of injury-induced changes in gene expression, thereby supporting the hypothesis that enhanced perinuclear PKA signaling promotes neuroprotective RGC gene expression.

Garlic-derived Exosomes Alleviate Osteoarthritis Through Inhibiting the MAPK Signaling Pathway.

Osteoarthritis (OA) is the most common degenerative joint disease affecting millions of people worldwide. Garlic-derived exosomes (GDEs) are nanoparticles extracted from garlic that exhibit anti-inflammatory effects on other diseases, but the effect of GDEs on OA has not been elucidated. In this study, GDEs were extracted and characterized. Chondrocytes were treated with IL-1ß and incubated with GDEs in vitro, and the expression of cartilage matrix components (collagen II and aggrecan) and matrix degrading enzymes (MMP3 and MMP9) was evaluated via Western blotting. Changes in the MAPK pathway was also examined using Western blotting. The transcriptomic changes associated with GDE intervention were evaluated using high-throughput RNA-seq method. In vivo, we used anterior cruciate ligament transection (ACLT) combined with destabilization of the medial meniscus (DMM) surgery to establish a mouse OA model, and GDEs was intraarticularly injected into the joint cavity. The therapeutic effect of GDE was evaluated by behavioral and histopathological analysis. The results showed that IL-1ß treatment inhibited the expression of collagen II and aggrecan, and upregulated the expression of MMP3 and MMP9, while GDE intervention alleviated these effects. GDEs also inhibited the phosphorylation of ERK, JNK, and P38. In vivo, GDE alleviated the sensitivity to heat stimulation and altered walking gait in a mouse OA model. Histopathological analysis indicated that GDE intervention ameliorated joint destruction in the knee joint without obvious toxicity. The results proved that GDEs alleviated the progression of OA in vitro and in vivo, and may be a potential disease-modifying drug for OA.

Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in Trappc9-linked brain developmental syndrome.

Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (Trappc9) cause autosomal recessive intellectual disability and obesity by unknown mechanisms. Genome-wide analysis links Trappc9 to nonalcoholic fatty liver disease (NAFLD). Trappc9-deficient mice have been shown to appear overweight shortly after weaning. Here, we analyzed serum biochemistry and histology of adipose and liver tissues to determine the incidence of obesity and NAFLD in Trappc9-deficient mice and combined transcriptomic and proteomic analyses, pharmacological studies, and biochemical and histological examinations of postmortem mouse brains to unveil mechanisms involved. We found that Trappc9-deficient mice presented with systemic glucose homeostatic disturbance, obesity, and NAFLD, which were relieved upon chronic treatment combining dopamine receptor D2 (DRD2) agonist quinpirole and DRD1 antagonist SCH23390. Blood glucose homeostasis in Trappc9-deficient mice was restored upon administering quinpirole alone. RNA-sequencing analysis of DRD2-containing neurons and proteomic study of brain synaptosomes revealed signs of impaired neurotransmitter secretion in Trappc9-deficient mice. Biochemical and histological studies of mouse brains showed that Trappc9-deficient mice synthesized dopamine normally, but their dopamine-secreting neurons had a lower abundance of structures for releasing dopamine in the striatum. Our study suggests that Trappc9 loss of function causes obesity and NAFLD by constraining dopamine synapse formation.

Click method preserves but EDC method compromises the therapeutic activities of the peptide-activated hydrogels for critical ischemic vessel regeneration.

Peptide-functionalized hydrogel is one of commonly used biomaterials to introduce hydrogel-induced vessel regeneration. Despite many reports about the discoveries of high-active peptides (or ligands) for regeneration, the study on the conjugating methods for the hydrogel functionalization with peptides is limited. Here, we compared the vasculogenic efficacy of the peptide-functionalized hydrogels prepared by two commonly used conjugating methods, 1-ethyl-3-(3-dimethylamino propyl) carbodiimide (EDC) and Click methods, through cell models, organ-on-chips models, animal models, and RNA sequencing analysis. Two vascular-related cell types, the human umbilical vein endothelial cells (HUVECs) and the adipose-derived stem cells (ADSCs), have been cultured on the hydrogel surfaces prepared by EDC/Click methods. It showed that the hydrogels prepared by Click method supported the higher vasculogenic activities while the ones made by EDC method compromised the peptide activities on hydrogels. The vasculogenesis assays further revealed that hydrogels prepared by Click method promoted a better vascular network formation. In a critical ischemic hindlimb model, only the peptide-functionalized hydrogels prepared by Click method successfully salvaged the ischemic limb, significantly improved blood perfusion, and enhanced the functional recoveries (through gait analysis and animal behavior studies). RNA sequencing studies revealed that the hydrogels prepared by Click method significantly promoted the PI3K-AKT pathway activation compared to the hydrogels prepared by EDC method. All the results suggested that EDC method compromised the functions of the peptides, while Click method preserved the vascular regenerating capacities of the peptides on the hydrogels, illustrating the importance of the conjugating method during the preparation of the peptide-functionalized hydrogels.

Optimizing the Biocompatibility of PLLA Stent Materials: Strategy with Biomimetic Coating.

Background: Poly-L-lactic acid (PLLA) stents have broad application prospects in the treatment of cardiovascular diseases due to their excellent mechanical properties and biodegradability. However, foreign body reactions caused by stent implantation remain a bottleneck that limits the clinical application of PLLA stents. To solve this problem, the biocompatibility of PLLA stents must be urgently improved. Albumin, the most abundant inert protein in the blood, possesses the ability to modify the surface of biomaterials, mitigating foreign body reactions-a phenomenon described as the "stealth effect". In recent years, a strategy based on albumin camouflage has become a focal point in nanomedicine delivery and tissue engineering research. Therefore, albumin surface modification is anticipated to enhance the surface biological characteristics required for vascular stents. However, the therapeutic applicability of this modification has not been fully explored. Methods: Herein, a bionic albumin (PDA-BSA) coating was constructed on the surface of PLLA by a mussel-inspired surface modification technique using polydopamine (PDA) to enhance the immobilization of bovine serum albumin (BSA). Results: Surface characterization revealed that the PDA-BSA coating was successfully constructed on the surface of PLLA materials, significantly improving their hydrophilicity. Furthermore, in vivo and in vitro studies demonstrated that this PDA-BSA coating enhanced the anticoagulant properties and pro-endothelialization effects of the PLLA material surface while inhibiting the inflammatory response and neointimal hyperplasia at the implantation site. Conclusion: These findings suggest that the PDA-BSA coating provides a multifunctional biointerface for PLLA stent materials, markedly improving their biocompatibility. Further research into the diverse applications of this coating in vascular implants is warranted.

Cross-species signaling pathways analysis inspire animal model selections for drug screening and target prediction in vascular aging diseases.

Age is a significant contributing factor to the occurrence and progression of cardiovascular disease (CVD). Pharmacological treatment can effectively alleviate CVD symptoms caused by aging. However, 90% of the drugs have failed in clinics because of the loss of drug effects or the occurrence of the side effects. One of the reasons is the disparity between animal models used and the actual physiological levels in humans. Therefore, we integrated multiple datasets from single-cell and bulk-seq RNA-sequencing data in rats, monkeys, and humans to identify genes and pathways with consistent/differential expression patterns across these three species. An approach called "Cross-species signaling pathway analysis" was developed to select suitable animal models for drug screening. The effectiveness of this method was validated through the analysis of the pharmacological predictions of four known anti-vascular aging drugs used in animal/clinical experiments. The effectiveness of drugs was consistently observed between the models and clinics when they targeted pathways with the same trend in our analysis. However, drugs might have exhibited adverse effects if they targeted pathways with opposite trends between the models and the clinics. Additionally, through our approach, we discovered four targets for anti-vascular aging drugs, which were consistent with their pharmaceutical effects in literatures, showing the value of this approach. In the end, software was established to facilitate the use of "Cross-species signaling pathway analysis." In sum, our study suggests utilizing bioinformatics analysis based on disease characteristics can help in choosing more appropriate animal models.

Liver Involvement is Associated with Higher Risk of Rapidly Progressive Interstitial Lung Disease and Mortality in Anti-Melanoma Differentiation-Associated Gene 5 Antibody- Positive Dermatomyositis.

Purpose: This study aimed to assess liver involvement and investigate its correlation with rapidly progressive interstitial lung disease (RP-ILD) and mortality in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5 positive) DM patients. Patients and Methods: This retrospective study included 159 patients diagnosed with anti-MDA5 positive DM or anti-synthetase syndrome (ASyS). Clinical features and laboratory findings were compared between patients with anti-MDA5 positive DM and patients with ASyS. In the anti-MDA5 positive DM cohort, clinical features and laboratory findings between patients with liver involvement and without liver involvement were further compared. The effects of liver involvement on the overall survival (OS) and development of RP-ILD were also analyzed using Kaplan-Meier method and Cox regression analysis. Results: Levels of serum aspartate aminotransferase (AST), alanine transaminase (ALT), γ-glutamyl transferase (γGT) and alkaline phosphatase (ALP) were all significantly higher in patients with anti-MDA5 positive DM than those in patients with ASyS. In our cohort of anti-MDA5 positive DM patents, 31 patients (34.4%) were complicated with liver involvement. Survival analysis revealed that serum ferritin >1030.0 ng/mL (p<0.001), ALT >103.0 U/l (p<0.001), AST >49.0 U/l (p<0.001), γGT >82.0 U/l (p<0.001), ALP >133.0 U/l (p<0.001), lactate dehydrogenase (LDH)>474.0 U/l (p<0.001), plasma albumin (ALB) <35.7 g/l (p<0.001) and direct bilirubin (DBIL) >2.80 µmol/l (p=0.002) predicted poor prognosis. The incidence of RP-ILD increased remarkably in patients with liver involvement compared to patients without liver involvement (58.1% vs 22.0%, p=0.001). Multivariate analysis revealed that elevated serum ALT level was an independent risk factor for mortality (HR 6.0, 95% CI 2.3, 16.2, p<0.001) and RP-ILD (HR 5.9, 95% CI 2.2, 15.9, p<0.001) in anti-MDA5 positive DM patents. Conclusion: Liver involvement is common in patients with anti-MDA5 positive DM. Elevated serum ALT level was an independent risk factor for RP-ILD and mortality in patients with anti-MDA5 positive DM.

PDZ-Binding Kinase, a Novel Regulator of Vascular Remodeling in Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is high blood pressure in the lungs that originates from structural changes in small resistance arteries. A defining feature of PAH is the inappropriate remodeling of pulmonary arteries (PA) leading to right ventricle failure and death. Although treatment of PAH has improved, the long-term prognosis for patients remains poor, and more effective targets are needed. METHODS: Gene expression was analyzed by microarray, RNA sequencing, quantitative polymerase chain reaction, Western blotting, and immunostaining of lung and isolated PA in multiple mouse and rat models of pulmonary hypertension (PH) and human PAH. PH was assessed by digital ultrasound, hemodynamic measurements, and morphometry. RESULTS: Microarray analysis of the transcriptome of hypertensive rat PA identified a novel candidate, PBK (PDZ-binding kinase), that was upregulated in multiple models and species including humans. PBK is a serine/threonine kinase with important roles in cell proliferation that is minimally expressed in normal tissues but significantly increased in highly proliferative tissues. PBK was robustly upregulated in the medial layer of PA, where it overlaps with markers of smooth muscle cells. Gain-of-function approaches show that active forms of PBK increase PA smooth muscle cell proliferation, whereas silencing PBK, dominant negative PBK, and pharmacological inhibitors of PBK all reduce proliferation. Pharmacological inhibitors of PBK were effective in PH reversal strategies in both mouse and rat models, providing translational significance. In a complementary genetic approach, PBK was knocked out in rats using CRISPR/Cas9 editing, and loss of PBK prevented the development of PH. We found that PBK bound to PRC1 (protein regulator of cytokinesis 1) in PA smooth muscle cells and that multiple genes involved in cytokinesis were upregulated in experimental models of PH and human PAH. Active PBK increased PRC1 phosphorylation and supported cytokinesis in PA smooth muscle cells, whereas silencing or dominant negative PBK reduced cytokinesis and the number of cells in the G2/M phase of the cell cycle. CONCLUSIONS: PBK is a newly described target for PAH that is upregulated in proliferating PA smooth muscle cells, where it contributes to proliferation through changes in cytokinesis and cell cycle dynamics to promote medial thickening, fibrosis, increased PA resistance, elevated right ventricular systolic pressure, right ventricular remodeling, and PH.

Self-assembly of metal-polyphenolic network on biomass for enhanced organic contaminant capturing from water with a high cost-to-benefit ratio.

Nanomaterials present a vast potential as functional materials in environmental engineering. However, there are challenges with nanocomplex for recyclability, reliable/stable, and scale-up industrial integration. Here, a versatile, low-cost, stable and recycled easily metal-polyphenolic-based material carried by wood powder (bioCar-MPNs) adsorption platform was nano-engineered by a simple, fast self-assembly strategy, in which wood powder is an excellent substrate serving as a scaffold and stabilizer to prevent the nanocomplex from aggregating and is easier to recycle. Life cycle analysis highlights a green preparation process and environmental sustainability for bioCar-MPNs. The metal-polyphenolic nanocomplex coated on the wood surface in bioCar-MPNs presents a remarkable surface adsorption property (1829.4 mg/g) at a low cost (2.4 US dollars per 1000 g bioCar-MPNs) for organic dye. Quartz crystal microbalance analysis (QCM) demonstrates an existing strong affinity between polyphenols and organic dyes. Furthermore, Independent Gradient Model (IGM) and Hirshfeld surface analysis reveal the presence of the electrostatic interactions, π-π interactions, and hydrogen bonding. Meanwhile, adsorption efficiency of bioCar-MPNs maintains over 95% in the presence of co-existing ions (Na+, 0.5 M). Importantly, the reasonable utilization of biomass for water treatment can contribute to achieving the high-value and resource utilization of biomass materials.

Anti-inflammatory naphthoquinone-monoterpene adducts and neolignans from Eugenia caryophyllata.

A phytochemical investigation on the buds of edible medicinal plant, Eugenia carvophyllata, led to the discovery of seven new compounds, caryophones A-G (1-7), along with two biogenetically-related known ones, 2-methoxy-7-methyl-1,4-naphthalenedione (8) and eugenol (9). Compounds 1-3 represent the first examples of C-5-C-1' connected naphthoquinone-monoterpene adducts with a new carbon skeleton. Compounds 4-7 are a class of novel neolignans with unusual linkage patterns, in which the C-9 position of one phenylpropene unit coupled with the aromatic core of another phenylpropene unit. The chemical structures of the new compounds were determined based on extensive spectroscopic analysis, X-ray diffraction crystallography, and quantum-chemical calculation. Among the isolates, compounds (-)-2, 3, 6, and 9 showed significant in vitro inhibitory activities against respiratory syncytial virus (RSV)-induced nitric oxide (NO) production in RAW264.7 cells.

Protein phosphatase 2A anchoring disruptor gene therapy for familial dilated cardiomyopathy.

Familial dilated cardiomyopathy is a prevalent cause of heart failure that results from the mutation of genes encoding proteins of diverse function. Despite modern therapy, dilated cardiomyopathy typically has a poor outcome and is the leading cause of cardiac transplantation. The phosphatase PP2A at cardiomyocyte perinuclear mAKAPß signalosomes promotes pathological eccentric cardiac remodeling, as is characteristic of dilated cardiomyopathy. Displacement of PP2A from mAKAPß, inhibiting PP2A function in that intracellular compartment, can be achieved by expression of a mAKAPß-derived PP2A binding domain-derived peptide. To test whether PP2A anchoring disruption would be effective at preventing dilated cardiomyopathy-associated cardiac dysfunction, the adeno-associated virus gene therapy vector AAV9sc.PBD was devised to express the disrupting peptide in cardiomyocytes in vivo. Proof-of-concept is now provided that AAV9sc.PBD improves the cardiac structure and function of a cardiomyopathy mouse model involving transgenic expression of a mutant α-tropomyosin E54K Tpm1 allele, while AAV9sc.PBD has no effect on normal non-transgenic mice. At the cellular level, AAV9sc.PBD restores cardiomyocyte morphology and gene expression in the mutant Tpm1 mouse. As the mechanism of AAV9sc.PBD action suggests potential efficacy in dilated cardiomyopathy regardless of the underlying etiology, these data support the further testing of AAV9sc.PBD as a broad-based treatment for dilated cardiomyopathy.

Spontaneous rupture of neonatal hepatic hemangioma diagnosed by ultrasound: A case report.

Hepatic hemangioma is the most prevalent benign liver tumor during the fetal and neonatal period, and its rupture poses a severe threat to newborns' lives-this article presents a case involving the spontaneous rupture of a hepatic hemangioma in a neonate. Early diagnosis through ultrasound enabled prompt treatment, resulting in the patient's timely discharge.

Nacc1 Mutation in Mice Models Rare Neurodevelopmental Disorder with Underlying Synaptic Dysfunction.

A missense mutation in the transcription repressor Nucleus accumbens-associated 1 (NACC1) gene at c.892C>T (p.Arg298Trp) on chromosome 19 causes severe neurodevelopmental delay ( Schoch et al., 2017). To model this disorder, we engineered the first mouse model with the homologous mutation (Nacc1+/R284W ) and examined mice from E17.5 to 8 months. Both genders had delayed weight gain, epileptiform discharges and altered power spectral distribution in cortical electroencephalogram, behavioral seizures, and marked hindlimb clasping; females displayed thigmotaxis in an open field. In the cortex, NACC1 long isoform, which harbors the mutation, increased from 3 to 6 months, whereas the short isoform, which is not present in humans and lacks aaR284 in mice, rose steadily from postnatal day (P) 7. Nuclear NACC1 immunoreactivity increased in cortical pyramidal neurons and parvalbumin containing interneurons but not in nuclei of astrocytes or oligodendroglia. Glial fibrillary acidic protein staining in astrocytic processes was diminished. RNA-seq of P14 mutant mice cortex revealed over 1,000 differentially expressed genes (DEGs). Glial transcripts were downregulated and synaptic genes upregulated. Top gene ontology terms from upregulated DEGs relate to postsynapse and ion channel function, while downregulated DEGs enriched for terms relating to metabolic function, mitochondria, and ribosomes. Levels of synaptic proteins were changed, but number and length of synaptic contacts were unaltered at 3 months. Homozygosity worsened some phenotypes including postnatal survival, weight gain delay, and increase in nuclear NACC1. This mouse model simulates a rare form of autism and will be indispensable for assessing pathophysiology and targets for therapeutic intervention.

Endoplasmic reticulum stress regulators exhibit different prognostic, therapeutic and immune landscapes in pancreatic adenocarcinoma.

Endoplasmic reticulum stress (ERS) and unfolded protein response are the critical processes of tumour biology. However, the roles of ERS regulatory genes in pancreatic adenocarcinoma (PAAD) remain elusive. A novel ERS-related risk signature was constructed using the Lasso regression analysis. Its prognostic value, immune effect, metabolic influence, mutational feature and therapeutic correlation were comprehensively analysed through multiple bioinformatic approaches. The biofunctions of KDELR3 and YWHAZ in pancreatic cancer (PC) cells were also investigated through colony formation, Transwell assays, flow cytometric detection and a xenograft model. The upstream miRNA regulatory mechanism of KDELR3 was predicted and validated. ERS risk score was identified as an independent prognostic factor and could improve traditional prognostic model. Meanwhile, it was closely associated with metabolic reprogramming and tumour immune. High ERS risk enhanced glycolysis process and nucleotide metabolism, but was unfavourable for anti-tumour immune response. Moreover, ERS risk score could act as a potential biomarker for predicting the efficacy of ICBs. Overexpression of KDELR3 and YWHAZ stimulated the proliferation, migration and invasion of SW1990 and BxPC-3 cells. Silencing KDELR3 suppressed tumour growth in a xenograft model. miR-137 could weaken the malignant potentials of PC cells through inhibiting KDELR3 (5'-AGCAAUAA-3'). ERS risk score greatly contributed to PAAD clinical assessment. KDELR3 and YWHAZ possessed cancer-promoting capacities, showing promise as a novel treatment target.

Modified Chinese disabilities of arm, shoulder and hand tool: Validity and reliability for upper extremity injuries.

DESIGN: Clinimetric evaluation study. INTRODUCTION: The Chinese Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire has necessitated the development of a revised version to the specific needs of individuals with upper extremity injuries with the progress of times and lifestyle changes. PURPOSE OF THE STUDY: This research aimed to evaluate the reliability and validity of Modified Chinese Disability of Arm, Shoulder and Hand (MC-DASH) questionnaire in individuals with upper extremity injuries. METHODS: One hundred and one individuals with upper extremity injuries (UEI) were recruited. The function of upper extremity was measured using the electronic version of MC-DASH, and compared against the Chinese Disability of Arm, Shoulder and Hand. The MC-DASH was reassessed within three days in all individuals. We investigated the internal consistency, test-retest reliability, content validity, criterion validity, and construct validity of MC-DASH. RESULTS: The internal consistency was deemed sufficient, as indicated by a Cronbach's alpha of 0.986 and an intraclass correlation coefficient of 0.957. Moreover, the mean total scores of MC-DASH on the first-test and retest were 37.86 and 38.19, respectively (ICC: 0.957, 95 %CI: 0.937-0.971, p < 0.001). Furthermore, the MC-DASH version exhibited satisfactory content validity evidenced by its strong correlation (R= 0.903, p < 0.001) with the Chinese DASH. Three major influencing factors were identified from 37 items. The cumulative variance contribution rate of the MC-DASH questionnaire was 75.76 %, confirming its construct validity. CONCLUSION: The Modified Chinese Disability of Arm, Shoulder and Hand questionnaire has been shown to be a valid, reliable, and practical tool for use in patients with upper extremity injuries.

Identification of gastric cancer types based on hyperspectral imaging technology.

Gastric cancer is becoming the second biggest cause of death from cancer. Treatment and prognosis of different types of gastric cancer vary greatly. However, the routine pathological examination is limited to the tissue level and is easily affected by subjective factors. In our study, we examined gastric mucosal samples from 50 normal tissue and 90 cancer tissues. Hyperspectral imaging technology was used to obtain spectral information. A two-classification model for normal tissue and cancer tissue identification and a four-classification model for cancer type identification are constructed based on the improved deep residual network (IDRN). The accuracy of the two-classification model and four-classification model are 0.947 and 0.965. Hyperspectral imaging technology was used to extract molecular information to realize real-time diagnosis and accurate typing. The results show that hyperspectral imaging technique has good effect on diagnosis and type differentiation of gastric cancer, which is expected to be used in auxiliary diagnosis and treatment.

Congener Variation of Genetic Dependent-Developmental Toxicology in Two Emerging Classes of Dioxin-like Compounds.

Emerging classes of dioxin-like compounds (DLCs) like hydroxylated/methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) and polychlorinated diphenyl sulfides (PCDPSs) could lead to diverse adverse outcomes in humans and wildlife, yet knowledge gaps exist in their molecular mechanisms associated with different structures following early life environmental exposure. This study integrated a genetic knockout technique and concentration-dependent reduced zebrafish transcriptome approach (CRZT) to unravel the toxicological pathways underpinning developmental toxicity of four HO-/MeO-PBDEs and five PCDPSs at environmentally relevant doses. Generally, the dependence of aryl hydrocarbon receptor (AhR) on the embryotoxicity and transcriptomic potencies induced by the HO-PBDEs and PCDPSs varied across different congeners. The knockout of the ahr2 gene led to 1.02- to 76.48-fold decreases of DLC-induced embryotoxicities and reduced the transcriptome-based potencies ranging from 1.38 to 2124.74 folds in the CRZT test. The fold changes denoting AhR-mediated potentials significantly increased with the increasing chlorination degrees of MeO-PBDEs and PCDPSs (p < 0.05). Moreover, ahr2 knockout primarily affected the DLC-induced early molecular responses relevant to DNA damage, enzyme activation, and organ development. Our integrated approach revealed the differential role of AhR in mediating the developmental toxicity of emerging DLCs possessing varied structures at environmentally relevant doses.