A combination of radiomic features, clinic characteristics, and serum tumor biomarkers to predict the possibility of the micropapillary/solid component of lung adenocarcinoma.

BACKGROUND: Invasive lung adenocarcinoma with MPP/SOL components has a poor prognosis and often shows a tendency to recurrence and metastasis. This poor prognosis may require adjustment of treatment strategies. Preoperative identification is essential for decision-making for subsequent treatment. OBJECTIVE: This study aimed to preoperatively predict the probability of MPP/SOL components in lung adenocarcinomas by a comprehensive model that includes radiomics features, clinical characteristics, and serum tumor biomarkers. DESIGN: A retrospective case control, diagnostic accuracy study. METHODS: This study retrospectively recruited 273 patients (males: females, 130: 143; mean age ± standard deviation, 63.29 ± 10.03 years; range 21-83 years) who underwent resection of invasive lung adenocarcinoma. Sixty-one patients (22.3%) were diagnosed with lung adenocarcinoma with MPP/SOL components. Radiomic features were extracted from CT before surgery. Clinical, radiomic, and combined models were developed using the logistic regression algorithm. The clinical and radiomic signatures were integrated into a nomogram. The diagnostic performance of the models was evaluated using the area under the curve (AUC). Studies were scored according to the Radiomics Quality Score and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines. RESULTS: The radiomics model achieved the best AUC values of 0.858 and 0.822 in the training and test cohort, respectively. Tumor size (T_size), solid tumor size (ST_size), consolidation-to-tumor ratio (CTR), years of smoking, CYFRA 21-1, and squamous cell carcinoma antigen were used to construct the clinical model. The clinical model achieved AUC values of 0.741 and 0.705 in the training and test cohort, respectively. The nomogram showed higher AUCs of 0.894 and 0.843 in the training and test cohort, respectively. CONCLUSION: This study has developed and validated a combined nomogram, a visual tool that integrates CT radiomics features with clinical indicators and serum tumor biomarkers. This innovative model facilitates the differentiation of micropapillary or solid components within lung adenocarcinoma and achieves a higher AUC, indicating superior predictive accuracy.

A new tool to predict aggressive lung cancer types before surgeryWe developed a tool to help doctors determine whether lung cancer is one of the more dangerous types, called micropapillary (MPP) or solid (SOL) patterns, before surgery. These patterns can be more harmful and spread quickly, so knowing they are there can help doctors plan the best treatment. We looked at the cases of 273 lung cancer patients who had surgery and found that 61 of them had these aggressive cancer types. To predict these patterns, we used a computer process known as logistic regression, analyzing CT scan details, health information, and blood tests for cancer markers. Based on CT scans, our tool was very good at predicting whether these patterns were present in two patient groups. However, predictions using only basic health information like the size of the tumor and whether the patient smoked needed to be more accurate. We found a way to make our predictions even better. Combining all information into one chart, known as a nomogram, significantly improved our ability to predict these dangerous cancer patterns. This combined chart could be a big help for doctors. It gives them a clearer picture of the cancer's aggressiveness before surgery, which can guide them to choose the best treatment options. This approach aims to offer a better understanding of the tumor, leading to more tailored and effective treatments for patients facing lung cancer.

Potential Effects of Traditional Chinese Medicine in Anti-Aging and Aging-Related Diseases: Current Evidence and Perspectives.

Aging and aging-related diseases present a global public health problem. Therefore, the development of efficient anti-aging drugs has become an important area of research. Traditional Chinese medicine is an important complementary and alternative branch of aging-related diseases therapy. Recently, a growing number of studies have revealed that traditional Chinese medicine has a certain delaying effect on the progression of aging and aging-related diseases. Here, we review the progress in research into using traditional Chinese medicine for aging and aging-related diseases (including neurodegenerative diseases, cardiovascular diseases, diabetes, and cancer). Furthermore, we summarize the potential mechanisms of action of traditional Chinese medicine and provide references for further studies on aging and aging-related diseases.

Identification of naphthalimide-derivatives as novel PBD-targeted polo-like kinase 1 inhibitors with efficacy in drug-resistant lung cancer cells.

Targeting polo-box domain (PBD) small molecule for polo-like kinase 1 (PLK1) inhibition is a viable alternative to target kinase domain (KD), which could avoid pan-selectivity and dose-limiting toxicity of ATP-competitive inhibitors. However, their efficacy in these settings is still low and inaccessible to clinical requirement. Herein, we utilized a structure-based high-throughput virtual screen to find novel chemical scaffold capable of inhibiting PLK1 via targeting PBD and identified an initial hit molecule compound 1a. Based on the lead compound 1a, a structural optimization approach was carried out and several series of derivatives with naphthalimide structural motif were synthesized. Compound 4Bb was identified as a new potent PLK1 inhibitor with a KD value of 0.29 µM. 4Bb could target PLK1 PBD to inhibit PLK1 activity and subsequently suppress the interaction of PLK1 with protein regulator of cytokinesis 1 (PRC1), finally leading to mitotic catastrophe in drug-resistant lung cancer cells. Furthermore, 4Bb could undergo nucleophilic substitution with the thiol group of glutathione (GSH) to disturb the redox homeostasis through exhausting GSH. By regulating cell cycle machinery and increasing cellular oxidative stress, 4Bb exhibited potent cytotoxicity to multiple cancer cells and drug-resistant cancer cells. Subcutaneous and oral administration of 4Bb could effectively inhibit the growth of drug-resistant tumors in vivo, doubling the survival time of tumor bearing mice without side effects in normal tissues. Thus, our study offers an orally-available, structurally-novel PLK1 inhibitor for drug-resistant lung cancer therapy.

The efficacy and safety of fexuprazan in treating erosive esophagitis: a phase III, randomized, double-blind, multicenter study.

BACKGROUND AND AIM: Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). This study aimed to explore the noninferior efficacy and safety of fexuprazan to esomeprazole in treating erosive esophagitis (EE). METHODS: This was a phase III, randomized, double-blind multicenter study. Patients with endoscopically confirmed EE were randomized to receive fexuprazan 40 mg or esomeprazole 40 mg once a daily for 4-8 weeks. The healing rates of EE, symptom response, GERD-health-related quality life (GERD-HRQL), and treatment-emergent adverse events (TEAEs) were compared between fexuprazan group and esomeprazole group. RESULTS: A total of 332 subjects were included in full analysis set (FAS) and 311 in per-protocol set (PPS). The healing rates of fexuprazan and esomeprazole groups at 8 weeks were 88.5% (146/165) and 89.0% (145/163), respectively, in FAS and 97.3% (145/149) and 97.9% (143/146), respectively, in PPS. Noninferiority of fexuprazan compared with esomeprazole according to EE healing rates at 8 weeks was demonstrated in both FAS and PPS analysis. No significant difference was found between groups in EE healing rates at 4 weeks, symptom responses, and changes of GERD-HRQL. The incidence of drug-related AEs was 19.4% (32/165) in fexuprazan arm and 19.6% (32/163) in esomeprazole arm. CONCLUSION: This study demonstrated noninferior efficacy of fexuprazan to esomeprazole in treating EE. The incidence of TEAEs was similar between fexuprazan and esomeprazole. Trial registration number NCT05813561.

Post-translational protein lactylation modification in health and diseases: a double-edged sword.

As more is learned about lactate, it acts as both a product and a substrate and functions as a shuttle system between different cell populations to provide the energy for sustaining tumor growth and proliferation. Recent discoveries of protein lactylation modification mediated by lactate play an increasingly significant role in human health (e.g., neural and osteogenic differentiation and maturation) and diseases (e.g., tumors, fibrosis and inflammation, etc.). These views are critically significant and first described in detail in this review. Hence, here, we focused on a new target, protein lactylation, which may be a "double-edged sword" of human health and diseases. The main purpose of this review was to describe how protein lactylation acts in multiple physiological and pathological processes and their potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. Our work aims to provide new ideas for treating different diseases and accelerate translation from bench to bedside.

Insight into increased risk of portal vein thrombosis in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the leading chronic liver diseases with increased morbidity and mortality rates for extrahepatic diseases (including cardiovascular disease, portal vein thrombosis, etc.). There is an increased risk of thrombosis in both the portal and systemic circulation in patients with NAFLD, independent of traditional liver cirrhosis. However, increased portal pressure, the most critical factor, is frequently observed in NAFLD patients, predisposing them to portal vein thrombosis (PVT). It has been reported that there is an 8.5% incidence of PVT among patients with non-cirrhotic NAFLD in a prospective cohort study. Based on the prothrombotic status of NAFLD itself, patients combined with cirrhosis may accelerate the development of PVT and lead to a poor prognosis. Moreover, PVT has been shown to complicate the procedure and adversely affect the outcome during liver transplantation surgery. NAFLD is in a prothrombotic state, and its underlying mechanisms have not been fully understood so far. Particularly noteworthy is that gastroenterologists currently overlook the higher risk of PVT in NAFLD. We investigate the pathogenesis of NAFLD complicated with PVT from the perspective of primary, secondary, and tertiary hemostasis, and also summarize relevant studies in humans. Some treatment options that may affect NAFLD and its PVT are also explored to improve patient-oriented outcomes.

Clinical significance of a novel uric-acid-based biomarker in the prediction of disease activity and response to infliximab therapy in Crohn's disease.

OBJECTIVES: Crohn's disease (CD) is an inflammatory bowel disease marked by a chronic remission-relapse cycle. Biomarkers are critical to reflect the bowel wall inflammation and detect the treatment response. Here, we investigated a new index-the ratio of neutrophil to uric acid (NUR)-as a predictor of CD activity and responses to infliximab (IFX) treatment. METHODS: Clinical and laboratory data were retrieved for CD patients and healthy control subjects from an electronic medical records database. Disease and endoscopic activity were determined using the Crohn's Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn's Disease (SES-CD), respectively. RESULTS: We found firstly that NUR was remarkably higher in CD patients (n = 162) than controls (n = 170) (0.27 ± 0.10 vs. 0.19 ± 0.04, p < .0001). NUR was positively correlated with disease activity and prior to treatment, it was lower in CD patients who responded to IFX than in those who did not (0.25 ± 0.07 vs. 0.38 ± 0.12, p = .0019). Pre-treatment NUR was effective in predicting the patients' responses to IFX (AUC = 0.8469, p = .0034). CONCLUSION: The results of this study support the utility of NUR for detecting CD activity and predicting the response to IFX treatment.

Artificial intelligence empowers the second-observer strategy for colonoscopy: a randomized clinical trial.

Background: In colonoscopy screening for colorectal cancer, human vision limitations may lead to higher miss rate of lesions; artificial intelligence (AI) assistance has been demonstrated to improve polyp detection. However, there still lacks direct evidence to demonstrate whether AI is superior to trainees or experienced nurses as a second observer to increase adenoma detection during colonoscopy. In this study, we aimed to compare the effectiveness of assistance from AI and human observer during colonoscopy. Methods: A prospective multicenter randomized study was conducted from 2 September 2019 to 29 May 2020 at four endoscopy centers in China. Eligible patients were randomized to either computer-aided detection (CADe)-assisted group or observer-assisted group. The primary outcome was adenoma per colonoscopy (APC). Secondary outcomes included polyp per colonoscopy (PPC), adenoma detection rate (ADR), and polyp detection rate (PDR). We compared continuous variables and categorical variables by using R studio (version 3.4.4). Results: A total of 1,261 (636 in the CADe-assisted group and 625 in the observer-assisted group) eligible patients were analysed. APC (0.42 vs 0.35, P = 0.034), PPC (1.13 vs 0.81, P < 0.001), PDR (47.5% vs 37.4%, P < 0.001), ADR (25.8% vs 24.0%, P = 0.464), the number of detected sessile polyps (683 vs 464, P < 0.001), and sessile adenomas (244 vs 182, P = 0.005) were significantly higher in the CADe-assisted group than in the observer-assisted group. False detections of the CADe system were lower than those of the human observer (122 vs 191, P < 0.001). Conclusions: Compared with the human observer, the CADe system may improve the clinical outcome of colonoscopy and reduce disturbance to routine practice (Chictr.org.cn No.: ChiCTR1900025235).

Adenosine kinase promotes post-infarction cardiac repair by epigenetically maintaining reparative macrophage phenotype.

Pro-inflammatory and reparative macrophages are crucial in clearing necrotic myocardium and promoting cardiac repair after myocardial infarction (MI), respectively. Extracellular adenosine has been demonstrated to modulate macrophage polarization through adenosine receptors. However, the role of intracellular adenosine in macrophage polarization has not been explored and adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels. Here, we aimed to elucidate the role of ADK in macrophage polarization and its subsequent impact on MI. We demonstrated that ADK was upregulated in bone marrow-derived macrophages (BMDMs) after IL-4 treatment and was highly expressed in the infarct area at day 7 post-MI, especially in macrophages. Compared with wild-type mice, myeloid-specific Adk knockout mice showed increased infarct size, limited myofibroblast differentiation, reduced collagen deposition and more severe cardiac dysfunction after MI, which was related to impaired reparative macrophage phenotype in MI tissue. We found that ADK deletion or inhibition significantly decreased the expression of reparative genes, such as Arg1, Ym1, Fizz1, and Cd206 in BMDMs after IL-4 treatment. The increased intracellular adenosine due to Adk deletion inhibited transmethylation reactions and decreased the trimethylation of H3K4 in BMDMs after IL-4 treatment. Mechanistically, we demonstrated that Adk deletion suppressed reparative macrophage phenotype through decreased IRF4 expression, which resulted from reduced levels of H3K4me3 on the Irf4 promotor. Together, our study reveals that ADK exerts a protective effect against MI by promoting reparative macrophage polarization through epigenetic mechanisms.

Traditional Chinese Medicine in Treatment of COVID-19 and Viral Disease: Efficacies and Clinical Evidence.

Coronavirus disease 2019 (COVID-19) remains an uncontained, worldwide pandemic. While battling the disease in China, the Chinese government has actively promoted the use of traditional Chinese medicine, and many studies have been conducted to determine the efficacy of traditional Chinese medicine for treating COVID-19. The present review discusses the effectiveness and safety of traditional Chinese medicine in curing COVID-19 and provides clinical evidence from all confirmed cases in China. Applications of traditional Chinese medicine and specific recipes for treating other viral infections, such as those caused by severe acute respiratory syndrome coronavirus and influenza A viruses (including H1N1), are also discussed. Studies have reported that traditional Chinese medicine treatment plays a significant role in improving clinical symptoms. Therefore, further investigation may be of high translational value in revealing novel targeted therapies for COVID-19.

Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer's disease.

Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer's disease (AD), but little is known about the molecular mechanisms underlying this regional vulnerability. Here we utilize the 10 × Visium platform to define the spatial transcriptomic profile in both AD and control (CT) MTG. We identify unique marker genes for cortical layers and the white matter, and layer-specific differentially expressed genes (DEGs) in human AD compared to CT. Deconvolution of the Visium spots showcases the significant difference in particular cell types among cortical layers and the white matter. Gene co-expression analyses reveal eight gene modules, four of which have significantly altered co-expression patterns in the presence of AD pathology. The co-expression patterns of hub genes and enriched pathways in the presence of AD pathology indicate an important role of cell-cell-communications among microglia, oligodendrocytes, astrocytes, and neurons, which may contribute to the cellular and regional vulnerability in early AD. Using single-molecule fluorescent in situ hybridization, we validated the cell-type-specific expression of three novel DEGs (e.g., KIF5A, PAQR6, and SLC1A3) and eleven previously reported DEGs associated with AD pathology (i.e., amyloid beta plaques and intraneuronal neurofibrillary tangles or neuropil threads) at the single cell level. Our results may contribute to the understanding of the complex architecture and neuronal and glial response to AD pathology of this vulnerable brain region.

Small-molecule MX-C2/3 suppresses non-small cell lung cancer progression via p53 activation.

p53 inactivation is a common feature in non-small cell lung cancer (NSCLC) resulting in NSCLC malignant transformation. Targeting serine 392 phosphorylation to restore p53 anticancer activity has proven to be an effective therapeutic strategy against NSCLC. A synthetic p53 activator, NA-17, has been developed that shows promise in preclinical models of NSCLC. However, NA-17 exhibits limited therapeutic efficacy in oncogene-driven tumors as well as relatively high toxicity to normal cells. It is possible that high efficiency and low toxicity p53 activators can be obtained by optimizing the leading molecule. Here, we performed high-throughput screening of compounds optimized based on NA-17 to identify new p53 activators. Two promising candidates named MX-C2 and MX-C3 were identified, both exhibited considerable therapeutic efficacy in oncogene-driven tumor models. Similar to NA-17, MX-C2/3 induced p53 activation via phosphorylating serine-392 without DNA damage. Both compounds showed broad antitumor activity in NSCLC cells and limited toxicity in normal cell lines. Moreover, MX-C2/3 suppressed tumor progression by arresting the cell cycle at G2/M phase, exhibiting a different mechanism of cell cycle arrest than NA-17. In addition, MX-C2/3 promoted the enrichment of p-p53 (s392) in mitochondria, leading to the conformational activation of Bak for cell apoptosis, which is consistent with NA-17. Finally, we demonstrated that MX-C2 significantly inhibited tumor growth without obvious systemic toxicity in oncogene-driven HCC-827 xenograft models. Collectively, we report two p53 activators with high-efficiency and low-toxicity that target p53 serine 392 phosphorylation for anticancer translational investigation.

CO2 Is Beneficial to Gut Microbiota Homeostasis during Colonoscopy: Randomized Controlled Trial.

BACKGROUND: Many studies have reported minor complications and disturbance of the gut microbiota after colonoscopy. Compared with air, carbon dioxide (CO2) insufflation could decrease minor complications, but its impact on gut microbiota remains unknown. METHODS: Thirty-eight healthy subjects were assessed and twenty were randomized to receive either CO2 or air insufflation during colonoscopy. Neither the participants nor the staff involved in the follow-up knew which gas was used. Minor complications were assessed using symptom scores. Fecal samples were collected at eight time-points for microbiome analysis by full-length 16S rRNA gene amplicon analysis. RESULTS: Baseline characteristics were similar in both groups. The recovery of minor complications after colonoscopy was faster in the CO2 group (the day of the colonoscopy) than in the air group (the day after the colonoscopy). There was no significant reduction in alpha diversity (species richness) of the first stool after colonoscopy in the CO2 group (115.0 ± 32.81 vs. 97.4 ± 42.31, p = 0.28) compared with the air group (123.8 ± 37.25 vs. 84.8 ± 31.67, p = 0.04). However, there were no differences in beta diversity between the groups. Linear discriminant analysis effect size (LEfSe) analysis indicated that anaerobic probiotics such as Bacteroides caccae, Bacteroides finegoldii and Bacteroides thetaiotaomicron were more abundant in the CO2 group than in the air group within 14 days after colonoscopy. On the contrary, the content of Escherichiacoli, Ruminococcus torques and Ruminococcus guavus was higher in the air group. CONCLUSIONS: CO2 is beneficial to gut microbiota homeostasis during colonoscopy in healthy subjects. The effects in patients with different diseases need to be further studied.

Integrated traditional Chinese medicine intervention for delaying HIV morbidity: study protocol for a multicentre randomised controlled trial.

BACKGROUND: Acquired immune deficiency syndrome is caused by humans and is high worldwide. Active antiretroviral therapy emerged in the late 1990s and is effective against AIDS. However, despite the extensive research on AIDS, there is still no vaccine or cure. The benefits of traditional Chinese medicine (TCM) for AIDS are increasingly recognised, especially by patients with asymptomatic HIV infection. METHODS/DESIGN: The proposed trial will enrol 216 eligible patients who will be randomised into treatment and control groups. After 72 weeks of intervention, the efficacy and safety of TCM for patients with AIDS will be assessed. The variables that will be measured include clinical symptoms, TCM syndromes, viral load, immunological indicators, inflammatory factors, quality of life, patient-reported outcomes and safety assessment. DISCUSSION: The study aim to compare the effectiveness and safety of TCM for asymptomatic AIDS and explore its potential underlying mechanism. Additionally, the findings will provide a reference for the use of TCM to delay the onset and control the progression of HIV/AIDS. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800018365. Registered on 13 September 2018.

Natural high-avidity T-cell receptor efficiently mediates regression of cancer/testis antigen 83 positive common solid cancers.

BACKGROUND: T-cell receptor-engineered T cells (TCR-Ts) have achieved encouraging success in anticancer clinical trials. The antigenic targets, however, were primarily focused on human leukocyte antigen (HLA) A*02:01 restricted epitopes from a few cancer/testis antigens (CTAs) which are not widely expressed in common solid cancers; the tested T-cell receptors (TCRs) were frequently from tumor-infiltrating lymphocytes of old patients and were not assured to have higher avidity. Here, we propose the isolation of high-avidity TCRs against CTAs that are frequently expressed in common solid cancers. METHODS: We selected the CT83 protein, which is frequently expressed in common solid cancers, as a model antigen for screening of its specific TCR. The predicted CT83 epitopes with strong or weak binding to HLA-I molecules, popular in the Chinese population, were integrated into three synthetic long peptides. CT83 reactive CD8+ T cells were stimulated with peptide-loaded dendritic cells (DCs) and sorted using the CD137 biomarker for single-cell sequencing to obtain the paired TCRαß sequence. The higher frequency TCRs were reconstructed for characterization of the CT83 epitope and for assessment of in vitro and in vivo antitumor activities. RESULTS: CT83 reactive T cells from young healthy donors (YHDs) were generated by repeated stimulation with DCs and peptides. The single-cell TCR sequencing results of reactive T cells indicated that a single TCR clonotype dominated the paired TCRs. T cells engineered with this dominant TCR led to HLA-A*11:01-restricted recognition of the CT8314-22 epitope, with higher avidity. Functional assays showed powerful cytotoxicity in vitro against the targets of several CT83-positive solid cancer cell lines. Furthermore, TCR-Ts showed therapeutic efficacy in three xenograft solid tumor models. The meta-analysis of gene expression of 92 CTAs indicated that most CTAs did not or at low levels in the thymus, which suggested that those CTAs may experience incomplete thymic central tolerance. CONCLUSIONS: High-avidity TCR against CT83 could be isolated from YHDs and efficiently mediate regression of well-established xenograft common solid tumors. The high-avidity TCR repertoire in the peripheral blood of some donors for CT83 and other CTAs provides the basis for the efficient isolation of high-avidity TCRs to target numerous solid cancers.

Therapeutic restoring p53 function with small molecule for oncogene-driven non-small cell lung cancer by targeting serine 392 phosphorylation.

p53 inactivation by disabling its function is a hallmark in lung carcinomas, emphasizing the significance of restoring p53 function as an attractive therapeutic strategy. However, the clinical efficacy of existing p53 activators is limited due to their inability to effectively activate p53 within the tumors. Here, we established a p53 activator screening assay in EGFR-driven lung cancer cells and identified a small molecular, MX-C4, as a promising candidate. Using high throughput compound screening and combination analyses, we found that MX-C4 effectively promoted the phosphorylation of p53 at serine-392 (s392). It exhibited potent antitumor activity in a variety of cancer cell lines, but only limited toxicity to NCI-H1299 (p53-null) and normal cell lines such as LX2 and HL-7702. Overexpression of p53 in NCI-H1299 cells by a p53 expressing virus vector sensitized cells to MX-C4 treatment, suggesting a p53-dependent anticancer activity. Furthermore, we demonstrated that MX-C4 bound to p53 and exerted its anticancer activity through cell cycle arrest at G2/M phase and apoptosis induction. Mechanistic study indicated that p53 activation regulated cell cycle and cell survival related targets at protein levels. Moreover, p53 activation raised phospho-p53 translocation to mitochondria and subsequently reorganized the Bcl-xl-Bak complex, thus conformationally activating Bak and inducing apoptosis. It is noteworthy that MX-C4 could effectively activate p53 within the tumors in EGFR-driven xenograft models, where tumor was significantly suppressed without obvious toxicity. Our study identified a promising candidate for lung cancer therapy by restoring p53 function.

Photoluminescent carbon dots (PCDs) from sour apple: a biocompatible nanomaterial for preventing UHMWPE wear-particle induced osteolysis via modulating Chemerin/ChemR23 and SIRT1 signaling pathway and its bioimaging application.

Photoluminescent nanomaterials have been widely employed in several biological applications both in vitro and in vivo. For the first time, we report a novel application of sour apple-derived photoluminescent carbon dots (PCDs) for reducing ultra-high molecular weight polyethylene (UHMWPE) wear particle-induced osteolysis using mouse calvarial model. Generally, aseptic prosthetic loosening seems to be a significant postoperative problem for artificial joints replacement, which is mainly contributed by UHMWPE-induced osteolysis. Hence, inhibiting osteoclastic bone-resorption could minimize UHMWPE-induced osteolysis for implant loosening. Prior to osteolysis studies, the prepared sour apple-derived PCDs were employed for bioimaging application. As expected, the prepared PCDs effectively inhibited the UHMWPE particle-induced osteoclastogenesis in vitro. The PCDs treatment effectively inhibited the UHMWPE-induced osteoclast differentiation, F-actin ring pattern, and bone resorption in vitro. Also, the PCDs reduced the UHMWPE-induced ROS stress as well as the expression level of pro-inflammatory cytokines, including TNF-α, IL-1, IL-6, and IL-8. Further, the qPCR and western blot results hypothesized that PCDs inhibited the UHMWPE wear particle-induced osteolysis through suppressing chemerin/ChemR23 signaling and NFATc1 pathway, along with upregulation of SIRT1 expression. Overall, these findings suggest that the synthesized PCDs could be a potential therapeutic material for minimizing UHMWPE particle-induced periprosthetic osteolysis to avoid postoperative complications.

A Novel Neutrophil-Based Biomarker to Monitor Disease Activity and Predict Response to Infliximab Therapy in Patients With Ulcerative Colitis.

Background: Ulcerative colitis (UC) is characterized by refractory and recurrent mucosal inflammation, leading to a substantial healthcare burden. Diagnostic biomarkers predicting disease activity and treatment response remain elusive. To evaluate the application value of a novel neutrophil-based index (the neutrophil-to-albumin ratio, NAR) as a novel diagnostic biomarker in patients with UC and a predictive marker for disease activity and response to infliximab (IFX) therapy. Methods: Clinical characteristics and laboratory parameters of enrolled subjects (patients with UC and healthy controls) were retrieved from the electronic medical record database of our hospital. Serum cytokine and fecal calprotectin levels were measured by enzyme-linked immunosorbent assay (ELISA). Mucosal expression levels of inflammatory agents were measured by quantitative RT-PCR (qRT-PCR). Results: We found that NAR, which had not yet been explored in UC, was significantly increased in patients with UC (n = 146) compared to that in controls (n = 133) (1.95 ± 0.41 vs. 1.41 ± 0.23, p < 0.0001). NAR showed a positive association with the disease activity and inflammatory load in patients with UC. Pre-treatment NAR was significantly lower in IFX responders than that in non-responders (2.18 ± 0.29 vs. 2.44 ± 0.21, p = 0.0118), showing a significant ability to discriminate initial responders from primary non-responders to IFX induction therapy (AUC = 0.7866, p = 0.0076). Moreover, pre-treatment NAR predicted postinduction serum IFX trough level. Conclusion: Our study provides evidences to utilize NAR in the diagnosis, activity monitoring, and IFX response prediction in patients with UC.

Wolframin is a novel regulator of tau pathology and neurodegeneration.

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD.