Cognitive Training for Reduction of Delirium in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

IMPORTANCE: Postoperative delirium is a common and impactful neuropsychiatric complication in patients undergoing coronary artery bypass grafting surgery. Cognitive training may enhance cognitive reserve, thereby reducing postoperative delirium. OBJECTIVE: To determine whether preoperative cognitive training reduces the incidence of delirium in patients undergoing coronary artery bypass grafting. DESIGN, SETTING, and PARTICIPANTS: This prospective, single-blind, randomized clinical trial was conducted at 3 university teaching hospitals in southeastern China with enrollment between April 2022 and May 2023. Eligible participants included those scheduled for elective coronary artery bypass grafting who consented and enrolled at least 10 days before surgery. INTERVENTIONS: Participating patients were randomly assigned 1:1, stratified by site, to either routine care or cognitive training, which included substantial practice with online tasks designed to enhance cognitive functions including memory, imagination, reasoning, reaction time, attention, and processing speed. MAIN OUTCOMES AND MEASURES: The primary outcome was occurrence of delirium during postoperative days 1 to 7 or until hospital discharge, diagnosed using the Confusion Assessment Method or the Confusion Assessment Method for Intensive Care Units. Secondary outcomes were postoperative cognitive dysfunction, delirium characteristics, and all-cause mortality within 30 days following the operation. RESULTS: A total of 218 patients were randomized and 208 (median [IQR] age, 66 [58-70] years; 64 female [30.8%] and 144 male [69.2%]) were included in final analysis, with 102 randomized to cognitive training and 106 randomized to routine care. Of all participants, 95 (45.7%) had only a primary school education and 54 (26.0%) had finished high school. In the cognitive training group, 28 participants (27.5%) developed delirium compared with 46 participants (43.4%) randomized to routine care. Those receiving cognitive training were 57% less likely to develop delirium compared with those receiving routine care (adjusted odds ratio [aOR] 0.43; 95% CI, 0.23-0.77; P = .007). Significant differences were observed in the incidence of severe delirium (aOR, 0.46; 95% CI, 0.25-0.82; P = .01), median (IQR) duration of delirium (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .008), and median (IQR) number of delirium-positive days (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .007). No other secondary outcomes differed significantly. CONCLUSIONS AND RELEVANCE: In this randomized trial of 208 patients undergoing coronary artery bypass grafting, preoperative cognitive training reduced the incidence of postoperative delirium. However, our primary analysis was based on fewer than 75 events and should therefore be considered exploratory and a basis for future larger trials. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200058243.

Knockdown of HMGB1 inhibits the crosstalk between oral squamous cell carcinoma cells and tumor-associated macrophages.

Tumor-associated macrophages (TAMs), the major component of the tumor microenvironment (TME), play distinctly different roles in different tumors. High mobility group box 1 (HMGB1), a nonhistone protein in the nucleus, can perform functions during inflammation and cancers. However, the role of HMGB1 in the crosstalk between oral squamous cell carcinoma (OSCC) cells and TAMs remains unclear. Here, we established a coculture system of TAMs and OSCC cells to explore the bidirectional effect and potential mechanism of HMGB1 in OSCC cell-TAM interactions. Our results showed that HMGB1 was significantly upregulated in OSCC tissues and positively associated with tumor progression, immune cell infiltration and macrophage polarization. Then, knocking down HMGB1 in OSCC cells inhibited the recruitment and polarization of cocultured TAMs. Moreover, the knockdown of HMGB1 in macrophages not only suppressed polarization, but also inhibited cocultured OSCC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, macrophages secreted higher levels of HMGB1 than OSCC cells, and dampening endogenous HMGB1 reduced HMGB1 secretion. Both OSCC cell-generated and macrophage-endogenous HMGB1 may regulate TAM polarization by promoting receptor TLR4 expression and NF-κB/p65 activation and enhancing IL-10/TGF-ß expression. HMGB1 in OSCC cells may regulate macrophage recruitment via IL-6/STAT3. In addition, TAM-derived HMGB1 may affect aggressive phenotypes of cocultured OSCC cells by regulating the immunosuppressive microenvironment through the IL-6/STAT3/PD-L1 and IL-6/NF-κB/MMP-9 pathways. In conclusion, HMGB1 may regulate the crosstalk between OSCC cells and TAMs, including modulating macrophage polarization and attraction, enhancing cytokine secretion, and remodeling and creating an immunosuppressive TME to further affect OSCC progression.

Secretome of human umbilical cord mesenchymal stem cell maintains skin homeostasis by regulating multiple skin physiological function.

Skin is the largest organ in the body and the first defense to resist various diseases and external stimuli that easily cause infection and inflammation. Aseptic inflammation, barrier damage, and foreign aid pressure induce the destruction and damage to the skin microenvironment. Subsequently, it destroys the skin's physiological function, leading to the maintenance and circulation of steady-state imbalance and aggravating the process of skin disorders. Our study evaluated the therapeutic potential of the secretome of human umbilical cord mesenchymal stem cells (UC-CM) for dermatological diseases in adult human skin cells, ex vivo skin tissue, and a 3D skin model. Our data suggested several advantages of UC-CM due to (1) their low cytotoxicity and sensitization properties; (2) their anti-inflammatory capacity for treating inflammatory chronic cutaneous diseases; (3) their enhanced capacity of the skin barrier for treating abnormal barrier metabolism; and (4) their positive impact on restoring skin homeostasis due to effective regulation ability of skin physiological function including cell apoptosis, detoxification, and anti-aging. We thus envisage that the possibility of harnessing the therapeutic potential of UC-CM might benefit patients suffering from inflammatory skin disorders such as atopic dermatitis, acne, and psoriasis.

The therapeutic inhibition of topoisomerase inhibitor and crizotinib combination in EGFR wild and mutant lung cancer cells.

Combination therapy can enhance therapeutic effect by activation of multiple downstream pathways. The present study was aimed to investigate a novel strategy to successfully inhibit the EGFR pathway in EGFR wild and mutated types lung cancer by combination method. Topotecan (TPT) and crizotinib (CRI) were used to evaluate the effect on EGFR-wild, primary and secondary mutant non-small cell lung cancer (NSCLC) cell lines (H1299, HCC827 and H1975 cells). The combination group significantly inhibited the lung cancer growth with combination index (CI) < 1, and they synergistically induced the cell apoptosis by disrupting the balance of Bax and Bcl-xL, loss of mitochondrial membrane potential (MMP), and accumulation of reactive oxygen species (ROS). In addition, EGFR downstream signaling pathways including AKT, ERK, JNK, and p38 MAPK were regulated when treated with the combination regimen. Meanwhile, a nano-liposomes co-loaded CRI and TPT was prepared and exhibited strong cytotoxicity to the lung cancer cells especially H1299 and H1975 cells. The animal study confirmed the synergy between TPT and CRI from the results that they remarkable repressed the tumor growth with the inhibition rate of 81.32 %. The nano-liposomes of TPT and CRI achieved an optimal curative effect (71.52 % of inhibition rate) at 2 mg/kg. Moreover, the synergistic mechanism of the combination was consistent with the in vitro cell experiment by regulating EGFR signaling pathways. Collectively, we proposed a preclinical rationale and potential formulation for the use of a combination therapy consisting of the topoisomerase inhibitor TPT and the ALK-TKI CRI for treatment of lung cancers.

Chemoprevention of 4NQO-Induced Mouse Tongue Carcinogenesis by AKT Inhibitor through the MMP-9/RhoC Signaling Pathway and Autophagy.

Oral cancer (OC), the most common cancer in the head and neck, which has a poor prognosis, histopathologically follows a stepwise pattern of hyperplasia, dysplasia, and cancer. Blocking the progression of OC in the precancer stage could greatly improve the survival and cure rates. AKT protein plays a critical role in the signal transduction of cancer cells, and we found that AKT was overexpressed in human OC samples through analysis of TCGA database. Therefore, this study is aimed at investigating the chemopreventive effect of an AKT inhibitor (MK2206 2HCl) on OC. In vivo, we established a 4-nitroquinoline-1-oxide- (4NQO-) induced mouse tongue carcinogenesis model to investigate the potential chemopreventive effect of MK2206 2HCl on mouse OC resulting from 4NQO. The results showed that MK2206 2HCl could significantly reduce the incidence rate and growth of OC, inhibit the transformation of dysplasia to cancer in the 4NQO-induced mouse tongue carcinogenesis model, and simultaneously markedly suppress cell proliferation, angiogenesis, and mast cell (MC) infiltration in 4NQO-induced mouse tongue cancers. In vitro, our results revealed that MK2206 2HCl could also inhibit oral squamous cell carcinoma (OSCC) cell malignant biological behaviors, including cell proliferation, colony formation, cell invasion, and migration, while promoting apoptosis. Mechanistic studies revealed that MK2206 2HCl suppressed matrix metalloproteinase 9 (MMP-9) and RhoC expression and promoted autophagy gene LC3 II expression. In summary, our findings demonstrated the chemopreventive effect of MK2206 2HCl on the 4NQO-induced mouse tongue carcinogenesis model, which likely has an underlying mechanism mediated by the MMP-9/RhoC signaling pathway and autophagy.

Bedside echocardiography for diagnosis of intracardiac cement embolism after percutaneous vertebroplasty: A case report.

This case report is to demonstrate that a female patient had suddenly become unconscious 14 hours after percutaneous vertebroplasty. Bedside echocardiogram showed that the patient had a strong echo in the right heart with a small amount of pericardial effusion. CT showed high density in the distal branches of both pulmonary arteries and a high density in the right heart. With the help of that, the doctor made the diagnosis of intracardiac cement embolism in a very short time. The bone cement in the heart was removed under emergency cardiopulmonary bypass, then the patient was discharged smoothly.

MMP-9 Knockdown Inhibits Oral Squamous Cell Carcinoma Lymph Node Metastasis in the Nude Mouse Tongue-Xenografted Model through the RhoC/Src Pathway.

Oral squamous cell carcinoma (OSCC) is one of the most common types of cancers in developing countries. A major contributor to the high mortality rate of OSCC is the tendency of oral cancer cells to metastasize to lymph nodes around the head and neck during the early stages of cancer development. Matrix metalloproteinase 9 (MMP-9), an endopeptidase, can degrade the extracellular matrix and basement membrane and plays a key role in tumor invasion and metastasis. In vitro, cell migration ability was conducted by scratching assays. We also investigated the interaction abilities between OSCC cells and vascular endothelial cells (ECs) by an adhesion assay and transendothelial migration assay. And we established a BALB/c nude mouse tongue-xenografted metastasis model to investigate the role of MMP-9 and explore its potential underlying mechanism in OSCC growth, lymph node metastasis, and angiogenesis in vivo. The results showed that knockdown of MMP-9 could significantly suppress OSCC cell migration, proliferation, interactions between endothelial cells, xenografted tumor growth, and angiogenesis and simultaneously markedly inhibited OSCC cell metastasis to mouse lymphonodi cervicales superficiales, axillary lymph nodes, and even distant inguinal lymph nodes. Mechanistic studies revealed that knockdown of MMP-9 also led to a decreased expression of RhoC, Src, and F-actin by RT-PCR, western blotting, and immunohistochemistry. And the bioinformatic analysis showed that MMP-9, RhoC, and Src mRNA expression was positively and linearly correlated in OSCC on TCGA database. Together, our findings indicated that MMP-9 plays a very important role in OSCC growth, migration, angiogenesis, and lymph node metastasis, and its potential mechanism may be mediated by RhoC and Src gene expression.

Knockdown of RhoC Inhibits Oral Squamous Cell Carcinoma Cell Invasion and Metastasis via Regulation of HMGA2.

Ras homolog family member C (RhoC) is an important component of intracellular signal transduction and its overexpression has been reported to be involved in regulating tumor proliferation, invasion, and metastasis in various malignant tumors. However, its role and underlying mechanism in oral squamous cell carcinoma (OSCC) still remain obscure. In our study, RhoC expression, its relation with clinical stages, and survival rate in OSCC were analyzed using datasets from The Cancer Genome Atlas (TCGA). Next, a RhoC knockdown cell model was established in vitro, and the effects of RhoC knockdown in OSCC cells were detected by the MTT assay, colony formation assay, transwell invasion assay, scratch assay, and F-actin phalloidin staining. An in vivo tongue-xenografted nude mouse model was established to measure the effects of knockdown of RhoC on tumor cell growth and lymph node metastasis. A mechanism study was conducted by real-time PCR and immunocytochemistry. The results of TCGA analysis showed that RhoC was overexpressed in OSCC tumor tissues. In vitro assays indicated that knockdown of RhoC did not have much effect on OSCC cell growth but significantly suppressed cell colony formation, invasion, and migration abilities, and F-actin polymerization was also reduced. The tongue-xenografted in vivo model demonstrated that knockdown of RhoC suppressed OSCC cell growth and inhibited metastasis to the superficial cervical lymph nodes. Further mechanism studies showed that knockdown of RhoC downregulated HMGA2 expression, and HMGA2 expression was highly correlated with RhoC expression in OSCC tumor tissues via the analysis of TCGA datasets. Overall, our study showed that knockdown of RhoC inhibited OSCC cells invasion and migration in vitro and OSCC cell growth and lymph node metastasis in vivo. Moreover, the potential mechanisms involved in these activities may be related to the regulation of HMGA2 expression. The RhoC gene could serve as a promising therapeutic target for OSCCs in the future.

Knockdown of Matrix Metallopeptidase 9 Inhibits Metastasis of Oral Squamous Cell Carcinoma Cells in a Zebrafish Xenograft Model.

Destruction of extracellular matrix (ECM) is one of the basic steps of tumor invasion and metastasis. Matrix metalloproteinase (MMP) 9, a kind of zinc-ion-dependent endopeptidase, can degrade almost all protein components in the ECM, destroy the histological barrier of tumor cell invasion, and play a key role in tumor invasion and metastasis. The role of MMP-9 in tumor invasion and metastasis has attracted increasing attention and is considered the main proteolytic enzyme in this process. Although the overexpression of MMP-9 was detected in Oral squamous cell carcinoma (OSCC) tissues, further basic studies in vivo and in vitro are needed to investigate the role of MMP-9 in OSCCs and provide scientific validation. In this research, we developed a novel OSCC zebrafish xenograft model to study the role of the MMP-9 gene in oral carcinogenesis. Firstly, the MMP-9/shRNA lentiviral clone and control virus were constructed and transfected into OSCC cells. Then, the decreasing expression of MMP-9 was verified by RT-PCR and immunocytochemistry. Cell proliferation was detected by MTT assay. Colony formation was evaluated by colony formation assay. Cell invasion was evaluated using transwell invasion assay in vitro. In addition, OSCC cells with MMP-9/shRNA knockdown and control vector were injected into zebrafish and an OSCC tumor model in zebrafish was established to evaluate invasion and metastasis in vivo. Knockdown of MMP-9 gene by shRNA could inhibit OSCC cell growth and clone formation and markedly suppress cell invasion in vitro. And the knockdown of the MMP-9 gene could also significantly decrease the metastatic distance and number of metastatic tumor cells or lesions in vivo and suppress the metastasis rate in xenografted zebrafish. Taken together, these evidences indicated that the knockdown of MMP-9 might suppress OSCC cell invasion and metastasis in vivo and in vitro. The MMP-9 gene may be a promising therapeutic target for OSCCs in the future.

Delivery of mesenchymal stem cells-derived extracellular vesicles with enriched miR-185 inhibits progression of OPMD.

Oral leukoplakia is one of the most common oral potentially malignant disorders (OPMDs) and its malignant transformation to oral cancer is highly associated with chronic inflammation. Extracellular vesicles (EVs) or exosome-delivered microRNAs modulate inflammatory responses and alleviate irritations that predisposes to cancer. We previously reported that microRNA-185 (miR-185) was significantly decreased in the buccal tissue of patients with oral cancer. In this study, we utilized genetically modified mesenchymal stem cells (MSCs) derived EVs with high expression of miR-185 to pasted MSC-EV-miR-185 on buccal lesions in dimethylbenzanthracene (DMBA) induced OPMD model. We found that treatment with MSC-EV-miR-185 remarkably attenuated inflammation severity and significantly decreased the incidence and the number of dysplasia in the OPMD tissue. Immunohistochemistry showed significantly decreased expression of proliferation marker PCNA and angiogenic marker CD31 in the lesion treated with MSC-EV-miR-185. Furthermore, miR-185 specifically targeted Akt genes by promoting activation of the apoptotic pathway, confirmed by the increased levels of activated caspase-3 and 9. In conclusion, genetically modified MSC-derived EVs enriched with miR-185 alleviate inflammatory response, inhibit cell proliferation and angiogenesis, and induce cell apoptosis, suggesting that their potential role as a novel therapeutic option for OPMD.