Impact of tonsillectomy on the efficacy of Alt-RAMEC/PFM treatment protocols in children with class III malocclusion and tonsillar hypertrophy: protocol for a cluster randomised controlled trial.

INTRODUCTION: Orthodontic treatment using face mask protraction combined with an alternate rapid maxillary expansion and constriction/protraction face mask (Alt-RAMEC/PFM) protocol is effective in the early treatment of patients with class III malocclusion, but the stability of treatment outcomes represents a major concern. Previous studies have suggested that tonsillar hypertrophy can be a risk factor for class III malocclusion and tonsillectomy may prompt the normalisation of dentofacial growth. However, these studies had a low-to-moderate level of evidence. This study was designed to identify the impact of tonsillectomy before orthodontic treatment on the efficacy and stability of Alt-RAMEC/PFM protocols and the sleep quality and oral health in children with anterior crossbite and tonsillar hypertrophy. METHODS AND ANALYSIS: This is a two-arm, parallel-group, superiority cluster randomised controlled trial, with four clinics randomly assigned to the surgery-first arm and the orthodontic-first arm in a 1:1 ratio. The Alt-RAMEC protocol involves alternate activation and deactivation of the expander's jet screw over 6 weeks to stimulate maxillary suture distraction. Patients will be instructed to wear the PFM for a minimum of 14 hours per day. The primary outcomes are changes in Wits appraisal and the degree of maxillary advancement from baseline to the end of orthodontic treatment. Lateral cephalometric radiographs, polysomnography, Obstructive Sleep Apnoea-18 questionnaire and Oral Health Impact Profile-14 questionnaire will be traced, collected and measured. We will recruit 96 patients intofor the study. To assess differences, repeated multilevel linear mixed modelling analyses will be used. ETHICS AND DISSEMINATION: This study has been granted ethical approval by the Ethics Committee of the School & Hospital of Stomatology, Wuhan University (approval No. 2023-D10). Written informed consent will be obtained from the participants and their guardians. The results of the trial will be disseminated through academic conferences and journal publications. TRIAL REGISTRATION NUMBER: ChiCTR2300078833.

PD-L1 Blockade Improves Survival in Sepsis by Reversing Monocyte Dysfunction and Immune Disorder.

Monocyte dysfunction is critical to sepsis-induced immunosuppression. Programmed death ligand-1 (PD-L1) has shown a close relationship with inflammatory disorder among animal models and patients. We aimed to investigate the potential beneficial immunologic mechanisms of anti-PD-L1 on monocyte dysfunction of mice with sepsis. Firstly, we assessed the potential association between PD-L1 expression on monocyte subsets and sepsis severity as well as 28-day mortality. In this study, 52 septic patients, 28 septic shock patients, and 40 healthy controls were enrolled and their peripheral whole blood was examined by flow cytometry. Then, cecal ligation and puncture (CLP) were performed for establishing the mouse sepsis model. Subsequently, effects of anti-PD-L1 antibody on monocyte subset, major histocompatibility complex II (MHC II) expression, cytokine production, and survival were investigated. PD-L1 expression on the classical monocytes (CD14 + + CD16 -) was significantly upregulated among septic shock patients and the 28-day death group than non-septic shock group and 28-day survival group (P < 0.05). Compared to septic mice, anti-PD-L1-treated mice had significantly elevated percentages of major histocompatibility complex (MHC) II on peripheral Ly6chi monocyte at 24 h after CLP. Our results showed that the anti-PD-L1 antibody markedly decreased the level of serum inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10 in sepsis mice at 24 h, 48 h, and 72 h, respectively (P < 0.05). The survival rate of CLP mice was significantly improved by anti-PD-L1 antibody treatment. Classical monocytes with high expression of PD-L1 were thought to be connected with sepsis progression. The PD-L1 blockade protects from sepsis, at least partially by inhibiting the reversal of monocyte dysfunction.

Expression of SMARCA2 and SMARCA4 in gastric adenocarcinoma and construction of a nomogram prognostic model.

BACKGROUND: Aberrant expression of SWI/SNF complex subunits is closely associated with tumorigenesis. The clinicopathological and prognostic significance of altered SMARCA2 and SMARCA4 subunits has not been well evaluated in gastric adenocarcinoma. METHODS: We collected 1271 postoperative cases of gastric adenocarcinoma and then constructed tissue microarrays (TMA), from which we obtained the immunohistochemistry expression of SMARCA2 and SMARCA4. Next, we screened the variables related to the loss of SMARCA2 and SMARCA4 by univariate correlation analysis and multivariate logistic regression analysis. Then, we identified the variables related to prognosis by univariate and multivariate Cox regression analysis. Finally, we constructed a nomogram prognostic model and evaluated it. RESULTS: The loss of SMARCA2 and SMARCA4 occurred in 236 (18.57%) and 86 (6.77%) cases, respectively, including 26 cases of co-loss. After multivariate logistic regression, variables independently associated with SMARCA2 loss were T stage, differentiation status, WHO histological classification, and EBER. Variables independently associated with SMARCA4 loss were differentiation status, WHO histological classification, PD-L1, and MMR. Survival analysis revealed that the SMARCA2 and SMARCA4 lost groups showed worse survival than the corresponding present groups (P = 0.032 and P = 0.0048, respectively). Univariate and multivariate Cox analyses identified independent prognostic factors, including age, T stage, N stage, M stage, SMARCA2, and chemotherapy. CONCLUSION: The loss of SMARCA2 and SMARCA4 correlated with poor differentiation, leading to a worse prognosis. SMARCA2, as an independent prognostic factor, combined with other clinicopathological variables, established a novel nomogram prognostic model, which outperformed the AJCC TNM model.

Prognostic and immune infiltration significance of ARID1A in TCGA molecular subtypes of gastric adenocarcinoma.

BACKGROUND: AT-rich interaction domain 1A (ARID1A) is an essential subunit of the switch/sucrose non-fermentable chromatin remodeling complex and is considered to be a tumor suppressor. The Cancer Genome Atlas (TCGA) molecular classification has deepened our understanding of gastric cancer at the molecular level. This study explored the significance of ARID1A expression in TCGA subtypes of gastric adenocarcinoma. METHODS: We collected 1248 postoperative patients with gastric adenocarcinoma, constructed tissue microarrays, performed immunohistochemistry for ARID1A, and obtained correlations between ARID1A and clinicopathological variables. We then carried out the prognostic analysis of ARID1A in TCGA subtypes. Finally, we screened patients by random sampling and propensity score matching method and performed multiplex immunofluorescence to explore the effects of ARID1A on CD4, CD8, and PD-L1 expression in TCGA subtypes. RESULTS: Seven variables independently associated with ARID1A were screened out: mismatch repair proteins, PD-L1, T stage, differentiation status, p53, E-cadherin, and EBER. The independent prognostic variables in the genomically stable (GS) subtype were N stage, M stage, T stage, chemotherapy, size, and ARID1A. PD-L1 expression was higher in the ARID1A negative group than in the ARID1A positive group in all TCGA subgroups. CD4 showed higher expression in the ARID1A negative group in most subtypes, while CD8 did not show the difference in most subtypes. When ARID1A was negative, PD-L1 expression was positively correlated with CD4/CD8 expression; while when ARID1A was positive, this correlation disappeared. CONCLUSIONS: The negative expression of ARID1A occurred more frequently in the Epstein-Barr virus and microsatellite instability subtypes and was an independent adverse prognostic factor in the GS subtype. In the TCGA subtypes, ARID1A negative expression caused increased CD4 and PD-L1 expression, whereas CD8 expression appeared independent of ARID1A. The expression of CD4/CD8 induced by ARID1A negativity was accompanied by an increase in PD-L1 expression.

Huntingtin-associated protein 1 is a potential tumor suppressor for gastric cancer.

BACKGROUND: Gastric cancer is heterogeneous cancer and the causes of this disease are complex. New diagnostic and therapeutic targets are urgently needed to explore. Huntingtin-associated protein 1 (HAP1) is directly related to Huntington's disease (HD). However, patients with Huntington's disease have a lower incidence of cancer. Therefore, we are committed to studying the correlation between HAP1 and gastric carcinogenesis and development. METHODS AND RESULTS: Immunohistochemical staining, western blot analysis, and RT-qPCR were conducted to explore the localization and expression of HAP1 in gastric cancer. To study the biological significance of HAP1, we overexpressed HAP1 in both MKN28 and AGS cell lines by lentivirus infection. To explore the role of HAP1 in cell proliferation, the cells counting assay, EdU incorporation assay, and colony formation assay were carried out. We performed the wound healing assay and transwell assay to study the cell migration and invasion. To further investigate whether HAP1 could regulate gastric cancer cell death during glucose deprivation, Annexin V-FITC/PI staining was performed. In our study, we elucidated that HAP1 was downregulated in gastric cancer. What's more, overexpressing HAP1 inhibited cell proliferation, cell migration and invasion, and triggered apoptosis during glucose deprivation. More importantly, the antitumor properties and mechanisms of HAP1 have been elucidated further in gastric cancer. CONCLUSIONS: Taken together, the available evidence implies that HAP1 may serve as a potential tumor suppressor, making it a significant target in preventing and treating gastric cancer. This research provides a theoretical basis for the early diagnosis, clinical targeted therapy, and prognosis evaluation of gastric cancer.

Clinicopathological and prognostic significance of SWI/SNF complex subunits in undifferentiated gastric carcinoma.

BACKGROUND: The switch/sucrose nonfermentable (SWI/SNF) complex is an evolutionarily conserved chromatin remodeling complex that displays dysfunction in many tumors, especially undifferentiated carcinoma. Cancer stem cells (CSC), a special type of undifferentiated cancer cells with stem cell-like properties, play an essential role in tumor cell proliferation, invasion, and metastasis. In undifferentiated gastric carcinomas, the association of SWI/SNF complexes with clinicopathological features, CSC phenotype, and the prognosis is not fully understood. METHODS: We collected a cohort of 21 patients with undifferentiated/dedifferentiated gastric carcinoma. We next performed immunohistochemistry staining for the five subunits of the SWI/SNF complex (ARID1A, ARID1B, SMARCA2, SMARCA4, and SMARCB1), and four mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), as well as other markers such as p53, PD-L1, and cancer stem cell (CSC) markers (SOX2, SALL4). Then, we investigated the correlation of SWI/SNF complex subunits with clinicopathological characters and performed prognostic analysis. RESULTS: We observed SMARCA2 loss in 12 cases (57.14%), followed by ARID1A (5 cases, 23.81%) and SMARCA4 (3 cases, 14.29%). Fourteen cases (66.67%) lost any one of the SWI/SNF complex subunits, including 3 cases with SMARCA2 and ARID1A co-loss, and 3 cases with SMARCA2 and SMARCA4 co-loss. Correlation analysis revealed that the CSC phenotype occurred more frequently in the SWI/SNF complex deficient group (P = 0.0158). Survival analysis revealed that SWI/WNF complex deficiency, undifferentiated status, CSC phenotype, and the loss of SMARCA2 and SMARCA4 resulted in worse survival. Univariate and multivariate Cox regression analyses screened out three independent factors associated with worse prognosis: undifferentiated status, SWI/SNF complex deficiency, and lymph node metastasis. CONCLUSIONS: The SWI/SNF complex deficiency was more likely to result in a CSC phenotype and worse survival and was an independent prognostic factor in undifferentiated/dedifferentiated gastric carcinoma.

Preparation of biodegradable carboxymethyl cellulose/dopamine/Ag NPs cryogel for rapid hemostasis and bacteria-infected wound repair.

Massive hemorrhage caused by accident or surgery is a major factor in accidental death. In addition, bacterial infection is also an important threat after bleeding. Cryogels with interpenetrating macroporous structures pose great application prospects in rapid hemostasis and infected wound repair. In this study, cryogels with different pore size are prepared by carboxymethyl cellulose (CMC) and dopamine (DA). The CMC grafted with different DA amounts is crosslinked by free DA through oxidative polymerization at low temperatures to form cryogels with different pore sizes. And the CMC/DA-3 cryogel is chosen as the optimal group for its high porosity, suitable mechanical, and good hemostatic ability. CMC/DA-3 cryogel is loaded with silver nanoparticles (Ag NPs) to prepare hemostatic cryogel with antibacterial properties. Antibacterial tests and animal hemostasis experiments confirm that the CMC/DA-3/Ag cryogel has good antibacterial properties and can finish rapid hemostasis. In the S. aureus infection skin defect model, the wound healing is significantly improved compared with commercial gelatin sponge. In summary, the novel cryogel has great potential in rapid hemostasis and infected wound healing.

SMARCA2 deficiency in NSCLC: a clinicopathologic and immunohistochemical analysis of a large series from a single institution.

BACKGROUND: SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 2) is an important ATPase catalytic subunit in the switch-sucrose nonfermenting (SWI/SNF) complex. However, its relationship with the pathological features of NSCLC and its prognosis remain unclear. METHODS: We retrospectively reviewed 2390 patients with surgically resected NSCLC, constructed tissue microarrays (TMAs) and performed immunohistochemical assays. We analyzed the correlation of SAMRCA2 with clinicopathological features and evaluated its prognostic value. RESULTS: Among 2390 NSCLC cases, the negative expression ratios of SAMRCA2, SMARCA4, ARID1A, ARID1B and INI1 were 9.3%, 1.8%, 1.2%, 0.4% and 0%, respectively. In NSCLC, male sex, T3 and T4 stage, moderate and poor differentiation, tumor ≥ 2 cm, Ki67 ≥ 15%, SOX-2 negative expression, middle lobe lesion and adenocarcinoma were relative risk factors affecting SMARCA2-negative expression. In lung adenocarcinomas, high-grade nuclei, histological morphology of acinar and papillary, solid and micropapillary and TTF-1-negative expression were relative risk factors affecting SMARCA2-negative expression. Kaplan-Meier survival analysis showed that the OS was shorter in the SMARCA2-negative group. Multivariate survival analysis revealed that SMARCA2-negative expression was an independent factor correlated with a poor prognosis in NSCLC. CONCLUSION: In conclusion, SMARCA2-negative expression is an independent predictor of a poor outcome of NSCLC and is a potential target for NSCLC treatment.

DNA Damage Repair Gene Mutations Are Indicative of a Favorable Prognosis in Colorectal Cancer Treated With Immune Checkpoint Inhibitors.

BACKGROUND: DNA damage repair (DDR) genes were recently implicated in the anti-tumor immune response. Therefore, it is worthwhile to unravel the implications of DDR pathways in the shaping of immune responsiveness in colorectal cancer (CRC) patients receiving immune checkpoint inhibitors (ICI). METHODS: We analyzed publicly available genomic data from a cohort treated with ICI from Memorial Sloan Kettering Cancer Center (MSK ICI cohort). To characterize the impact of the DDR mutation, the genomic data of The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma (COADREAD) dataset was explored. We also analyzed the incidence of DDR mutation and microsatellite instability-high (MSI-H) in a Chinese CRC cohort using panel sequencing. RESULTS: The DDR pathway was commonly mutated (21.8%) in the multicancer MSK ICI cohort, with the highest frequency of 36.4% in CRCs. Survival analysis showed that DDR mutation correlated with an improved overall survival (OS) in CRCs and pan-cancer in the MSK ICI cohort. However, no significant associations were identified in the TCGA COADREAD and MSK non-ICI CRCs. DDR mutation was associated with higher tumor mutational burden (TMB) levels and increased immune cell infiltration and immune checkpoint molecule expression in the TCGA COADREAD dataset. Last, we investigated the DDR mutational pattern and its associations with MSI-H and other genomic features in a Chinese CRC cohort. Notably, MSI-H and DDR mutation was present in 5.7% and 13.4% of cases, respectively, which suggests that DDR identifies a higher proportion of potential responders than MSI-H. CONCLUSION: Our data suggest that DDR mutation as an indication of enhanced cancer immunity, and it may function as a biomarker for patients with CRCs receiving ICI treatment. The high incidence of DDR mutation in the Chinese CRC cohort emphasizes the future utility of panel-based DDR evaluation in guiding ICI treatment.

Recent development on liquid chromatography-mass spectrometry analysis of oxidized lipids.

Polyunsaturated fatty acids (PUFAs) in the cellular membrane can be oxidized by various enzymes or reactive oxygen species (ROS) to form many oxidized lipids. These metabolites are highly bioactive, participating in a variety of physiological and pathophysiological processes. Mass spectrometry (MS), coupled with Liquid Chromatography, has been increasingly recognized as an indispensable tool for the analysis of oxidized lipids due to its excellent sensitivity and selectivity. We will give an update on the understanding of the molecular mechanisms related to generation of various oxidized lipids and recent progress on the development of LC-MS in the detection of these bioactive lipids derived from fatty acids, cholesterol esters, and phospholipids. The purpose of this review is to provide an overview of the formation mechanisms and technological advances in LC-MS for the study of oxidized lipids in human diseases, and to shed new light on the potential of using oxidized lipids as biomarkers and mechanistic clues of pathogenesis related to lipid metabolism. The key technical problems associated with analysis of oxidized lipids and challenges in the field will also discussed.

An update on lipid oxidation and inflammation in cardiovascular diseases.

Cardiovascular diseases (CVD), including ischemic heart diseases and cerebrovascular diseases, are the leading causes of morbidity and mortality worldwide. Atherosclerosis is the major underlying factor for most CVD. It is well-established that oxidative stress and inflammation are two major mechanisms leading to atherosclerosis. Under oxidative stress, polyunsaturated fatty acids (PUFA)-containing phospholipids and cholesterol esters in cellular membrane and lipoproteins can be readily oxidized through a free radical-induced lipid peroxidation (LPO) process to form a complex mixture of oxidation products. Overwhelming evidence demonstrates that these oxidized lipids are actively involved in the inflammatory responses in atherosclerosis by interacting with immune cells (such as macrophages) and endothelial cells. In addition to lipid lowering in the prevention and treatment of atherosclerotic CVD, targeting chronic inflammation has been entering the medical realm. Clinical trials are under way to lower the lipoprotein (a) (Lp(a)) and its associated oxidized phospholipids, which will provide clinical evidence that targeting inflammation caused by oxidized lipids is a viable approach for CVD. In this review, we aim to give an update on our understanding of the free radical oxidation of LPO, analytical technique to analyze the oxidation products, especially the oxidized phospholipids and cholesterol esters in low density lipoproteins (LDL), and focusing on the experimental and clinical evidence on the role of lipid oxidation in the inflammatory responses associated with CVD, including myocardial infarction and calcific aortic valve stenosis. The challenges and future directions in understanding the role of LPO in CVD will also be discussed.

MiR-382 targets GOLM1 to inhibit metastasis of hepatocellular carcinoma and its down-regulation predicts a poor survival.

Accumulating evidences have illuminated that an amount of microRNAs are involved in human diseases including hepatocellular carcinoma (HCC). In this study, we found that the expression of miR-382 in HCC tissues was down-regulated compared with the non-cancerous tissues. Over-expression of miR-382 could significantly inhibit the migration and invasion of HCC cells in vitro and in vivo. Bioinformatic algorithms and luciferase reporter assays suggested that Golgi Membrane Protein 1 (GOLM1) was a direct target of miR-382. Interestingly, we found the down-regulation of GOLM1 in HCC cells could rescue these cells from miR-382-mediated suppression of migration and invasion. Our findings might demonstrate that miR-382 inhibited the metastasis of HCC by targeting GOLM1. Furthermore, cox proportional hazards analyses suggested that low expression of miR-382 was an independent prognostic factor for the HCC patients. In conclusion, our results highlighted that miR-382, a novel prognostic factor, target GOLM1 to inhibit metastasis of hepatocellular carcinoma.

Reproductive Factors, Steroid Receptor Status, and Tumour Markers of HER2-Positive Breast Cancer in Northern China.

BACKGROUND: Although China has a breast cancer incidence that surpasses all other cancer registries, there have been few reports to evaluate the relationships of reproductive history, steroid receptor status, and tumour markers with HER2 status of breast cancer. PATIENTS AND METHODS: This project included 274 primary invasive ductal breast cancer patients. Information concerning the reproductive factors and tumour characteristics of the patients had previously been collected. HER2 and steroid receptor status were detected in tumour tissues. Serum CEA, CA15-3, and CA125 levels were analyzed for all patients. RESULTS: Younger age at menarche was observed in patients with HER2-positive than in those with HER2negative status (p = 0.03). Statistically significant differences were found between the HER2-positive group and HER2-negative group for estrogen receptor (ER) and progesterone receptor (PR) status (p < 0.01). Age of onset, other reproductive factors, tumour characteristics, and serum tumour marker level were not significantly different between those patients with HER2-positive and those with HER2-negative status. CONCLUSION: We confirm that age at menarche may plausibly be differentially correlated with the risk of HER2-positive invasive ductal breast cancer because it is presumed to impact exposure to endogenous sex hormones. HER2 is inversely related to ER and PR in invasive ductal breast cancer patients of Northern China.

HINTERGRUND: Obwohl China eine Brustkrebsrate aufweist, die sämtliche anderen Krebsregister übersteigt, gab es bislang nur wenige Arbeiten, die die Beziehung zwischen vorangegangenen Schwangerschaften, Steroidrezeptor-Status und Tumormarkern mit dem HER2-Status des Brustkrebses evaluieren. PATIENTEN UND METHODEN: Dieses Projekt umfasste 274 Patienten mit primär invasivem duktalem Brustkrebs. Informationen zu den Reproduktionsfaktoren und den Tumorcharakteristika der Patienten wurden im Vorfeld gesammelt. Der HER2- und der Steroidrezeptor-Status wurde im Tumorgewebe erfasst. Bei allen Patienten wurden die Werte von CEA, CA15-3 und CA125 im Serum analysiert. ERGEBNISSE: Ein jüngeres Alter bei der Menarche wurde bei Patienten mit HER2-positivem im Vergleich zu Patienten mit HER2-negativem Status festgestellt (p = 0.03). Statistisch signifikante Differenzen wurden zwischen der HER2-positiven und der HER2-negativen Gruppe für den Östrogenrezeptoren(ÖR)- und den Progesteronrezeptoren (PR)-Status festgestellt (p < 0.01). Alter beim Krankheitsausbruch, weitere reproduktive Faktoren, Tumorcharakteristika und der Wert der Tumormarker im Serum unterschieden sich nicht signifikant zwischen den Patienten mit HER2-positivem und denen mit HER2-negativem Status. SCHLUSSFOLGERUNG: Wir bestätigen, dass das Alter der Menarche glaubhaft differenziell mit dem Risiko des HER2-positiven invasiven duktalen Brustkrebses korrelieren mag, da angenommen wird, dass es die Einwirkung von endogenen Sexualhormonen beeinflusst. HER2 steht invers mit ÖR und PR bei nordchinesischen Patienten mit invasivem duktalem Brustkrebs in Beziehung.