Low energy intake and nutritional maladaptation in terminal stage IV periodontitis.

AIM: Impairment of masticatory function in elderly patients with terminal dentition due to stage IV periodontitis (TDS4P) may lead to lower nutritional intake. The study aimed to report the dietary intake and nutrition status of elderly patients with TDS4P and compare them with those of the elderly Chinese population and the Chinese Dietary Reference Intakes (DRIs). MATERIALS AND METHODS: Fifty-one consecutive subjects (≥55 years old) with TDS4P were enrolled. Average dietary intake was evaluated based on a 3-day 24-h dietary recall (24HR) and food frequency questionnaire (FFQ). The daily intake of fresh vegetables and fruits, dietary energy as well as macro and micronutrients were calculated and compared with matched national data and the Chinese DRIs. Nutritional status was assessed by Short-Form Mini-Nutritional assessment. RESULTS: Of the subjects, 19.6% (95% CI: 7.2%-28.1%) were at risk of malnutrition. The mean daily energy intake was 1517.4 kcal (95% CI: 1400.5-1634.3) for males and 1110.7 kcal (95% CI: 1001.5-1219.9) for females, which were very low compared with both the national data and the DRIs. Females derived a higher percentage of energy from fat. The mean daily intake of vegetables was 151.4 g (95% CI: 128.1-174.8) by FFQ and 130.9 g (95% CI: 104.6-157.3) by 24HR. Both results were significantly lower than the national reports (95% CI: 310.3-340.1) and the DRIs (300-450 g). Insufficient micronutrient intake, especially vitamins A, C and E, was also found. CONCLUSIONS: Elderly subjects with TDS4P had a lower daily energy intake, vegetable and fruit consumption and essential macro and micronutrient intake. More studies are needed to clarify the impact of periodontitis and tooth loss/replacement on nutrition and healthy ageing.

FASN Inhibition Decreases MHC-I Degradation and Synergizes with PD-L1 Checkpoint Blockade in Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICI) transformed the treatment landscape of hepatocellular carcinoma (HCC). Unfortunately, patients with attenuated MHC-I expression remain refractory to ICIs, and druggable targets for upregulating MHC-I are limited. Here, we found that genetic or pharmacologic inhibition of fatty acid synthase (FASN) increased MHC-I levels in HCC cells, promoting antigen presentation and stimulating antigen-specific CD8+ T-cell cytotoxicity. Mechanistically, FASN inhibition reduced palmitoylation of MHC-I that led to its lysosomal degradation. The palmitoyltransferase DHHC3 directly bound MHC-I and negatively regulated MHC-I protein levels. In an orthotopic HCC mouse model, Fasn deficiency enhanced MHC-I levels and promoted cancer cell killing by tumor-infiltrating CD8+ T cells. Moreover, the combination of two different FASN inhibitors, orlistat and TVB-2640, with anti-PD-L1 antibody robustly suppressed tumor growth in vivo. Multiplex IHC of human HCC samples and bioinformatic analysis of The Cancer Genome Atlas data further illustrated that lower expression of FASN was correlated with a higher percentage of cytotoxic CD8+ T cells. The identification of FASN as a negative regulator of MHC-I provides the rationale for combining FASN inhibitors and immunotherapy for treating HCC. SIGNIFICANCE: Inhibition of FASN increases MHC-I protein levels by suppressing its palmitoylation and lysosomal degradation, which stimulates immune activity against hepatocellular carcinoma and enhances the efficacy of immune checkpoint inhibition.

The potential causal path between periodontitis stage diagnosis and vegetable consumption is mediated by loss of posterior functional tooth units and masticatory function.

AIM: Emerging evidence points to a two-way relationship between periodontitis and dietary choices and, thus, nutrition. This study aimed to assess the potential cause-effect relationship between the periodontitis stage, loss of functional tooth units (FTUs), masticatory function, and intake of different food groups using path analysis. MATERIALS AND METHODS: A single calibrated examiner determined the periodontitis stage of a consecutive sample of 241 Chinese subjects reporting for tooth replacement. Their masticatory function was quantified by the mixing ability of a two-colour chewing gum. Validated food frequency questionnaires were used to calculate the intake of 33 food group items by an experienced calibrated rater. After verification of assumptions, visual structural equation modeling was performed with Amos 23. The consistency of results and the potential modifying effect of age were assessed in 9043 subjects from the NHANES database. RESULTS: Highly significant models were constructed using periodontitis stage and age as exogenous factors. Periodontitis stage diagnosis significantly affected the number of posterior FTUs and oral health-related quality of life (OHRQoL, path coefficient [PC] = -0.55 and -0.20, p < .05, respectively). In the model, FTUs also had an independent effect on OHRQoL (PC = 0.23, p < .05). FTUs determined the level of masticatory function (PC = -0.38, p < .05), which in turn affected vegetable intake but not fruit or meat intake (PC = -0.18, p < .0.5, PC = 0.06, NS and PC = 0.11, NS, respectively). The effect of age was significant for vegetable and meat intake and was also correlated with periodontitis stage diagnosis. Analysis of the NHANES database confirmed the negative impact of periodontitis on the number of occluding pairs and vegetable consumption for the 18-44, 45-60 and >60 age groups. CONCLUSIONS: Periodontitis showed a potential cause-effect pathway affecting vegetable intake across cultures and age groups. The size of the effect is potentially of clinical and public health significance. Additional studies, including intervention trials, are required to test this potential mechanism linking oral health to nutrition.

Enhanced mitophagy driven by ADAR1-GLI1 editing supports the self-renewal of cancer stem cells in HCC.

BACKGROUND AND AIMS: Deregulation of adenosine-to-inosine editing by adenosine deaminase acting on RNA 1 (ADAR1) leads to tumor-specific transcriptome diversity with prognostic values for HCC. However, ADAR1 editase-dependent mechanisms governing liver cancer stem cell (LCSC) generation and maintenance have remained elusive. APPROACH AND RESULTS: RNA-seq profiling identified ADAR1-responsive recoding editing events in HCC and showed editing frequency of GLI1 , rather than transcript abundance was clinically relevant. Functional differences in LCSC self-renewal and tumor aggressiveness between wild-type (GLI1 wt ) and edited GLI1 (GLI1 edit ) were elucidated. We showed that overediting of GLI1 induced an arginine-to-glycine (R701G) substitution, augmenting tumor-initiating potential and exhibiting a more aggressive phenotype. GLI1 R701G harbored weak affinity to SUFU, which in turn, promoted its cytoplasmic-to-nuclear translocation to support LCSC self-renewal by increased pluripotency gene expression. Moreover, editing predisposed to stabilize GLI1 by abrogating ß-TrCP-GLI1 interaction. Integrative analysis of single-cell transcriptome further revealed hyperactivated mitophagy in ADAR1-enriched LCSCs. GLI1 editing promoted a metabolic switch to oxidative phosphorylation to control stress and stem-like state through PINK1-Parkin-mediated mitophagy in HCC, thereby conferring exclusive metastatic and sorafenib-resistant capacities. CONCLUSIONS: Our findings demonstrate a novel role of ADAR1 as an active regulator for LCSCs properties through editing GLI1 in the highly heterogeneous HCC.

Improved positional accuracy of dental implant placement using a haptic and machine-vision-controlled collaborative surgery robot: A pilot randomized controlled trial.

AIM: To compare the implant accuracy, safety and morbidity between robot-assisted and freehand dental implant placement. MATERIALS AND METHODS: Subjects requiring single-site dental implant placement were recruited. Patients were randomly allocated to freehand implant placement and robot-assisted implant placement. Differences in positional accuracy of the implant, surgical morbidity and complications were assessed. The significance of intergroup differences was tested with an intention-to-treat analysis and a per-protocol (PP) analysis (excluding one patient due to calibration error). RESULTS: Twenty patients (with a median age of 37, 13 female) were included. One subject assigned to the robotic arm was excluded from the PP analysis because of a large calibration error due to the dislodgement of the index. For robot-assisted and freehand implant placement, with the PP analysis, the median (25th-75th percentile) platform global deviation, apex global deviation and angular deviation were 1.23 (0.9-1.4) mm/1.9 (1.2-2.3) mm (p = .03, the Mann-Whitney U-test), 1.40 (1.1-1.6) mm/2.1 (1.7-3.9) mm (p < .01) and 3.0 (0.9-6.0)°/6.7 (2.2-13.9)° (p = .08), respectively. Both methods showed limited damage to the alveolar ridge and had similar peri- and post-operative morbidity and safety. CONCLUSIONS: Robot-assisted implant placement enabled greater positional accuracy of the implant compared to freehand placement in this pilot trial. The robotic system should be further developed to simplify surgical procedures and improve accuracy and be validated in properly sized trials assessing the full spectrum of relevant outcomes.

Targeting MFGE8 secreted by cancer-associated fibroblasts blocks angiogenesis and metastasis in esophageal squamous cell carcinoma.

Cancer-associated fibroblasts (CAFs) play vital roles in establishing a suitable tumor microenvironment. In this study, RNA sequencing data revealed that CAFs could promote cell proliferation, angiogenesis, and ECM reconstitution by binding to integrin families and activating PI3K/AKT pathways in esophageal squamous cell carcinoma (ESCC). The secretions of CAFs play an important role in regulating these biological activities. Among these secretions, we found that MFGE8 is specifically secreted by CAFs in ESCC. Additionally, the secreted MFGE8 protein is essential in CAF-regulated vascularization, tumor proliferation, drug resistance, and metastasis. By binding to Integrin αVß3/αVß5 receptors, MFGE8 promotes tumor progression by activating both the PI3K/AKT and ERK/AKT pathways. Interestingly, the biological function of MFGE8 secreted by CAFs fully demonstrated the major role of CAFs in ESCC and its mode of mechanism, showing that MFGE8 could be a driver factor of CAFs in remodeling the tumor environment. In vivo treatment targeting CAFs-secreting MFGE8 or its receptor produced significant inhibitory effects on ESCC growth and metastasis, which provides an approach for the treatment of ESCC.

Accuracy of intraoral scan with prefabricated aids and stereophotogrammetry compared with open tray impressions for complete-arch implant-supported prosthesis: A clinical study.

OBJECTIVES: The aim of this clinical study was to compare the accuracy of intraoral scan system (IOS) with prefabricated aids and stereophotogrammetry (SPG) compared with open tray implant impression (OI) for complete-arch implant-supported fixed dental prostheses (CIFDP). MATERIALS AND METHODS: Patients needing CIFDP were enrolled in this study. OI, reference standard, IOS with prefabricated aids, and SPG were performed for each patient. Distance and angle deviations between all pairs of abutment analogs, root mean square (RMS) errors between the aligned test and reference model, and chairside time were measured. The effect of inter-abutment distance, jaw (maxilla or mandible), number of implants, and arch length on deviations was analyzed. The mixed effect model was applied to analyze deviations and RMS errors. RESULTS: Fifteen consecutive individuals (6 females and 9 males, 47-77 years old) with 22 arches (9 upper and 13 lower jaws) and 115 implants were included. There was no significant difference in distance deviation comparing SPG and IOS with OI (p > .05). IOS showed a significantly greater angle deviation and RMS errors than SPG (median 0.40° vs. 0.31°, 69 µm vs. 45 µm, p < .01). The inter-abutment distance was negatively correlated with the accuracy of SPG and IOS (p < .05). The chairside time for IOS, SPG, and OI was 10.49 ± 3.50, 14.71 ± 2.86, and 20.20 ± 3.01 min, respectively (p < .01). CONCLUSIONS: The accuracy of SPG and IOS with prefabricated aids was comparable. IOS was the most efficient workflow.

Doubly Screened Coulomb Correction Approach for Strongly Correlated Systems.

Strongly correlated systems containing d/f electrons present a challenge to conventional density functional theory such as the local density approximation or generalized gradient approximation. We developed a doubly screened Coulomb correction (DSCC) approach to perform on-site Coulomb interaction correction for strongly correlated materials. The on-site Coulomb interaction between localized d/f electrons is self-consistently determined from a model dielectric function that includes both the static dielectric and Thomas-Fermi screening. We applied DSCC to simulate the electronic and magnetic properties of typical 3d, 4f, and 5f strongly correlated systems. The accuracy of DSCC is comparable to that of hybrid functionals but an order of magnitude faster. In addition, DSCC can reflect the difference in the Coulomb interaction between metallic and insulating situations, similar to the popular but computationally expensive constrained random phase approximation approach. This feature suggests that DSCC is also a promising method for simulating Coulomb interaction parameters.

Effect of SH2B1 on glucose metabolism during pressure overload-induced cardiac hypertrophy and cardiac dysfunction.

This study mainly explored the effect and mechanism of Src homology 2 (SH2) B adaptor protein 1 (SH2B1) on cardiac glucose metabolism during pressure overload-induced cardiac hypertrophy and dysfunction. A pressure-overloaded cardiac hypertrophy model was constructed, and SH2B1-siRNA was injected through the tail vein. Haematoxylin and eosin (H&E) staining was used to detect myocardial morphology. ANP, BNP, ß-MHC and the diameter of myocardial fibres were quantitatively measured to evaluate the degree of cardiac hypertrophy, respectively. GLUT1, GLUT4, and IR were detected to assess cardiac glucose metabolism. Cardiac function was determined by echocardiography. Then, glucose oxidation and uptake, glycolysis and fatty acid metabolism were assessed in Langendorff perfusion of hearts. Finally, PI3K/AKT activator was used to further explore the relevant mechanism. The results showed that during cardiac pressure overload, with the aggravation of cardiac hypertrophy and dysfunction, cardiac glucose metabolism and glycolysis increased, and fatty acid metabolism decreased. After SH2B1-siRNA transfection, cardiac SH2B1 expression was knocked down, and the degree of cardiac hypertrophy and dysfunction was alleviated compared with the Control-siRNA transfected group. Simultaneously, cardiac glucose metabolism and glycolysis were reduced, and fatty acid metabolism was enhanced. The SH2B1 expression knockdown mitigated the cardiac hypertrophy and dysfunction by reducing cardiac glucose metabolism. After using PI3K/AKT activator, the effect of SH2B1 expression knockdown on cardiac glucose metabolism was reversed during cardiac hypertrophy and dysfunction. Collectively, SH2B1 regulated cardiac glucose metabolism by activating the PI3K/AKT pathway during pressure overload-induced cardiac hypertrophy and cardiac dysfunction.

Perturbation of mitochondrial dynamics links to the aggravation of periodontitis by diabetes.

Diabetes and periodontitis are prevalent diseases that considerably impact global economy and diabetes is a major risk factor of periodontitis. Mitochondrial dynamic alterations are involved in many diseases including diabetes and this study aims to evaluate their relevance with diabetes aggravated periodontitis. Sixty mice are randomly divided into 4 groups: control, periodontitis, diabetes and diabetic periodontitis. Periodontitis severity is evaluated by alveolar bone loss, inflammation and oxidative stress status. Mitochondrial structural and functional defects are evaluated by the mitochondrial fission/fusion events, mitochondrial reactive oxygen species (ROS) accumulation, complex activities and adenosine triphosphate (ATP) production. Advanced glycation end product (AGE) and Porphyromonas gingivalis are closely related to periodontitis occurrence and development. Human gingival fibroblast cells (HGF-1) are used to investigate the AGE role and lipopolysaccharide (LPS) from Porphyromonas gingivalis (P-LPS) in aggravating diabetic periodontitis by mitochondrial dynamic and function alterations. In vivo, diabetic mice with periodontitis show severe bone loss, increased inflammation and oxidative stress accumulation. Among mice with periodontitis, diabetic mice show worse mitochondrial dynamic perturbations than lean mice, along with fusion protein levels inducing more mitochondrial fission in gingival tissue. In vitro, AGEs and P-LPS co-treatment causes severe.

Carnosic acid protects against doxorubicin-induced cardiotoxicity through enhancing the Nrf2/HO-1 pathway.

Doxorubicin (DOX) is used extensively in anticancer therapy, but its clinical application is limited due to its cardiotoxicity. Carnosic acid (CA) is a bioactive compound found in rosemary. It has been shown to reduce inflammation and reactive oxygen species. The purpose of this study was to investigate the potential cardioprotective effects of CA in response to DOX-induced cardiotoxicity. Here, C57BL/6 mice were administered an intraperitoneal injection of DOX (5 mg kg-1, ip) once a week for three consecutive weeks and treated with CA (40 mg kg-1, ig) for a three-week experimental period. For in vitro study, neonatal rat ventricular cardiomyocytes were used to validate the protective effects of CA (20 µM) in response to DOX-induced cardiotoxicity. CA markedly suppressed oxidative stress, apoptosis, and pyroptosis responses in the mouse hearts, eventually improving cardiac function. CA showed its antioxidant effect by activating nuclear factor erythroid 2-related factor (Nrf2) and its downstream heme oxygenase-1 (HO-1); CA also reduced oxidative stress by lowering the MDA and lipid ROS levels and raising the SOD and GSH-px levels. Additionally, CA treatment significantly increased Bcl-2 and inhibited Bax and Caspase-3 cleavage in DOX-induced cardiotoxicity. Moreover, CA suppressed the NOD-like receptor protein 3 (NLRP3) pathway to mitigate pyroptosis, as evidenced by lowered caspase1, interleukin-18, and interleukin-1ß. Consistently, the transfection of Nrf2-siRNA eliminated the protective effects of CA on cardiomyocytes. Altogether, our findings demonstrated that CA inhibited NLRP3 inflammasomes via activating the Nrf2-related cytoprotective system and protected the heart from oxidative damage, apoptosis, and pyroptosis, implying that the use of CA could be a potential therapeutic strategy in the prevention of DOX-associated myocardiopathy.

Comparative study of first-principles approaches for effective Coulomb interaction strength Ueff between localized f-electrons: Lanthanide metals as an example.

As correlation strength has a key influence on the simulation of strongly correlated materials, many approaches have been proposed to obtain the parameter using first-principles calculations. However, a comparison of the different Coulomb strengths obtained using these approaches and an investigation of the mechanisms behind them are still needed. Taking lanthanide metals as an example, we research the factors that affect the effective Coulomb interaction strength, Ueff, by local screened Coulomb correction (LSCC), linear response (LR), and constrained random-phase approximation (cRPA) in the Vienna Ab initio Simulation Package. The Ueff LSCC value increases from 4.75 to 7.78 eV, Ueff LR is almost stable at about 6.0 eV (except for Eu, Er, and Yb), and Ueff cRPA shows a two-stage decreasing trend in both light and heavy lanthanides. To investigate these differences, we establish a scheme to analyze the coexistence and competition between the orbital localization and the screening effect. We find that LSCC and cRPA are dominated by the orbital localization and the screening effect, respectively, whereas LR shows the balance of the competition between the two factors. Additionally, the performance of these approaches is influenced by different starting points from the Perdew-Burke-Ernzerhof (PBE) and PBE + U, especially for cRPA. Our results provide useful knowledge for understanding the Ueff of lanthanide materials, and similar analyses can also be used in the research of other correlation strength simulation approaches.

Cancer stem cells: Recent insights and therapies.

Tumors are intricate ecosystems containing malignant components that generate adaptive and evolutionarily driven abnormal tissues. Through self-renewal and differentiation, cancers are reconstructed by a dynamic subset of stem-like cells that enforce tumor heterogeneity and remodel the tumor microenvironment (TME). Through recent technology advances, we are now better equipped to investigate the fundamental role of cancer stem cells (CSCs) in cancer biology. In this review, we discuss the latest insights into characteristics, markers and mechanism of CSCs and describe the crosstalk between CSCs and other cells in TME. Additionally, we explore the performance of single-cell sequencing and spatial transcriptome analysis in CSCs studies and summarize the therapeutic strategies to eliminate CSCs, which could broaden the understanding of CSCs and exploit for therapeutic benefit.

Clinical, radiographic, and esthetic evaluation of immediate implant placement with buccal bone dehiscence in the anterior maxilla: A 1-year prospective case series.

OBJECTIVES: To evaluate the clinical, radiographic, and esthetic outcomes of immediate implant placement with buccal bone dehiscence in the anterior maxilla. METHODS: In this case series, implants were inserted immediately after tooth extraction in sockets with buccal bone dehiscence. Guided bone regeneration (GBR) with a papilla preservation flap and simultaneous connective tissue grafting (CTG) was used. The following outcome variables were measured: mid-facial mucosal recession, probing depth, bleeding on probing, Pink Esthetic Score (PES), marginal bone loss, and thickness of buccal bone plate (TBP). RESULTS: 12 patients were recruited. Stable mid-facial mucosal level (-0.03 ± 0.17 mm) and excellent soft-tissue esthetic outcomes (PES, 9.17 ± 0.72) were achieved at 1 year. The TBP at platform level was 2.01 ± 0.31 mm at 1-year follow up with a resorption rate of 28.90% ± 15.14%. CONCLUSIONS: Immediate implant placement using GBR performed with a papilla preservation approach and simultaneous CTG is a feasible treatment procedure in compromised extraction sockets in the anterior region. Favorable esthetic outcomes and buccal bone thickness were obtained. Further studies were needed to evaluate the long-term tissue alteration.

Clinical evaluation of narrow-diameter implants versus standard-diameter implants with lateral bone augmentation in posterior jaws: Three-year results of a randomized controlled trial.

BACKGROUND: The aim of this study was to compare the 3-year clinical outcomes of narrow-diameter implants (NDI) with standard-diameter implants (SDI) in conjunction with lateral bone augmentation in atrophic posterior jaws. MATERIALS AND METHODS: Fifty patients were included and randomly assigned into two groups: Patients in Group 1 received NDI (Ø3.5 mm); patients in Group 2 received SDI (Ø4.3 mm) with simultaneous lateral bone augmentation. Implant survival rates, complications, crestal bone loss, peri-implant conditions, treatment cost, and patient satisfaction were compared. RESULTS: Three patients dropped out the follow-up. No implant loss was observed. The difference in technical complication rates between the two groups was 3.8% (95% CI: -13.7% to 21.3%). No significant differences in crestal bone loss were found between two groups at 3-year follow-up (0.55 ± 0.76 vs 0.41 ± 0.41 mm, p = .429). A total of 20.8% (5/24) of NDI were diagnosed with mucositis and 8.3% (2/24) with peri-implantitis. A total of 17.4% (4/23) of SDI showed mucositis and (1/23) 4.3% showed peri-implantitis. The total cumulative cost of treatment per patient in Group 1 (2849.6 USD, 95% CI: 2726.8-2972.4) was significantly lower than that in Group 2 (3581.4 USD, 95% CI, 3460.9-3701.9) over the 3-year follow-up (p < .01). The patient satisfaction rating of operation was significantly higher in Group 1 (85.42 ± 7.41 vs 80.48 ± 7.95, p = .033). DISCUSSION: NDI yielded favorable implant survival, acceptable technical and biological complications, and high patient satisfaction supporting single crowns in the atrophic posterior region after 3-year follow-up. NDI might be a reasonable alternative in horizontally deficient posterior jaws. TRIAL REGISTRATION: Clinicaltrials.gov identifier: ChiCTR1800020426.

The Role of Tumor Microenvironment in Invasion and Metastasis of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in the world, with a high rate of morbidity. The invasion and metastasis of ESCC is the main reason for high mortality. More and more evidence suggests that metastasized cancer cells require cellular elements that contribute to ESCC tumor microenvironment (TME) formation. TME contains many immune cells and stromal components, which are critical to epithelial-mesenchymal transition, immune escape, angiogenesis/lymphangiogenesis, metastasis niche formation, and invasion/metastasis. In this review, we will focus on the mechanism of different microenvironment cellular elements in ESCC invasion and metastasis and discuss recent therapeutic attempts to restore the tumor-suppressing function of cells within the TME. It will represent the whole picture of TME in the metastasis and invasion process of ESCC.

Effects of Dental Implants and Nutrition on Elderly Edentulous Subjects: Protocol for a Factorial Randomized Clinical Trial.

Background: Loss of masticatory function consequent to tooth loss has been associated with changes in food choices and insufficient nutritional intake. To date, interventions based on dental prostheses alone did not significantly improve nutrient intake. Pilot studies have shown positive impacts of interventions combining implant-supported fixed dental prosthesis with brief dietary advice. The relative contribution and the potential synergy of the components of such interventions need to be determined as it has major public health implications for the community-dwelling aging population that continues to disproportionately suffer from tooth loss and its consequences. Objective: To assess the effect of rehabilitation of masticatory function with fixed implant supported dentures and nutrition education in older subjects with terminal dentition (stage IV periodontitis) or full edentulism. Methods: A 2 × 2 factorial randomized controlled trial with 16-month follow-up of eligible adults (≥60 years) with loss of masticatory function consequent to full arch edentulism or terminal dentition (n = 120) will be conducted to test whether the rehabilitation of masticatory function with fixed implant supported dentures, nutrition education and/or their combination improves intake of fresh fruits and vegetables for aging subjects. The study has been designed to detect changes in fresh fruits and fresh vegetables intake at 4 months using the 24-h dietary recall method. Changes in protein as percentage of total energy, nutritional biomarkers, plasma metabolomics, oral and gut microbiome, quality of life and masticatory function will also be assessed. Discussion: We hypothesize that receiving rehabilitation of masticatory function with fixed implant dentures together with nutrition education is the most effective intervention for improving nutrient intake in aging community-dwelling subjects with extensive tooth loss. The results of this study will assist in designing better treatment regimens, guide medical care for individual subjects, and inform public health and policy. Clinical Trials Registration: NCT05334407.

Inhibition of lysyl oxidase-like 2 overcomes adhesion-dependent drug resistance in the collagen-enriched liver cancer microenvironment.

The tumor microenvironment (TME) is considered to be one of the vital mediators of tumor progression. Extracellular matrix (ECM), infiltrating immune cells, and stromal cells collectively constitute the complex ecosystem with varied biochemical and biophysical properties. The development of liver cancer is strongly tied with fibrosis and cirrhosis that alters the microenvironmental landscape, especially ECM composition. Enhanced deposition and cross-linking of type I collagen are frequently detected in patients with liver cancer and have been shown to facilitate tumor growth and metastasis by epithelial-to-mesenchymal transition. However, information on the effect of collagen enrichment on drug resistance is lacking. Thus, the present study has comprehensively illustrated phenotypical and mechanistic changes in an in vitro mimicry of collagen-enriched TME and revealed that collagen enrichment could induce 5-fluorouracil (5FU) and sorafenib resistance in liver cancer cells through hypoxia-induced up-regulation of lysyl oxidase-like 2 (LOXL2). LOXL2, an enzyme that facilitates collagen cross-linking, enhances cell adhesion-mediated drug resistance by activating the integrin alpha 5 (ITGA5)/focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/rho-associated kinase 1 (ROCK1) signaling axis. Conclusion: We demonstrated that inhibition of LOXL2 in a collagen-enriched microenvironment synergistically promotes the efficacy of sorafenib and 5FU through deterioration of focal adhesion signaling. These findings have clinical implications for developing LOXL2-targeted strategies in patients with chemoresistant liver cancer and especially for those patients with advanced fibrosis and cirrhosis.

Targeting TROY-mediated P85a/AKT/TBX3 signaling attenuates tumor stemness and elevates treatment response in hepatocellular carcinoma.

BACKGROUND: Previous in vitro hepatocyte differentiation model showed that TROY was specifically expressed in liver progenitor cells and a small proportion of hepatocellular carcinoma cells, suggesting that TROY may participate in hepatocellular carcinoma (HCC) stemness regulation. Here, we aim to investigate the role and mechanism of TROY in HCC pathogenesis. METHOD: Bioinformatics analysis of the TCGA dataset has been used to identify the function and mechanism of TROY. Spheroid, apoptosis, and ALDH assay were performed to evaluate the stemness functions. Validation of the downstream pathway was based on Western blot, co-immunoprecipitation, and double immunofluorescence. RESULTS: HCC tissue microarray study found that a high frequency of TROY-positive cells was detected in 53/130 (40.8%) of HCC cases, which was significantly associated with poor prognosis and tumor metastasis. Functional studies revealed that TROY could promote self-renewal, drug resistance, tumorigenicity, and metastasis of HCC cells. Mechanism study found that TROY could interact with PI3K subunit p85α, inducing its polyubiquitylation and degradation. The degradation of p85α subsequently activate PI3K/AKT/TBX3 signaling and upregulated pluripotent genes expression including SOX2, NANOG, and OCT4, and promoted EMT in HCC cells. Interestingly, immune cell infiltration analysis found that upregulation of TROY in HCC tissues was induced by TGF-ß1 secreted from CAFs. PI3K inhibitor wortmannin could effectively impair tumor stemness to sorafenib. CONCLUSION: We demonstrated that TROY is an HCC CSC marker and plays an important role in HCC stemness regulation. Targeting TROY-positive CSCs with PI3K inhibitor wortmannin combined with chemo- or targeted drugs might be a novel therapeutic strategy for HCC patients.

Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity.

OBJECTIVE: Solid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC). DESIGN: Anti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses. RESULTS: A negative correlation between WNT2+ CAFs and active CD8+ T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades. CONCLUSIONS: CAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.