Iron overload promotes the progression of MLL-AF9 induced acute myeloid leukemia by upregulation of FOS.

Systemic iron overload is a common clinical challenge leading to significantly serious complications in patients with acute myeloid leukemia (AML), which affects both the quality of life and the overall survival of patients. Symptoms can be relieved after iron chelation therapy in clinical practice. However, the roles and mechanisms of iron overload on the initiation and progression of leukemia remain elusive. Here we studied the correlation between iron overload and AML clinical outcome, and further explored the role and pathophysiologic mechanism of iron overload in AML by using two mouse models: an iron overload MLL-AF9-induced AML mouse model and a nude xenograft mouse model. Patients with AML had an increased ferritin level, particularly in the myelomonocytic (M4) or monocytic (M5) subtypes. High level of iron expression correlated with a worsened prognosis in AML patients and a shortened survival time in AML mice. Furthermore, iron overload increased the tumor load in the bone marrow (BM) and extramedullary tissues by promoting the proliferation of leukemia cells through the upregulation of FOS. Collectively, our findings provide new insights into the roles of iron overload in AML. Additionally, this study may provide a potential therapeutic target to improve the outcome of AML patients and a rationale for the prospective evaluation of iron chelation therapy in AML.

Teaching Dental Drawings for Freshman Dental Students and Its Correlation with Manual Dexterity.

Objective: To assess whether the implementation of teeth drawing exercises in a dental anatomy course improves first-year (D1) dental students' understanding of tooth morphology, their dexterity, and their clinical skills compared with D1s who did not participate in the drawing exercises. Methods: In 2020, a "Teeth Drawing Module" was implemented within the D1 dental anatomy curriculum. In this course, students learn how to draw accurate outlines of teeth. The students are required to complete two types of drawing projects. Illustrations and instructions of teeth drawings that are outlined in a manual drawing book, PowerPoint presentations, illustration videos, and assessments are provided. Students' grades in the drawing module, waxing skills assessments, and their didactic exams were used to evaluate and assess the correlation between their drawing aptitude and their manual skills. Students who took the drawing course were compared with students who did not take the drawing course to determine if the drawings improved students' understanding of tooth morphology, their dexterity, and their clinical skills. A comprehensive survey was also developed and distributed to students who had the drawing module in their curriculum. Results: Students who participated in the drawing module were more successful in the dental anatomy course compared with students in the control classes. Classes that had drawing exercises scored significantly higher in all dental anatomy waxing exercises compared with classes that did not have drawing exercises (p < 0.001). There was a significant positive correlation between drawing and waxing scores (p < 0.05). Moreover, there was a significant positive correlation between drawing and didactic scores (p < 0.001). Conclusions: Drawing exercises can be useful instruments for effectively representing and integrating the spatial domain of anatomical information. Teeth drawings as an adjunctive tool offer excellent visualization and allow students to improve their manual dexterity and knowledge in the dental anatomy course.

Sox13 and M2-like leukemia-associated macrophages contribute to endogenous IL-34 caused accelerated progression of acute myeloid leukemia.

Interleukin 34 (IL-34) mainly plays physiologic and pathologic roles through the sophisticated multi-ligand signaling system, macrophage colony-stimulating factor (M-CSF, CSF-1)/IL-34-CSF-1R axis, which exhibits functional redundancy, tissue-restriction and diversity. This axis is vital for the survival, differentiation and function of monocytic lineage cells and plays pathologic roles in a broad range of diseases. However, the role of IL-34 in leukemia has not been established. Here MLL-AF9 induced mouse acute myeloid leukemia (AML) model overexpressing IL-34 (MA9-IL-34) was used to explore its role in AML. MA9-IL-34 mice exhibited accelerated disease progression and short survival time with significant subcutaneous infiltration of AML cells. MA9-IL-34 cells showed increased proliferation. In vitro colony forming assays and limiting dilution transplantation experiments demonstrated that MA9-IL-34 cells had elevated leukemia stem cell (LSC) levels. Gene expression microarray analysis revealed a panel of differential expressed genes including Sex-determining region Y (SRY)-box 13 (Sox13). Furthermore, a positive correlation between the expressions of IL-34 and Sox13 was detected human datasets. Knockdown of Sox13 rescued the enhanced proliferation, high LSC level and subcutaneous infiltration in MA9-IL-34 cells. Moreover, more leukemia-associated macrophages (LAMs) were detected in MA9-IL-34 microenvironment. Additionally, those LAMs showed M2-like phenotype since they expressed high level of M2-associated genes and had attenuated phagocytic potential, suggesting that LAMs should also contribute to IL-34 caused adverse phenotypes. Therefore, our findings uncover the intrinsic and microenvironmental mechanisms of IL-34 in AML and broadens the knowledge of M-CSF/IL-34-CSF-1R axis in malignancies.

CBCT analysis of crestal soft tissue thickness before implant placement and its relationship with cortical bone thickness.

BACKGROUND: The importance of crestal soft tissue thickness and its influence in peri-implant tissue health has been evaluated in few clinical studies. Cone beam computed tomography imaging offers a unique opportunity to investigate variations in crestal soft tissue thickness. The aim of this retrospective study was to evaluate the possible correlation between crestal soft tissue thickness and hard tissue measurements on CBCT images, and to compare crestal soft tissue thickness among different patients and edentulous site groups. METHODS: CBCT images of partially edentulous adult patients treated at ECU School of Dental Medicine were evaluated. 267 patients with 321 edentulous sites were included. Demographic data were collected from electronic health records. Cross-sectional CBCT images at the center of each edentulous site were used to measure soft tissue and hard tissue parameters. Linear mixed models were used to compare crestal soft tissue thickness and hard tissue measurements by gender, age groups, and edentulous sites. Pearson correlation was applied to evaluate the correlation between crestal soft tissue thickness and different hard tissue measurements. Association between crestal soft tissue thickness and independent variables (gender, age groups, edentulous sites) was evaluated using repeated measure logistic regression, while the crestal soft tissue thickness was dichotomized by a threshold of 2 mm. RESULTS: Mean age of patients included was 60 (range 21-85 years). Female to male ratio was 1.07. Mean crestal soft tissue thickness of all non-grafted native bone sites was 2.17 mm. Mean thickness of cortical bone at alveolar crest was 0.94 mm. Thickness of buccal and lingual cortical plates 5 mm apical to alveolar crest were 1.17 mm and 1.58 mm, respectively. Pearson's correlation showed moderate positive correlation among hard tissue measurements, but weak correlation between soft tissue thickness and hard tissue measurements. Anterior sites [OR = 3.429 (1.100-10.69)] and maxillary posterior sites [OR = 1.937 (1.077-3.482)] had higher odds of presenting with more than 2 mm of soft tissue at the alveolar crest. CONCLUSION: More than half of the patients had crestal soft tissues at edentulous sites thicker than 2 mm. Thickness of crestal soft tissue was not significantly associated with hard tissue measurements. Edentulous anterior sites and maxillary posterior sites presented with thicker crestal soft tissue at alveolar crest as compared to mandibular posterior sites.

Fbxw11 impairs the repopulation capacity of hematopoietic stem/progenitor cells.

BACKGROUND: The ubiquitin-proteasome system plays important roles in maintaining the self-renewal and differentiation of stem and progenitor cells through highly ordered degradation of cellular proteins. Fbxw11, an E3 ligase, participates in many important biological processes by targeting a broad range of proteins. However, its roles in hematopoietic stem/progenitor cells (HSPCs) have not been established. METHODS: In this study, the effects of Fbxw11 on HSPCs were studied in vitro and in vivo by an overexpression strategy. Real-time PCR was performed to detect the expression of Fbxw11 in hematopoietic subpopulations. Colony-forming assays were performed to evaluate the in vitro function of Fbxw11 on HSPCs. Hoechst 33342 and Ki67 staining was performed to determine the cell-cycle distribution of HSPCs. Competitive transplantation experiments were used to evaluate the effect of Fbxw11 on the reconstitution potential of HSPCs. Single-cell RNA sequencing (scRNA-seq) was employed to reveal the transcriptomic alterations in HSPCs. RESULTS: The expression of Fbxw11 was higher in Lin-c-Kit+Sca-1+ (LSK) cells and myeloid progenitors than in lymphoid progenitors. Fbxw11 played negative roles in colony-forming and quiescence maintenance of HSPCs in vitro. Furthermore, serial competitive transplantation experiments revealed that Fbxw11 impaired the repopulation capacity of HSPCs. The proportion of granulocytes (Gr-1+CD11b+) in the differentiated mature cells was significantly higher than that in the control group, T cells and B cells were lower. Moreover, scRNA-seq revealed seven cell clusters in HSPCs. In addition, Fbxw11 downregulated the expression of Cebpa, Myc and Arid5b, which are significant regulators of HSPC activity, in most cell clusters. CONCLUSION: Our data demonstrate that Fbxw11 plays a negative role in the maintenance of HSPCs in vitro and repopulation capacity in vivo. Our data also provide valuable transcriptome references for HSPCs in homeostasis.

Loss of IRF7 accelerates acute myeloid leukemia progression and induces VCAM1-VLA-4 mediated intracerebral invasion.

Interferon regulatory factor 7 (IRF7) is widely studied in inflammatory models. Its effects on malignant progression have been documented mainly from the perspective of the microenvironment. However, its role in leukemia has not been established. Here we used MLL-AF9-induced acute myeloid leukemia (AML) mouse models with IRF7 knockout or overexpression and xenograft mouse models to explore the intrinsic effects of IRF7 in AML. AML-IRF7-/- mice exhibited accelerated disease progression with intracerebral invasion of AML cells. AML-IRF7-/- cells showed increased proliferation and elevated leukemia stem cell (LSC) levels. Overexpression of IRF7 in AML cells decreased cell proliferation and LSC levels. Furthermore, overexpression of transforming growth-interacting factor 1 (TGIF1) rescued the enhanced proliferation and high LSC levels caused by IRF7 deficiency. Moreover, upregulation of vascular cell adhesion molecule 1 (VCAM1), which correlated with high LSC levels, was detected in AML-IRF7-/- cells. In addition, blocking VCAM1-very late antigen 4 (VLA-4) axis delayed disease progression and attenuated intracerebral invasion of AML cells. Therefore, our findings uncover the intrinsic effects of IRF7 in AML and provide a potential strategy to control central nervous system myeloid leukemia.

poly(I:C) synergizes with proteasome inhibitors to induce apoptosis in cervical cancer cells.

Cervical cancer is one of the most common malignancies in women, with a poor survival rate. Thus, there is a need to define effective combination strategies to improve therapy. In this study, we report that dsRNA poly(I:C) up-regulated the expression of IFNß and apoptosis-associated genes in cervical cancer cells, activating both intrinsic and extrinsic apoptotic pathways, and eventually inducing cell death. Similarly, proteasome inhibitors also effectively induced cervical cancer cell apoptosis, probably through prevention of p53 degradation, inhibiting NF-κB signal activation and decreasing BCL-2 expression. Importantly, the combination of poly(I:C) with proteasome inhibitors enhanced caspase-8 and caspase-9 activation, and synergistically induced cervical cancer cell apoptosis. Both activated p38 signals and increased ROS levels, and their combination extended these effects. Collectively, we show that the activation of multiple pro-apoptotic pathways by poly(I:C) and proteasome inhibitors underpin a synergistic effect on inducing cervical cancer cell death, suggesting a potential therapeutic combination with clinical relevance.

DDIT4 mediates the proliferation-promotive effect of IL-34 in human monocytic leukemia cells.

Interleukin 34 (IL-34) is a cytokine that shares the receptor with colony-stimulating factor 1 (CSF-1). IL-34 is involved in a broad range of pathologic processes including cancer. We previously demonstrated that IL-34 promoted the proliferation and colony formation of human acute monocytic leukemia (AMoL) cells. However, the mechanism has not been elucidated. Here, by analyzing the gene profiles of Molm13 and THP1 cells overexpressing IL-34 (Molm13-IL-34 and THP1-IL-34), upregulation of the DNA damage-inducible transcript 4 (DDIT4) was detected in both series. Knockdown of DDIT4 effectively inhibited the proliferation, promoted apoptosis and colony formation in Molm13-IL-34 and THP1-IL-34 cells. Our results suggest that DDIT4 mediates the proliferation-promotive effect of IL-34 whereas does not mediate the promotive effect of IL-34 on colony formation in AMoL cells.

Subgingival microbiome in Chinese patients with generalized aggressive periodontitis compared to healthy controls.

OBJECTIVE: The aim of the study was to profile the subgingival microbiome of Chinese adults with generalized aggressive periodontitis (GAgP) using human oral microbe identification microarray (HOMIM), and to compare the results with matched periodontal healthy controls. DESIGN: 15 subjects with GAgP and 15 age- and gender- matched periodontal healthy controls were included. Subgingival plaque samples were collected from the deepest pockets of patients with GAgP and matched sites in controls and then analyzed by 16S rRNA-based microarrays. Student's paired t-test was used to compare clinical parameters and mean number of bacterial taxa detected between the two groups. Fisher's exact probability test and Wilcoxon Rank Sum were used to compare bacterial species between all samples. A multiple linear regression model was used for correlations among age, gender and bacterial with clinical parameters. RESULTS: From a total sum of 379 strains tested, 171 bacterial strains were detected from subgingival plaques of the GAgP patients, more than the 157 strains detected in control group. Mean number of subgingival bacterial taxa detected in GAgP group was 68 (SD = 21.06) while in control group was 45 (SD = 21.60). 47 bacterial taxa were detected more frequently in GAgP group while 12 taxa were more prevalent in control group. The significantly more prevalent and abundant taxa of bacteria in GAgP group included Filifactor alocis, Desulfobulbus sp., Fretibacterium sp., Porphyromonas gingivalis, Tannerella forsythia, Porphyromon as endodontalis, Peptostreptococcaceae spp., Parvimonas micra, Eubacterium nodatum and Eubacterium saphenum. Meanwhile the more abundant taxa in control group were Streptococcus spp. and Pseudomonas aeruginosa. CONCLUSIONS: There are more taxa of bacteria in subgingival plaques of Chinese patients with GAgP than in healthy controls. F. alocis, Desulfobulbus sp., Fretibacterium sp., P. gingivalis and T. forsythia are strongly associated with GAgP. High-throughout microbiological results may help dentists have a better understanding of subgingival microbiome of GAgP.

Satisfaction among early and mid-career dentists in a metropolitan dental hospital in China.

A growing body of research has examined career satisfaction among dentists using a standardized instrument, dentist satisfaction survey (DSS). This project examined career satisfaction of early to mid-career dentists in China, a population whose career satisfaction, heretofore, has not been studied. This is an especially critical time to examine career satisfaction because of health care reform measures being implemented in China. A culturally sensitive Chinese-language version of the DSS (CDSS) was developed and electronically administered to 367 early and mid-career dentists in a tertiary dental hospital in Beijing, China. One hundred and seventy respondents completed the survey. The average total career score was 123, with a range of 82-157. Data analysis showed some significant differences in total career score and several subscales based on gender, working hours per week, and years in practice. A stepwise regression model revealed that two variables predicted total career score: working hours per week and gender. Stepwise regression also demonstrated that four subscales significantly predicted the overall professional satisfaction subscale score: respect, delivery of care, income and patient relations. Implications of these results are discussed in light of the health care delivery system and dentist career paths in China.