Early megakaryocyte lineage-committed progenitors in adult mouse bone marrow.

Hematopoietic stem cells (HSCs) have been considered to progressively lose their self-renewal and differentiation potentials prior to the commitment to each blood lineage. However, recent studies have suggested that megakaryocyte progenitors (MkPs) are generated at the level of HSCs. In this study, we newly identified early megakaryocyte lineage-committed progenitors (MgPs) mainly in CD201-CD48- cells and CD48+ cells separated from the CD150+CD34-Kit+Sca-1+Lin- HSC population of the bone marrow in adult mice. Single-cell colony assay and single-cell transplantation showed that MgPs, unlike platelet-biased HSCs, had little repopulating potential in vivo, but formed larger megakaryocyte colonies in vitro (on average 8 megakaryocytes per colony) than did previously reported MkPs. Single-cell RNA sequencing supported that HSCs give rise to MkPs through MgPs along a Mk differentiation pathway. Single-cell reverse transcription polymerase chain reaction (RT-PCR) analysis showed that MgPs expressed Mk-related genes, but were transcriptionally heterogenous. Clonal culture of HSCs suggested that MgPs are not direct progeny of HSCs. We propose a differentiation model in which HSCs give rise to MgPs which then give rise to MkPs, supporting a classic model in which Mk-lineage commitment takes place at a late stage of differentiation.

Recent Trends and Innovations in Bead-Based Biosensors for Cancer Detection.

Demand is strong for sensitive, reliable, and cost-effective diagnostic tools for cancer detection. Accordingly, bead-based biosensors have emerged in recent years as promising diagnostic platforms based on wide-ranging cancer biomarkers owing to the versatility, high sensitivity, and flexibility to perform the multiplexing of beads. This comprehensive review highlights recent trends and innovations in the development of bead-based biosensors for cancer-biomarker detection. We introduce various types of bead-based biosensors such as optical, electrochemical, and magnetic biosensors, along with their respective advantages and limitations. Moreover, the review summarizes the latest advancements, including fabrication techniques, signal-amplification strategies, and integration with microfluidics and nanotechnology. Additionally, the challenges and future perspectives in the field of bead-based biosensors for cancer-biomarker detection are discussed. Understanding these innovations in bead-based biosensors can greatly contribute to improvements in cancer diagnostics, thereby facilitating early detection and personalized treatments.

p21/Zbtb18 repress the expression of cKit to regulate the self-renewal of hematopoietic stem cells.

The maintenance of hematopoietic stem cells (HSCs) is a complex process involving numerous cell-extrinsic and -intrinsic regulators. The first member of the cyclin-dependent kinase family of inhibitors to be identified, p21, has been reported to perform a wide range of critical biological functions, including cell cycle regulation, transcription, differentiation, and so on. Given the previous inconsistent results regarding the functions of p21 in HSCs in a p21-knockout mouse model, we employed p21-tdTomato (tdT) mice to further elucidate its role in HSCs during homeostasis. The results showed that p21-tdT+ HSCs exhibited increased self-renewal capacity compared to p21-tdT- HSCs. Zbtb18, a transcriptional repressor, was upregulated in p21-tdT+ HSCs, and its knockdown significantly impaired the reconstitution capability of HSCs. Furthermore, p21 interacted with ZBTB18 to co-repress the expression of cKit in HSCs and thus regulated the self-renewal of HSCs. Our data provide novel insights into the physiological role and mechanisms of p21 in HSCs during homeostasis independent of its conventional role as a cell cycle inhibitor.

A novel long non-coding RNA MIR4500HG003 promotes tumor metastasis through miR-483-3p-MMP9 axis in triple-negative breast cancer.

Breast cancer (BC) is the most common cancer and the leading cause of cancer-related deaths in women worldwide. The 5-year survival rate is over 90% in BC patients, but once BC cells metastasis into distal organs, it is dramatically decreasing to less than 30%. Especially, triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. Understanding the underline mechanisms of TNBC metastasis is a critical issue. Non-coding RNAs, including of lncRNAs and microRNAs, are non-protein-coding transcripts and have been reported as important regulators in TNBC metastasis. However, the underline mechanisms for non-coding RNAs regulating TNBC metastasis remain largely unclear. Here, we found that lncRNA MIR4500HG003 was highly expressed in highly metastatic MDA-MB-231 TNBC cells and overexpression of MIR4500HG003 enhanced metastasis ability in vitro and in vivo and promoted MMP9 expression. Furthermore, we found MIR4500HG003 physically interacted with miR-483-3p and reporter assay showed miR-483-3p attenuated MMP9 expression. Importantly, endogenous high expressions of MIR4500HG003 were correlated with tumor recurrence in TNBC patients with tumor metastasis. Taken together, our findings suggested that MIR4500HG003 promotes metastasis of TNBC through miR-483-3p-MMP9 signaling axis and may be used as potential prognostic marker for TNBC patients.

Comparison of different treatment strategies for T3N1-3 stage gastric cancer based on the SEER database.

Treatment options for T3N1 stage gastric cancer exhibit regional variation, with optimal approach remaining unclear. We derived our data from the SEER database, using Cox proportional risk regression models for univariate and multivariate analyses of 5-years overall survival (5yOS) and 5-years cancer-specific survival (5yCSS). The results showed that younger age, female, non-white race, highly differentiated histologic grade, non-Signet ring cell adenocarcinoma, low N stage, lesser curvature of the stomach, OP followed by adjuvant C/T with or without RT, partial gastrectomy, C/T and others, Radiation therapy, and Chemotherapy were significantly associated with better 5yOS and 5yCSS. For patients with stage T3N1-3 gastric cancer, multimodal treatment regimens demonstrate superior survival outcomes compared to surgery or radiotherapy alone. Among them, OP followed by adjuvant C/T with or without RT emerges as particularly efficacious, potentially offering enhanced benefits for non-Asian populations.

Preoperative localization for pulmonary nodules: a meta-analysis of coil and liquid materials.

PURPOSE: This study was designed to conduct pooled comparisons of the relative clinical efficacy and safety of computed tomography (CT)-guided localization for pulmonary nodules (PNs) using either coil- or liquid material-based approaches. MATERIAL AND METHODS: Relevant articles published as of July 2023 were identified in the Web of Science, PubMed, and Wanfang databases, and pooled analyses of relevant endpoints were then conducted. RESULTS: Six articles that enrolled 287 patients (341 PNs) and 247 patients (301 PNs) that had respectively undergone CT-guided localization procedures using coil- and liquid material-based approaches prior to video-assisted thoracic surgery (VATS) were included in this meta-analysis. The liquid material group exhibited a significantly higher pooled successful localization rate as compared to the coil group (p = 0.01), together with significantly lower pooled total complication rates (p = 0.0008) and pneumothorax rates (p = 0.01). Both groups exhibited similar rates of pulmonary hemorrhage (p = 0.44) and successful wedge resection (p = 0.26). Liquid-based localization was also associated with significant reductions in pooled localization and VATS procedure durations (p = 0.004 and 0.007). CONCLUSIONS: These data are consistent with CT-guided localization procedures performed using liquid materials being safer and more efficacious than coil-based localization in patients with PNs prior to VATS resection.

The FGFR2 Variant rs13387042 is Associated With Breast Cancer Risk: A Meta-Analysis and Systematic Review.

OBJECTIVE: The association of FGFR2-rs13387042 polymorphism with breast cancer (BC) susceptibility in women remains inconclusive due to varying reports. In this study, we conducted a meta-analysis to explore the relationship between FGFR2-rs13387042 polymorphism and susceptibility to BC. METHODS: Relevant literature were acquired through searches across multiple databases. Odds ratio (OR) values were pooled to assess the risk of BC for different alleles and genotypes. The heterogeneity among the included literature was evaluated. Sensitivity analysis was used to verify the stability of the results. Egger's linear regression test was used to assess the significance of publication bias of the included literature. RESULTS: A total of 17 publications were included, encompassing 122,607 cases and 175,966 controls. There was significantly increased risk of BC for allele A compared with G (OR = 1.15, 95% CI = 1.14-1.67, P < .001), genotype AA compared with GG (OR = 1.34, 95% CI = 1.29-1.38, P < .001), and genotype GA compared with GG (OR = 1.19, 95% CI = 1.12-1.26, P < .001). Both Egger's test and funnel plot indicated the presence of publication bias. After adjusting potential publication bias by the trim-and-fill method, the comparison of allele A versus G (OR = 1.15, 95% CI = 1.13-1.17, P < .001), genotype AA versus GG (OR = 1.32, 95% CI = 1.28-1.37, P < .001), and genotype GA versus GG (OR = 1.15, 95% CI = 1.09-1.22, P < .001) remained statistically significant. In various subgroups, the allele A showed significantly higher risk of BC upon allele G in estrogen receptor (ER) positive BC, ER negative BC, progesterone receptor (PR) positive BC, PR negative BC, triple-negative BC, pathological grade I BC, grade II BC, and grade III breast cancer. The subsequent sensitivity analysis suggested the above findings stable and reliable. CONCLUSION: In this study, we found that the allele A of the FGFR2-rs13387042 polymorphism is associated with increased risk of developing breast cancer. This study underscores its potential as a genetic marker for personalized risk assessment and targeted interventions.

Immunogenic Material Vaccine for Cancer Immunotherapy by Structure-Dependent Immune Cell Trafficking and Modulation.

Inherently immunogenic materials offer enormous prospects in enhancing vaccine efficacy. However, the understanding and improving material adjuvanticity remain elusive. Herein how the structural presentation of immunopotentiators in a material governs the dynamic dialogue between innate and adaptive immunity for enhanced cancer vaccination is reported. The immunopotentiator manganese into six differing structures that resemble the architectures of two types of pathogens (spherical viruses or rod-like bacteria) is precisely manipulated. The results reveal that innate immune cells accurately sense and respond to the architectures, of which two outperformed material candidates (151 nm hollow spheres and hollow microrods with an aspect ratio of 4.5) show higher competence in creating local proinflammatory environment with promoted innate immune cell influx and stimulation on dendritic cells (DCs). In combination with viral peptides, model proteins, or cell lysate antigens, the outperformed microrod material remarkably primes antigen-specific CD8 cytolytic T cells. In prophylactic and therapeutic regimens, the microrod adjuvanted vaccines display optimal aptitude in tumor suppression in four aggressive murine tumor models, by promoting the infiltration of heterogeneous cytolytic effector cells while decreasing suppressive immunoregulatory populations in tumors. This study demonstrates that a rationally selected architecture of immunogenic materials potentially advances the clinical reality of cancer vaccination.

The ATF4-RPS19BP1 axis modulates ribosome biogenesis to promote erythropoiesis.

Hematopoietic differentiation is controlled by intrinsic regulators and the extrinsic hematopoietic niche. Activating transcription factor 4 (ATF4) plays a crucial role in the function of fetal and adult hematopoietic stem cell maintenance; however, the precise function of ATF4 in the bone marrow niche and the mechanism by which ATF4 regulates adult hematopoiesis remain largely unknown. Here, we employ four cell-type-specific mouse Cre lines to achieve conditional knockout of Atf4 in Cdh5+ endothelial cells, Prx1+ bone marrow stromal cells, Osx+ osteo-progenitor cells, and Mx1+ hematopoietic cells, and uncover the role of Atf4 in niche cells and hematopoiesis. Intriguingly, depletion of Atf4 in niche cells does not affect hematopoiesis; however, Atf4-deficient hematopoietic cells exhibit erythroid differentiation defects, leading to hypoplastic anemia. Mechanistically, ATF4 mediates direct regulation of Rps19bp1 transcription, which is, in turn, involved in 40S ribosomal subunit assembly to coordinate ribosome biogenesis and promote erythropoiesis. Finally, we demonstrate that under conditions of 5-fluorouracil-induced stress, Atf4 depletion impedes the recovery of hematopoietic lineages, which requires efficient ribosome biogenesis. Taken together, our findings highlight the indispensable role of the ATF4-RPS19BP1 axis in the regulation of erythropoiesis.

Insufficient secretion of pancreatic FGF21 is the toxicological mechanism and therapeutic target of asparaginase-associated pancreatitis.

Asparaginase-associated pancreatitis (AAP) is a severe and potentially life-threatening drug-induced pancreas targeted toxicity in the combined chemotherapy of acute lymphoblastic leukemia among children and adolescents. The toxicological mechanism of AAP is not yet clear, and there are no effective preventive and treatment measures available clinically. Fibroblast growth factor 21 (FGF21) is a secretory hormone that regulates lipid, glucose, and energy metabolism balance. Acinar tissue is the main source of pancreatic FGF21 protein and plays an important role in maintaining pancreatic metabolic balance. In this study, we found that the decrease of FGF21 in pancreas is closely related to AAP. Pegaspargase (1 IU/g) induces widespread edema and inflammatory infiltration in the pancreas of rats/mice. The specific expression of FGF21 in the acinar tissue of AAP rats was significantly downregulated. Asparaginase caused dysregulation of the ATF4/ATF3/FGF21 axis in acinar tissue or cells, and thus mediated the decrease of FGF21. It greatly activated ATF3 in the acinar, which competed with ATF4 for the Fgf21 promoter, thereby inhibiting the expression of FGF21. Pharmacological replacement of FGF21 (1 mg/kg) or PERK inhibitors (GSK2656157, 25 mg/kg) can significantly mitigate the pancreatic tissue damage and reduce markers of inflammation associated with AAP, representing potential strategies for the prevention and treatment of AAP.

Identification of prognostic signatures in remnant gastric cancer through an interpretable risk model based on machine learning: a multicenter cohort study.

OBJECTIVE: The purpose of this study was to develop an individual survival prediction model based on multiple machine learning (ML) algorithms to predict survival probability for remnant gastric cancer (RGC). METHODS: Clinicopathologic data of 286 patients with RGC undergoing operation (radical resection and palliative resection) from a multi-institution database were enrolled and analyzed retrospectively. These individuals were split into training (80%) and test cohort (20%) by using random allocation. Nine commonly used ML methods were employed to construct survival prediction models. Algorithm performance was estimated by analyzing accuracy, precision, recall, F1-score, area under the receiver operating characteristic curve (AUC), confusion matrices, five-fold cross-validation, decision curve analysis (DCA), and calibration curve. The best model was selected through appropriate verification and validation and was suitably explained by the SHapley Additive exPlanations (SHAP) approach. RESULTS: Compared with the traditional methods, the RGC survival prediction models employing ML exhibited good performance. Except for the decision tree model, all other models performed well, with a mean ROC AUC above 0.7. The DCA findings suggest that the developed models have the potential to enhance clinical decision-making processes, thereby improving patient outcomes. The calibration curve reveals that all models except the decision tree model displayed commendable predictive performance. Through CatBoost-based modeling and SHAP analysis, the five-year survival probability is significantly influenced by several factors: the lymph node ratio (LNR), T stage, tumor size, resection margins, perineural invasion, and distant metastasis. CONCLUSIONS: This study established predictive models for survival probability at five years in RGC patients based on ML algorithms which showed high accuracy and applicative value.

Recombinant Human Thrombopoietin Promotes Platelet Engraftment in Severe Aplastic Anemia Patients Following Treatment With Haploid Hematopoietic Stem Cell Transplantation using Modified Post-Transplantation Cyclophosphamide.

BACKGROUND: Recombinant human TPO (rhTPO) promotes platelet engraftment in patients after allogeneic HSCT (allo-HSCT). However, the effects of rhTPO on platelet recovery after Haplo-HSCT in patients with severe aplastic anemia (SAA) have not been intensively studied. OBJECTIVE: We aimed to evaluate the efficacy of rhTPO on platelet engraftment in patients with SAA who were treated with Haplo-HSCT using post-transplantation cyclophosphamide (PTCy). STUDY DESIGN: SAA patients who received Haplo-HSCT plus PTCy regimen were divided into the rhTPO group (with subcutaneous injection of rhTPO, n = 28) and Control group (no rhTPO administration, n = 27). The engraftment of platelet/neutrophil, platelet infusion amount, and transplant-related complications between the 2 groups were compared. RESULTS: All 55 patients showed successful hematopoietic reconstitution. The median time of platelet engraftment was 11 (9 to 29) days in the rhTPO group and 14 (9 to 28) days in the Control group (P = .003). The rhTPO group had a significantly reduced amount of infused platelets compared to the Control group (2 (1 to 11.5) versus 3 (1 to 14) therapeutic doses; P = .004). There was no significant difference between the 2 groups regarding median time of neutrophil engraftment, incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), incidence of cytomegalovirus or Epstein-Barr virus reactivation, 3-yr overall survival rate, and failure-free-survival rate. No obvious adverse reactions were observed in the rhTPO group. CONCLUSION: rhTPO promoted platelet engraftment, reduced the amount of transfused platelets, and demonstrated good safety profiles without evidence of adverse reactions in patients with SAA who received Haplo-HSCT using PTCy regimen.

Pulse pressure variation guided goal-direct fluid therapy decreases postoperative complications in elderly patients undergoing laparoscopic radical resection of colorectal cancer: a randomized controlled trial.

OBJECTIVE: The use of goal-directed fluid therapy (GDFT) has been shown to reduce complications and improve prognosis in high-risk abdominal surgery patients. However, the utilization of pulse pressure variation (PPV) guided GDFT in laparoscopic surgery remains a subject of debate. We hypothesized that utilizing PPV guidance for GDFT would optimize short-term prognosis in elderly patients undergoing laparoscopic radical resection for colorectal cancer compared to conventional fluid therapy. METHODS: Elderly patients undergoing laparoscopic radical resection of colorectal cancer were randomized to receive either PPV guided GDFT or conventional fluid therapy and explore whether PPV guided GDFT can optimize the short-term prognosis of elderly patients undergoing laparoscopic radical resection of colorectal cancer compared with conventional fluid therapy. RESULTS: The incidence of complications was significantly lower in the PPV group compared to the control group (32.8% vs. 57.1%, P = .009). Additionally, the PPV group had a lower occurrence of gastrointestinal dysfunction (19.0% vs. 39.3%, P = .017) and postoperative pneumonia (8.6% vs. 23.2%, P = .033) than the control group. CONCLUSION: Utilizing PPV as a monitoring index for GDFT can improve short-term prognosis in elderly patients undergoing laparoscopic radical resection of colorectal cancer. REGISTRATION NUMBER: ChiCTR2300067361; date of registration: January 5, 2023.

Small extracellular vesicles derived from acute myeloid leukemia cells promote leukemogenesis by transferring miR-221-3p.

Small extracellular vesicles (sEVs) transfer cargos between cells and participate in various physiological and pathological processes through their autocrine and paracrine effects. However, the pathological mechanisms employed by sEV-encapsulated microRNAs (miRNAs) in acute myeloid leukemia (AML) are still obscure. In this study, we aimed to investigate the effects of AML cells-derived sEVs (AML-sEVs) on AML cells and delineate the underlying mechanisms. We initially used high-throughput sequencing to identify miR-221-3p as the miRNA prominently enriched in AML-sEVs. Our findings revealed that miR-221-3p promoted AML cell proliferation and leukemogenesis by accelerating cell cycle entry and inhibiting apoptosis. Furthermore, Gbp2 was confirmed as a target gene of miR-221-3p by dual luciferase reporter assays and rescue experiments. Additionally, AML-sEVs impaired the clonogenicity, particularly the erythroid differentiation ability, of hematopoietic stem and progenitor cells. Taken together, our findings reveal how sEVs-delivered miRNAs contribute to AML pathogenesis, which can be exploited as a potential therapeutic target to attenuate AML progression.

Histological analysis of (antral) follicle density in ovarian cortex tissue attached to stripped endometriomas.

PURPOSE: When resecting endometriomas with the stripping technique, in the majority of cases, a thin line of adjacent ovarian cortex is attached to the endometrioma. In this study, we performed histological analysis to determine (antral) follicle density in the ovarian cortex tissue attached to stripped endometriomas and assessed patient- and surgical characteristics that could affect this. METHODS: Histological slides of previously removed endometriomas were assessed. Follicles in the attached ovarian tissue were classified according to maturation, and follicular density was determined. Immunofluorescent staining of antral follicles in a subset of endometriomas was also performed. RESULTS: In 90 out of 96 included endometriomas (93.7%), ovarian tissue attached to the cyst wall was observed. One thousand nine hundred forty-four follicles at different maturation stages were identified (3 follicles/mm3). Follicle density was negatively associated with age (p < 0.001). Antral follicles (< 7-mm diameter) were present in the ovarian tissue attached to 35 endometriomas (36.5%) derived from younger patients compared to endometriomas where none were detected (30 versus 35 years, p = 0.003). Antral follicle density was 1 follicle/mm3. Based on immunofluorescence, healthy antral follicles were identified in two out of four examined endometriomas. CONCLUSIONS: Ovarian tissue attached to stripped endometriomas holds potential as a non-invasive source for antral follicles. In theory, application of IVM could be an interesting alternative FP option in young patients with endometriomas who undergo cystectomy in order to transform the surgical collateral damage to a potential oocyte source. Our results encourage future research with fresh tissue to further assess the quality and potential of these follicles. TRIAL REGISTRATION: Clinical Trials.gov Identifier: B21.055 (METC LDD), date of registration 12-08-2021, retrospectively registered.

Arenobufagin modulation of PCSK9-mediated cholesterol metabolism induces tumor-associated macrophages polarisation to inhibit hepatocellular carcinoma progression.

BACKGROUND: The tumor microenvironment (TME) of hepatocellular carcinoma is heterogeneous enough to be prone to drug resistance and multidrug resistance during treatment, and reprogramming of cholesterol metabolism in TME mediates tumor-associated macrophages (TAMs) polarization, which has an impact on the regulation of malignant tumor progression. Arenobufagin (ARBU) was extracted and isolated from toad venom (purity ≥98 %), which is the main active ingredient of the traditional Chinese medicine Chan'su with good anti-tumor effects. PURPOSE: To investigate the regulatory effect of ARBU on lipid metabolism in tumor microenvironment, interfere with macrophage polarization, and determine its mechanism of action on liver cancer progression. METHODS: In this study, the inhibitory effect of ARBU on the proliferation of Hepa1-6 in C57 mice and the safety of administration were evaluated by establishing a transplanted tumor model of Hepa1-6 hepatocellular carcinoma mice and using 5-FU as a positive control drug. In addition, we constructed a co-culture system of Hepa1-6 cells and primary mouse macrophages to study the effects of ARBU on the polarization phenotypic transformation of macrophages and the proliferation and migration of hepatoma cells. The influence of ARBU on the metabolism of lipids in the hepatocellular carcinoma mouse model was investigated by combining it with lipidomics technology. The influence of ARBU on the PCSK9/LDL-R signaling pathway and macrophage polarization, which regulate cholesterol metabolism, was tested by using qRT-PCR, gene editing, IF, and WB. CONCLUSION: ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration.

Differentiation route determines the functional outputs of adult megakaryopoiesis.

Emerging evidence has revealed a direct differentiation route from hematopoietic stem cells to megakaryocytes (direct route), in addition to the classical differentiation route through a series of restricted hematopoietic progenitors (stepwise route). This raises the question of the importance of two alternative routes for megakaryopoiesis. Here, we developed fate-mapping systems to distinguish the two routes, comparing their quantitative and functional outputs. We found that megakaryocytes were produced through the two routes with comparable kinetics and quantity under homeostasis. Single-cell RNA sequencing of the fate-mapped megakaryocytes revealed that the direct and stepwise routes contributed to the niche-supporting and immune megakaryocytes, respectively, but contributed to the platelet-producing megakaryocytes together. Megakaryocytes derived from the two routes displayed different activities and were differentially regulated by chemotherapy and inflammation. Our work links differentiation route to the heterogeneity of megakaryocytes. Alternative differentiation routes result in variable combinations of functionally distinct megakaryocyte subpopulations poised for different physiological demands.

Three-dimensional facial soft-tissue changes after surgical orthodontics in different vertical facial types of skeletal Class III malocclusion: A retrospective study.

The study compared the soft-tissue response to hard-tissue movement among different Class III vertical facial types after orthognathic surgery (OGS). The study included 90 consecutive adult patients with skeletal Class III malocclusion who underwent two-jaw OGS. Patients were divided into three groups (high, medium, and low angle) based on the presurgical Frankfort-mandibular plane angle. Cone-beam computerized tomographs were taken before surgery and after debonding. Soft- and hard-tissue linear and angular measurements were performed using three-dimensional reconstruction images. One-way analysis of variance was used for intergroup comparisons. Soft tissue tended to respond more to hard-tissue movement in the lower lip area in patients with low angle (mean = 0.089, SD = 0.047, p = 0.023), whereas no significant difference was observed for other sites. Consistently, L1/Li thickness increased most significantly in the high-angle group (mean = 1.98, SD = 2.14, p = 0.0001), and B/Si thickness decreased most significantly after surgery (mean = 2.16, SD = 2.68, p = 0.016). The findings suggest that the high-angle group had a higher chance of undergoing genioplasty to enhance chin contour. Different OGS plans should be considered for different Class III vertical facial types.

Ferritin-mediated mitochondrial iron homeostasis is essential for the survival of hematopoietic stem cells and leukemic stem cells.

Iron metabolism plays a crucial role in cell viability, but its relationship with adult stem cells and cancer stem cells is not fully understood. The ferritin complex, responsible for intracellular iron storage, is important in this process. We report that conditional deletion of ferritin heavy chain 1 (Fth1) in the hematopoietic system reduced the number and repopulation capacity of hematopoietic stem cells (HSCs). These effects were associated with a decrease in cellular iron level, leading to impaired mitochondrial function and the initiation of apoptosis. Iron supplementation, antioxidant, and apoptosis inhibitors reversed the reduced cell viability of Fth1-deleted hematopoietic stem and progenitor cells (HSPCs). Importantly, leukemic stem cells (LSCs) derived from MLL-AF9-induced acute myeloid leukemia (AML) mice exhibited reduced Fth1 expression, rendering them more susceptible to apoptosis induced by the iron chelation compared to normal HSPCs. Modulating FTH1 expression using mono-methyl fumarate increased LSCs resistance to iron chelator-induced apoptosis. Additionally, iron supplementation, antioxidant, and apoptosis inhibitors protected LSCs from iron chelator-induced cell death. Fth1 deletion also extended the survival of AML mice. These findings unveil a novel mechanism by which ferritin-mediated iron homeostasis regulates the survival of both HSCs and LSCs, suggesting potential therapeutic strategies for blood cancer with iron dysregulation.

Functional profile of perilesional gray matter in focal cortical dysplasia: an fMRI study.

Objectives: We aim to investigate the functional profiles of perilesional gray matter (GM) in epileptic patients with focal cortical dysplasia (FCD) and to correlate these profiles with FCD II subtypes, surgical outcomes, and different antiseizure medications (ASMs) treatment response patterns. Methods: Nine patients with drug-responsive epilepsy and 30 patients with drug-resistant epilepsy (11 were histologically confirmed FCD type IIa, 19 were FCD type IIb) were included. Individual-specific perilesional GM and contralateral homotopic GM layer masks were generated. These masks underwent a two-voxel (2 mm) dilation from the FCD lesion and contralateral homotopic region, resulting in 10 GM layers (20 mm). Layer 1, the innermost, progressed to Layer 10, the outermost. Amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) analyses were conducted to assess the functional characteristics of ipsilateral perilesional GM and contralateral homotopic GM. Results: Compared to the contralateral homotopic GM, a significant reduction of ALFF was detected at ipsilateral perilesional GM layer 1 to 6 in FCD type IIa (after Bonferroni correction p < 0.005, paired t-test), whereas a significant decrease was observed at ipsilateral perilesional GM layer 1 to 2 in FCD type IIb (after Bonferroni correction p < 0.005, paired t-test). Additionally, a significant decrease of the ReHo was detected at ipsilateral perilesional GM layer 1 compared to the CHRs in FCD type IIb. Notably, complete resection of functional perilesional GM alterations did not correlate with surgical outcomes. Compared to the contralateral homotopic GM, a decreased ALFF in the ipsilateral perilesional GM layer was detected in drug-responsive patients, whereas decreased ALFF in the ipsilateral perilesional GM layer 1-6 and decreased ReHo at ipsilateral perilesional GM layer 1 were observed in drug-resistant patients (after Bonferroni correction p < 0.005, paired t-test). Conclusion: Our findings indicate distinct functional profiles of perilesional GM based on FCD histological subtypes and ASMs' response patterns. Importantly, our study illustrates that the identified functional alterations in perilesional GM may not provide sufficient evidence to determine the epileptogenic boundary required for surgical resection.