Traditional Chinese medicine for post-viral olfactory dysfunction: A systematic review.

Background: Post-viral olfactory dysfunction (PVOD) is the common symptoms of long COVID, lacking of effective treatments. Traditional Chinese medicine (TCM) is claimed to be effective in treating olfactory dysfunction, but the evidence has not yet been critically appraised. We conducted a systematic review to evaluate the effectiveness and safety of TCM for PVOD. Methods: We searched eight databases to identified clinical controlled studies about TCM for PVOD. The Cochrane risk of bias tools and GRADE were used to evaluate the quality of evidence. Risk ratio (RR), mean differences (MD), and 95 % confidence interval (CI), were used for effect estimation and RevMan 5.4.1 was used for data analysis. Results: Six randomized controlled trials (RCTs) (545 participants), two non-randomized controlled trials (non-RCTs) (112 participants), and one retrospective cohort study (30 participants) were included. The overall quality of included studies was low. Acupuncture (n = 8) and acupoint injection (n = 3) were the mainly used TCM therapies. Five RCTs showed a better effect in TCM group. Four trials used acupuncture, and three trials used acupoint injection. The results of two non-RCTs and one cohort study were not statistically significant. Two trials reported mild to moderate adverse events (pain and brief syncope caused by acupuncture or acupoint injection). Conclusions: Limited evidence focus on acupuncture and acupoint injection for PVOD and suggests that acupuncture and acupoint injection may be effective in improving PVOD. More well-designed trials should focus on acupuncture to confirm the benefit. Protocol registration: The protocol of this review was registered at PROSPERO: CRD42022366776.

Leptin attenuates the osteogenic induction potential of BMP9 by increasing ß-catenin malonylation modification via Sirt5 down-regulation.

BMP9 has demonstrated significant osteogenic potential. In this study, we investigated the effect of Leptin on BMP9-induced osteogenic differentiation. Firstly, we found Leptin was decreased during BMP9-induced osteogenic differentiation and serum Leptin concentrations were increased in the ovariectomized (OVX) rats. Both in vitro and in vivo, exogenous expression of Leptin inhibited the process of osteogenic differentiation, whereas silencing Leptin enhanced. Exogenous Leptin could increase the malonylation of ß-catenin. However, BMP9 could increase the level of Sirt5 and subsequently decrease the malonylation of ß-catenin; the BMP9-induced osteogenic differentiation was inhibited by silencing Sirt5. These data suggested that Leptin can inhibit the BMP9-induced osteogenic differentiation, which may be mediated through reducing the activity of Wnt/ß-catenin signalling via down-regulating Sirt5 to increase the malonylation level of ß-catenin partly.

Performance of ChatGPT on Chinese Master's Degree Entrance Examination in Clinical Medicine.

BACKGROUND: ChatGPT is a large language model designed to generate responses based on a contextual understanding of user queries and requests. This study utilised the entrance examination for the Master of Clinical Medicine in Traditional Chinese Medicine to assesses the reliability and practicality of ChatGPT within the domain of medical education. METHODS: We selected 330 single and multiple-choice questions from the 2021 and 2022 Chinese Master of Clinical Medicine comprehensive examinations, which did not include any images or tables. To ensure the test's accuracy and authenticity, we preserved the original format of the query and alternative test texts, without any modifications or explanations. RESULTS: Both ChatGPT3.5 and GPT-4 attained average scores surpassing the admission threshold. Noteworthy is that ChatGPT achieved the highest score in the Medical Humanities section, boasting a correct rate of 93.75%. However, it is worth noting that ChatGPT3.5 exhibited the lowest accuracy percentage of 37.5% in the Pathology division, while GPT-4 also displayed a relatively lower correctness percentage of 60.23% in the Biochemistry section. An analysis of sub-questions revealed that ChatGPT demonstrates superior performance in handling single-choice questions but performs poorly in multiple-choice questions. CONCLUSION: ChatGPT exhibits a degree of medical knowledge and the capacity to aid in diagnosing and treating diseases. Nevertheless, enhancements are warranted to address its accuracy and reliability limitations. Imperatively, rigorous evaluation and oversight must accompany its utilization, accompanied by proactive measures to surmount prevailing constraints.

Copper regulates the host innate immune response against bacterial infection via activation of ALPK1 kinase.

Copper is an essential trace element for the human body, and its requirement for optimistic immune functions has been recognized for decades. How copper is involved in the innate immune pathway, however, remains to be clarified. Here, we report that copper serves as a signal molecule to regulate the kinase activity of alpha-kinase 1 (ALPK1), a cytosolic pattern-recognition receptor (PRR), and therefore promotes host cell defense against bacterial infection. We show that in response to infection, host cells actively accumulate copper in the cytosol, and the accumulated cytosolic copper enhances host cell defense against evading pathogens, including intracellular and, unexpectedly, extracellular bacteria. Subsequently, we demonstrate that copper activates the innate immune pathway of host cells in an ALPK1-dependent manner. Further mechanistic studies reveal that copper binds to ALPK1 directly and is essential for the kinase activity of this cytosolic PRR. Moreover, the binding of copper to ALPK1 enhances the sensitivity of ALPK1 to the bacterial metabolite ADP-heptose and eventually prompts host cells to elicit an enhanced immune response during bacterial infection. Finally, using a zebrafish in vivo model, we show that a copper-treated host shows an increased production of proinflammatory cytokines, enhanced recruitment of phagosome cells, and promoted bacterial clearance. Our findings uncover a previously unrecognized role of copper in the modulation of host innate immune response against bacterial pathogens and advance our knowledge on the cross talk between cytosolic copper homeostasis and immune system.

3D hippocampal segmentation based on spatial and frequency domain features adaptive fusion and inter⁃class boundary region enhancement / 解剖学报

Objective Hippocampal atrophy is a clinically important marker for the diagnosis of many psychiatric disorders such as Alzheimer’s disease‚ so accurate segmentation of the hippocampus is an important scientific issue. With the development of deep learning‚ a large number of advanced automatic segmentation method have been proposed. However‚ 3D hippocampal segmentation is still challenging due to the effects of various noises in MRI and unclear boundaries between various classes of the hippocampus. Therefore‚ the aim of this paper is to propose new method to segment the hippocampal head‚ body‚ and tail more accurately. Methods To overcome these challenges‚ this paper proposed two strategies. One was the spatial and frequency domain features adaptive fusion strategy‚ which reduced the influence of noise on feature extraction by automatically selecting the appropriate frequency combination through fast Fourier transform and convolution. The other was an inter-class boundary region enhancement strategy‚ which allowed the network to focus on learning the boundary regions by weighting the loss function of the boundary regions between each class to achieve the goal of pinpointing the boundaries and regulating the size of the hippocampal head‚ body and tail. Results Experiments performed on a 50-case teenager brain MRI dataset show that our method achieves state-of-the-art hippocampal segmentation. Hippocampal head‚ body and tail had been improved compared to the existing method. Ablation experiments demonstrated the effectiveness of our two proposed strategies‚ and we also validated that the network had a strong generalization ability on a 260-case Task04_Hippocampus dataset. It was shown that the method proposed in this paper could be used in more hippocampal segmentation scenarios. Conclusion The method proposed in this paper can help clinicians to observe hippocampal atrophy more clearly and accomplish more accurate diagnosis and follow-up of the condition.

Epidemiological analysis reveals a surge in inflammatory bowel disease among children and adolescents: A global, regional, and national perspective from 1990 to 2019 - insights from the China study.

Background: The burden of inflammatory bowel disease (IBD) among children and adolescents is rising globally, with substantial variation in levels and trends of disease in different countries and regions, while data on the burden and trends were sparse in children and adolescents. We aimed to assess the trends and geographical differences in children and adolescents aged zero to 19 in 204 countries and territories over the past 30 years. Methods: Data on IBD among children and adolescents was collected from the Global Burden of Disease (GBD) 2019 database from 1990 to 2019. We used the GBD data and methodologies to describe the change in the burden of IBD among children and adolescents involving prevalence, incidence, disability-adjusted life years (DALYs), and mortality. Results: Globally, the IBD prevalence cases increased between 1990 and 2019. Annual percentage changes (AAPC) = 0.15; 95% confidence interval (CI) = 0.11-0.19, and incidence cases of IBD increased from 20 897.4 (95% CI = 17 008.6-25 520.2 in 1990 to 25 658.6 (95% CI = 21 268.5-31 075.6) in 2019, representing a 22.78% increase, DALYs cases decreased between 1990 and 2019 (AAPC = -3.02; 95% CI = -3.15 to -2.89), and mortality cases of IBD decreased from 2756.5 (95% CI = 1162.6-4484.9) in 1990 to 1208.0 (95% CI = 802.4-1651.4) in 2019, representing a 56.17% decrease. Decomposition analysis showed that IBD prevalence and incidence increased significantly, and a trend exhibited a decrease in underlying age and population-adjusted IBD DALYs and mortality rates. Correlation analysis showed that countries with high health care quality and access (HAQ) had relatively higher IBD age-standardised prevalence rate (ASPR) and age-standardised incidence rate (ASIR), but lower age-standardised DALYs rate (ASDR) and age-standardised mortality rate (ASMR). Conclusions: Global prevalence and incidence rate of IBD among children and adolescents have been increasing from 1990 to 2019, while the DALYs and mortality have been decreasing. Rising prevalence and rising incidence in areas with historically low rates will have crucial health and economic implications.

Dissemination feature based on PET/CT is a risk factor for diffuse large B cell lymphoma patients outcome.

BACKGROUND: 18F-FDG PET/CT provides precise information about dissemination of lymphoma lesions. Dmax, defined as distance between the two lesions that were farthest apart by PET/CT, was found to be a promising predictor of Diffuse large B-cell lymphoma (DLBCL) outcome in a small size of clinical trial data. We analyzed the impact of Dmax on the outcome of a large real-world DLBCL cohort. METHODS: Data of newly diagnosed DLBCL at the Third Affiliated Hospital of Soochow University were retrospectively collected. Baseline Dmax, clinical data and survival information were recorded. A metabolic parameter, metabolic bulk volume (MBV), was also measured to verify the independent impact of Dmax. RESULTS: Optimal cut-off values for Dmax and MBV were 45.34 cm and 21.65 cm3. With a median follow-up of 32 months, Dmax significantly impacted progression-free survival (PFS) and overall survival (OS) in 253 DLBCL patients. For Dmaxlow and Dmaxhigh groups, estimated 3-year OS were 87.0% and 53.8% (p < 0.001), while 3-year PFS were 77.3% and 37.3% (p < 0.001). And for MBVlow and MBVhighgroups, 3-year OS were 84.5% and 58.8% (p < 0.001), and 3-year PFS were 68.7% and 50.4% (p = 0.003). Multivariate analysis identified Dmax and Eastern Cooperative Oncology Group performance status (ECOG PS) independently associated with PFS and OS, while MBV only independently associated with OS. A Dmax revised prognostic index (DRPI) combining Dmax and ECOG PS identified an ultra-risk DLBCL population with 3-year PFS of 31.7% and 3-year OS of 38.5%. The area under the curve (AUC) showed that this model performed better than International prognostic Index (IPI). CONCLUSION: Dmax is a new and promising indicator to investigate dissemination of lymphoma lesions associated with the outcome of DLBCL. It significantly contributes to stratification of patients with disparate outcomes. TRIAL REGISTRATION: This research has been retrospectively registered in the Ethics Committee institutional of the Third Affiliated Hospital of Soochow University, and the registration number was approval No. 155 (approved date: 31 May 2022).

MMP13 promotes the osteogenic potential of BMP9 by enhancing Wnt/ß-catenin signaling via HIF-1α upregulation in mouse embryonic fibroblasts.

Bone morphogenetic protein 9 (BMP9) has been validated as one of the most potent osteoinduction factors, but its underlying mechanism remains unclear. As a member of the matrix metalloproteinase (MMP) family, MMP13 may be involved in regulating the lineage-specific differentiation of mouse embryonic fibroblasts (MEFs). The goal of this study was to determine whether MMP13 regulates the osteoinduction potential of BMP9 in MEFs, which are multipotent progenitor cells widely used for stem cell biology research. In vitro and in vivo experiments showed that BMP9-induced osteogenic markers and/or bone were enhanced by exogenous MMP13 in MEFs, but were reduced by MMP13 knockdown or inhibition. The expression of hypoxia inducible factor 1 alpha (HIF-1α) was induced by BMP9, which was enhanced by MMP13. The protein expression of ß-catenin and phosphorylation level of glycogen synthase kinase-3 beta (GSK-3ß) were increased by BMP9 in MEFs, as was the translocation of ß-catenin from the cytoplasm to the nucleus; all these effects of BMP9 were enhanced by MMP13. Furthermore, the MMP13 effects of increasing BMP9-induced ß-catenin protein expression and GSK-3ß phosphorylation level were partially reversed by HIF-1α knockdown. These results suggest that MMP13 can enhance the osteoinduction potential of BMP9, which may be mediated, at least in part, through the HIF-1α/ß-catenin axis. Our findings demonstrate a novel role of MMP13 in the lineage decision of progenitor cells and provide a promising strategy to speed up bone regeneration.

Global trans-lesional computed tomography-derived fractional flow reserve gradient is associated with clinical outcomes in diabetic patients with non-obstructive coronary artery disease.

BACKGROUND: Coronary computed tomography angiography (CCTA)-derived fractional flow reserve (CT-FFR) enables physiological assessment and risk stratification, which is of significance in diabetic patients with nonobstructive coronary artery disease (CAD). We aim to evaluate prognostic value of the global trans-lesional CT-FFR gradient (GΔCT-FFR), a novel metric, in patients with diabetes without flow-limiting stenosis. METHODS: Patients with diabetes suspected of having CAD were prospectively enrolled. GΔCT-FFR was calculated as the sum of trans-lesional CT-FFR gradient in all epicardial vessels greater than 2 mm. Patients were stratified into low-gradient without flow-limiting group (CT-FFR > 0.75 and GΔCT-FFR < 0.20), high-gradient without flow-limiting group (CT-FFR > 0.75 and GΔCT-FFR ≥ 0.20), and flow-limiting group (CT-FFR ≤ 0.75). Discriminant ability for major adverse cardiovascular events (MACE) prediction was compared among 4 models [model 1: Framingham risk score; model 2: model 1 + Leiden score; model 3: model 2 + high-risk plaques (HRP); model 4: model 3 + GΔCT-FFR] to determine incremental prognostic value of GΔCT-FFR. RESULTS: Of 1215 patients (60.1 ± 10.3 years, 53.7% male), 11.3% suffered from MACE after a median follow-up of 57.3 months. GΔCT-FFR (HR: 2.88, 95% CI 1.76-4.70, P < 0.001) remained independent risk factors of MACE in multivariable analysis. Compared with the low-gradient without flow-limiting group, the high-gradient without flow-limiting group (HR: 2.86, 95% CI 1.75-4.68, P < 0.001) was associated with higher risk of MACE. Among the 4 risk models, model 4, which included GΔCT-FFR, showed the highest C-statistics (C-statistics: 0.75, P = 0.002) as well as a significant net reclassification improvement (NRI) beyond model 3 (NRI: 0.605, P < 0.001). CONCLUSIONS: In diabetic patients with non-obstructive CAD, GΔCT-FFR was associated with clinical outcomes at 5 year follow-up, which illuminates a novel and feasible approach to improved risk stratification for a global hemodynamic assessment of coronary artery in diabetic patients.

Validation of hemodynamic stress calculation in coronary computed tomography angiography versus intravascular ultrasound.

Background: Development in computational fluid dynamics and 3D construction could facilitate the calculation of hemodynamic stresses in coronary computed tomography angiography (CCTA). However, the agreement between CCTA derived stresses and intravascular ultrasound/intravascular coronary angiography (IVUS/ICA)-derived stresses remains undetermined. Thus, the purpose of this study is to investigate if CCTA can serve as alternative to IVUS/ICA for hemodynamic evaluation. Methods: In this retrospective study, 13 patients (14 arteries) with unstable angina who underwent both CCTA and IVUS/ICA at an interval of less than 7 days were consecutively included at the Chinese PLA General Hospital within the year of 2021. Slice-level minimal lumen area (MLA), percent area stenosis, velocity, pressure, Reynolds number, wall shear stress (WSS) and axial plaque stress (APS) were determined by both modalities. The agreement between CCTA and IVUS/ICA was assessed using the intraclass correlation coefficient (ICC), Pearson's correlation coefficient and Bland-Altman analysis. Results: CCTA overestimated the degree of area stenosis (50.22%±16.15% vs. 36.41%±19.37%, P=0.004) with the MLA showing no significant difference (5.81±2.24 vs. 6.72±2.04 mm2, P=0.126). No statistical difference was observed in WSS (6.57±6.26 vs. 5.98±5.55 Pa, P=0.420) and APS (16.03±1,159.45 vs. -1.27±890.39 Pa, P=0.691) between CCTA and IVUS. Good correlation was found in velocity (ICC: 0.796, 95% CI: 0.752-0.833), Reynolds number (ICC: 0.810, 95% CI: 0.768-0.844) and WSS (ICC: 0.769, 95% CI: 0.718-0.810), while the ICC of APS was (ICC: 0.341, 95% CI: 0.197-0.458), indicating a relatively poor correlation. Conclusions: CCTA can serve as a satisfactory alternative to the reference standard, IVUS/ICA in morphology simulation and hemodynamic stress calculation, especially in the calculation of WSS.

Wnt/ß-Catenin Promotes the Osteoblastic Potential of BMP9 Through Down-Regulating Cyp26b1 in Mesenchymal Stem Cells.

BACKGROUND: All-trans retinoic acid (ATRA) promotes the osteogenic differentiation induced by bone morphogenetic protein 9 (BMP9), but the intrinsic relationship between BMP9 and ATRA keeps unknown. Herein, we investigated the effect of Cyp26b1, a critical enzyme of ATRA degradation, on the BMP9-induced osteogenic differentiation in mesenchymal stem cells (MSCs), and unveiled possible mechanism through which BMP9 regulates the expression of Cyp26b1. METHODS: ATRA content was detected with ELISA and HPLC-MS/MS. PCR, Western blot, and histochemical staining were used to assay the osteogenic markers. Fetal limbs culture, cranial defect repair model, and micro-computed tomographic were used to evaluate the quality of bone formation. IP and ChIP assay were used to explore possible mechanism. RESULTS: We found that the protein level of Cyp26b1 was increased with age, whereas the ATRA content decreased. The osteogenic markers induced by BMP9 were increased by inhibiting or silencing Cyp26b1 but reduced by exogenous Cyp26b1. The BMP9-induced bone formation was enhanced by inhibiting Cyp26b1. The cranial defect repair was promoted by BMP9, which was strengthened by silencing Cyp26b1 and reduced by exogenous Cyp26b1. Mechanically, Cyp26b1 was reduced by BMP9, which was enhanced by activating Wnt/ß-catenin, and reduced by inhibiting this pathway. ß-catenin interacts with Smad1/5/9, and both were recruited at the promoter of Cyp26b1. CONCLUSIONS: Our findings suggested the BMP9-induced osteoblastic differentiation was mediated by activating retinoic acid signalling, viadown-regulating Cyp26b1. Meanwhile, Cyp26b1 may be a novel potential therapeutic target for the treatment of bone-related diseases or accelerating bone-tissue engineering.

LCN2 Inhibits the BMP9-induced Osteogenic Differentiation through Reducing Wnt/ß-catenin Signaling via Interacting with LRP6 in Mouse Embryonic Fibroblasts.

BACKGROUND: Due to its effective osteogenic ability, BMP9 is a promising candidate for bone regeneration medicine. Whereas, BMP9 can also induce adipogenesis simultaneously. LCN2 is a cytokine associated with osteogenesis and adipogenesis. Reducing the adipogenic potential may be a feasible measure to enhance the osteogenic capability of BMP9. OBJECTIVE: The objective of the study was to explore the role of LCN2 in regulating the BMP9-initialized osteogenic and adipogenic differentiation in mouse embryonic fibroblasts (MEFs), and clarify the possible underlying mechanism. METHODS: Histochemical stain, western blot, real-time PCR, laser confocal, immunoprecipitation, cranial defect repair, and fetal limb culture assays were used to evaluate the effects of LCN2 on BMP9-induced osteogenic and adipogenic differentiation, as well as Wnt/ß-catenin signaling. RESULTS: LCN2 was down-regulated by BMP9. The BMP9-induced osteogenic markers were inhibited by LCN2 overexpression, but the adipogenic markers were increased; LCN2 knockdown exhibited opposite effects. Similar results were found in bone defect repair and fetal limb culture tests. The level of ß-catenin nucleus translocation was found to be reduced by LCN2 overexpression, but increased by LCN2 knockdown. The inhibitory effect of LCN2 overexpression on the osteogenic capability of BMP9 was reversed by ß-catenin overexpression; whereas, the effect of LCN2 knockdown on promoting BMP9 osteogenic potential was almost eliminated by ß-catenin knockdown. LCN2 could bind with LRP6 specifically, and the inhibitory effect of LCN2 on the osteogenic potential of BMP9 could not be enhanced by LRP6 knockdown. CONCLUSION: LCN2 inhibits the BMP9-induced osteogenic differentiation but promotes its adipogenic potential in MEFs, which may be partially mediated by reducing Wnt/ß-catenin signaling via binding with LRP6.

Incremental diagnostic value of perivascular fat attenuation index for identifying hemodynamically significant ischemia with severe calcification.

PURPOSE: To explore the incremental value of perivascular fat attenuation index (FAI) to identify hemodynamically significant ischemia in severe calcified vessels. METHODS: Patients who underwent coronary computed tomographic angiography (CCTA) examination at Chinese PLA General Hospital from 2017 to 2020 and subsequently underwent fractional flow reserve (FFR) examination within 1 month were consecutively included. Several CCTA-derived indices were measured, including the coronary artery calcification score (CACS), lesion length, ≥CAD-RADS 4 proportion, perivascular FAI and CT-FFR. The included vessels were divided into a nonsevere calcification group and a severe calcification group according to the quartile of CACS. FFR ≤ 0.80 represents the presence of hemodynamically significant ischemia. RESULTS: A total of 124 patients with 152 vessels were included (age: 61.1 ± 9.2 years; male 64.5%). Significant differences in lesion length (28.4 ± 14.2 vs. 23.1 ± 12.3 mm, P = 0.021), perivascular FAI (-73.0 ± 7.5 vs. -79.0 ± 7.4 HU, P < 0.001) and CT-FFR (0.78 ± 0.06 vs. 0.86 ± 0.04, P < 0.001) were noted between the FFR ≤ 0.80 group (47 vessels) and the FFR > 0.80 group (105 vessels). Furthermore, the perivascular FAI in the FFR ≤ 0.80 group was significantly greater than that in the FFR > 0.80 group (nonsevere calcification: -73.2 ± 7.5 vs. -78.2 ± 7.4 HU, P = 0.002; severe calcification: -72.8 ± 7.7 vs. -82.7 ± 6.3 HU, P < 0.001). In discriminating hemodynamically significant ischemia, the specificity and accuracy of CT-FFR were significantly affected by severe calcification, which demonstrated a significantly declining trend (P = 0.033 and P = 0.010, respectively). The diagnostic performance of CT-FFR in the severe calcification group was lower than that in the nonsevere calcified group. However, perivascular FAI showed good discriminative performance in the severe calcification group. In combination with perivascular FAI, the predictive value of CT-FFR in identifying hemodynamically significant ischemia with severe calcification increased from an AUC of 0.740 to 0.919. CONCLUSION: For coronary artery with severe calcification, the diagnostic performance of CT-FFR in discriminating flow-limiting lesions could be greatly impaired. Perivascular FAI represents a potential reliable imaging marker to provide incremental diagnostic value over CT-FFR for identifying hemodynamically significant ischemia with severe calcification.

Interleukin 6 promotes BMP9-induced osteoblastic differentiation through Stat3/mTORC1 in mouse embryonic fibroblasts.

Interleukin 6 (IL-6) plays a dual role in regulating bone metabolism, although the concrete mechanism is unclear. Bone morphogenetic protein 9 (BMP9) is one of the most potent osteogenic inducers, and a promising alternative for bone tissue engineering. The relationship between IL-6 and BMP9 in osteogenic differentiation remains to be elucidated, and the osteoblastic potential of BMP9 needs to be enhanced to overcome certain shortcomings of BMP9. In this study, we used real-time PCR, western blot, immunofluorescent stain, fetal limb culture and cranial defects repair model to explore the IL-6 role in BMP9-induced osteogenic differentiation in mouse embryonic fibroblasts (MEFs). We found that the rat serum level of IL-6 was increased in the dexamethasone-induced osteoporosis model, and IL-6 expression was detectable in several progenitor cells and MEFs. BMP9 upregulated IL-6 in MEFs, and the BMP9-induced osteoblastic markers were elevated by IL-6, but reduced by IL-6 knockdown. BMP9 and/or IL-6 both activated mTOR, and the IL-6 effect on BMP9-induced osteoblastic markers and bone formation were reduced greatly by mTOR inhibition. Raptor was up-regulated by IL-6 and/or BMP9 specifically, and the osteoblastic markers induced by IL-6 and/or BMP9 were reduced by Raptor knockdown. Meanwhile, Stat-3 was activated by IL-6 and/or BMP9, and the increase of Raptor or osteoblastic markers by IL-6 and/or BMP9 were reduced by Stat-3 inhibition. The Raptor promoter activity was regulated by p-Stat-3. Our finding suggested that IL-6 can promote the BMP9 osteoblastic potential, which may be mediated through activating Stat-3/mTORC1 pathway.

Transgenic IDH2R172K and IDH2R140Q zebrafish models recapitulated features of human acute myeloid leukemia.

Isocitrate dehydrogenase 2 (IDH2) mutations occur in more than 15% of cytogenetically normal acute myeloid leukemia (CN-AML) but comparative studies of their roles in leukemogenesis have been scarce. We generated zebrafish models of IDH2R172K and IDH2R140Q AML and reported their pathologic, functional and transcriptomic features and therapeutic responses to target therapies. Transgenic embryos co-expressing FLT3ITD and IDH2 mutations showed accentuation of myelopoiesis. As these embryos were raised to adulthood, full-blown leukemia ensued with multi-lineage dysplasia, increase in myeloblasts and marrow cellularity and splenomegaly. The leukemia cells were transplantable into primary and secondary recipients and resulted in more aggressive disease. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in T-cell development at embryonic and adult stages. Single-cell transcriptomic analysis revealed increased myeloid skewing, differentiation blockade and enrichment of leukemia-associated gene signatures in both zebrafish models. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in interferon signals at the adult stage. Leukemic phenotypes in both zebrafish could be ameliorated by quizartinib and enasidenib. In conclusion, the zebrafish models of IDH2 mutated AML recapitulated the morphologic, clinical, functional and transcriptomic characteristics of human diseases, and provided the prototype for developing zebrafish leukemia models of other genotypes that would become a platform for high throughput drug screening.

lncRNA MEG3 Promotes PDK4/GSK-3ß/ß-Catenin Axis in MEFs by Targeting miR-532-5p.

Studies reported the positive and negative osteogenic effects of MEG3 in mesenchymal stem cells (MSCs). This study aims at clarifying the osteogenic potential of MEG3 and the underlying mechanism. Bone morphogenetic protein 9- (BMP9-) transfected MSCs were recruited as an osteogenic model in vitro, and ectopic bone formation were used in vivo to explore the effect of MEG3 on osteogenesis. We found that overexpression of MEG3 facilitated BMP9-induced osteogenic markers, ALP activities, and matrix mineralization. However, knockdown of MEG3 attenuated BMP9-induced osteogenic markers. MEG3 increased the phosphorylation of GSK-3ß and the protein level of ß-catenin. Pyruvate dehydrogenase kinase 4 (PDK4) can also combine with GSK-3ß and increase the latter phosphorylation. Moreover, MEG3 increased the mRNA level of PDK4. The ceRNA analysis showed that MEG3 may regulate the expression of PDK4 via microRNA 532-5p (miR-532-5p). The MEG3-enhanced GSK-3ß/ß-catenin axis can be attenuated by miR-532-5p, and miR-532-5p inhibitor partly rescued endogenous PDK4 and MEG3-mediated expression of PDK4. MEG3 may potentiate PDK4 and GSK-3ß/ß-catenin by inhibiting miR-532-5p.

Transgenic PDGF-BB sericin hydrogel potentiates bone regeneration of BMP9-stimulated mesenchymal stem cells through a crosstalk of the Smad-STAT pathways.

Silk as a natural biomaterial is considered as a promising bone substitute in tissue regeneration. Sericin and fibroin are the main components of silk and display unique features for their programmable mechanical properties, biocompatibility, biodegradability and morphological plasticity. It has been reported that sericin recombinant growth factors (GFs) can support cell proliferation and induce stem cell differentiation through cross-talk of signaling pathways during tissue regeneration. The transgenic technology allows the productions of bioactive heterologous GFs as fusion proteins with sericin, which are then fabricated into solid matrix or hydrogel format. Herein, using an injectable hydrogel derived from transgenic platelet-derived GF (PDGF)-BB silk sericin, we demonstrated that the PDGF-BB sericin hydrogel effectively augmented osteogenesis induced by bone morphogenetic protein (BMP9)-stimulated mesenchymal stem cells (MSCs) in vivo and in vitro, while inhibiting adipogenic differentiation. Further gene expression and protein-protein interactions studies demonstrated that BMP9 and PDGF-BB synergistically induced osteogenic differentiation through the cross-talk between Smad and Stat3 pathways in MSCs. Thus, our results provide a novel strategy to encapsulate osteogenic factors and osteoblastic progenitors in transgenic sericin-based hydrogel for robust bone tissue engineering.

Altered serum lipid levels are associated with prognosis of diffuse large B cell lymphoma and influenced by utility of rituximab.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the prognosis of the disease varied. This research aims to investigate the impact of serum lipid level on the outcome of DLBCL patients and their interaction with rituximab (RTX). Data of newly diagnosed DLBCL in the third affiliated hospital of Soochow University were retrospectively collected. Baseline serum lipid levels, clinical data, and survival information were simultaneously recorded. Data of healthy controls were collected with age matching. Serum lipid levels significantly differed for the patients. All were transformed into categorical variables for the analysis of survival. During a median follow-up of 58 months, 32.8% patients died. Univariate analysis revealed all serum lipid indicators were associated with overall survival (OS); all except for total cholesterol (TC) and apolipoprotein B (apoB) showed significant impact on progression-free survival (PFS). Multivariable analysis confirmed the adverse effect of triglyceride (TG) on PFS (P = 0.013) and favorable impact of high-density lipoprotein (HDL) on OS (P = 0.003). For cases treated without RTX, apolipoprotein A (apoA) had independent favorable effect on both PFS (P = 0.004) and OS (P = 0.001). Comparably, for patients who received RTX, HDL showed remarkably predictive value of PFS (P = 0.011) and OS (P = 0.019). In conclusion, the abnormal serum lipids occurred throughout the course of DLBCL, and the associations of serum lipids and the prognosis of the disease were interfered by RTX. Trial registration: 2022()CL033; June 26, 2022, retrospectively registered.