This review aimed to provide a comprehensive analysis of the etiology, epidemiology, pathology, and conventional treatment of heterotopic ossification (HO), especially emerging potential therapies. HO is the process of ectopic bone formation at non-skeletal sites. HO can be subdivided into two major forms, acquired and hereditary, with acquired HO predominating. Hereditary HO is a rare and life-threatening genetic disorder, but both acquired and hereditary form can cause severe complications, such as peripheral nerve entrapment, pressure ulcers, and disability if joint ankylosis develops, which heavily contributes to a reduced quality of life. Modalities have been proposed to treat HO, but none have emerged as the gold standard. Surgical excision remains the only effective modality; however, the optimal timing is controversial and may cause HO recurrence. Recently, potential therapeutic strategies have emerged that focus on the signaling pathways involved in HO, and small molecule inhibitors have been shown to be promising. Moreover, additional specific targets, such as small interfering RNAs (siRNAs) and non-coding RNAs, could be used to effectively block HO or develop combinatorial therapies for HO.
Humans ; Ossification, Heterotopic/genetics*

Colorectal cancer(CRC) is a common malignant tumor worldwide. Due to the treatment intolerance and side effects, CRC rank the top among various cancers regarding the incidence and mortality rates. Therefore, exploring new therapies is of great significance for the treatment of CRC. Aerobic glycolysis(AEG) plays an important role in the microenvironment formation, proliferation, metastasis, and recurrence of CRC and other tumor cells. It has been confirmed that intervening in the AEG pathway can effectively curb CRC. The active ingredients and compound prescriptions of traditional Chinese medicine(TCM) can effectively inhibit the proliferation, metastasis, and drug resistance and regulate the apoptosis of tumor cells by modulating AEG-associated transport proteins [eg, glucose transporters(GLUT)], key enzymes [hexokinase(HK) and phosphofructokinase(PFK)], key genes [hypoxia-inducible factor 1(HIF-1) and oncogene(c-Myc)], and signaling pathways(MET/PI3K/Akt/mTOR). Accordingly, they can treat CRC, reduce the recurrence, and improve the prognosis of CRC. Although AEG plays a key role in the development and progression of CRC, the specific mechanisms are not yet fully understood. Therefore, this article delves into the intrinsic connection of the targets and mechanisms of the AEG pathway with CRC from the perspective of tumor cell glycolysis and explores how active ingredients(oxymatrine, kaempferol, and dioscin) and compound prescriptions(Quxie Capsules, Jiedu Sangen Decoction, and Xianlian Jiedu Prescription) of TCM treat CRC by intervening in the AEG pathway. Additionally, this article explores the shortcomings in the current research, aiming to provide reliable targets and a theoretical basis for treating CRC with TCM.
Humans ; Colorectal Neoplasms/genetics* ; Drugs, Chinese Herbal/therapeutic use* ; Glycolysis/drug effects* ; Animals ; Medicine, Chinese Traditional ; Signal Transduction/drug effects*

Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA⁺ dental follicle stem cells (DFSCs) and CD31⁺ Endomucin⁺ endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA⁺ DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA⁺ DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
Receptor, Platelet-Derived Growth Factor alpha/metabolism* ; Humans ; Neovascularization, Physiologic/physiology* ; Dental Sac/cytology* ; Single-Cell Analysis ; Transcriptome ; Mesenchymal Stem Cells/metabolism* ; Bone Regeneration ; Animals ; Dental Papilla/cytology* ; Periodontium/physiology* ; Stem Cells/metabolism* ; Regeneration ; Angiogenesis

BACKGROUND AND OBJECTIVE: Patients with glioma experience a high symptom burden and have diverse palliative care needs. However, the assessment scales used in palliative care remain non-standardized and highly heterogeneous. To evaluate the application patterns of the current scales used in palliative care for glioma, we aim to identify gaps and assess the need for disease-specific scales in glioma palliative care. METHODS: We conducted a systematic search of five databases including PubMed, Web of Science, Medline, EMBASE, and CINAHL for quantitative studies that reported scale-based assessments in glioma palliative care. We extracted data on scale characteristics, domains, frequency, and psychometric properties. Quality assessments were performed using the Cochrane ROB 2.0 and ROBINS-I tools. RESULTS: Of the 3,405 records initially identified, 72 studies were included. These studies contained 75 distinct scales that were used 193 times. Mood (21.7%), quality of life (24.4%), and supportive care needs (5.2%) assessments were the most frequently assessed items, exceeding half of all scale applications. Among the various assessment dimensions, the Distress Thermometer (DT) was the most frequently used tool for assessing mood, while the Short Form-36 Health Survey Questionnaire (SF-36) was the most frequently used tool for assessing quality of life. The Mini Mental Status Examination (MMSE) was the most common tool for cognitive assessment. Performance status (5.2%) and social support (6.8%) were underrepresented. Only three brain tumor-specific scales were identified. Caregiver-focused scales were limited and predominantly burden-oriented. CONCLUSIONS: There are significant heterogeneity, domain imbalances, and validation gaps in the current use of assessment scales for patients with glioma receiving palliative care. The scale selected for use should be comprehensive and user-friendly.
Humans ; Glioma/psychology* ; Palliative Care/methods* ; Quality of Life ; Psychometrics ; Brain Neoplasms/psychology*

Hepatocellular carcinoma (HCC) expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming. Aldolase A (ALDOA) plays a prominent role in glycolysis; however, little is known about its role in HCC development. In the present study, we aim to explore how ALDOA is involved in HCC proliferation. HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout, which is consistent with ALDOA overexpression encouraging HCC proliferation. Mechanistically, ALDOA knockout partially limits the glycolytic flux in HCC cells. Meanwhile, ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase; ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function. A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun, and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells. In HCC patients, the expression level of ALDOA was correlated with the phosphorylation level of c-Jun (Thr93) and poor prognosis. Remarkably, hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models, and the knockdown of A ldoa strikingly decreased HCC development in vivo. Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription, opening additional avenues for anti-cancer therapies.

OBJECTIVE: Gastric cancer (GC) is one of the most common malignancies seen in clinic and requires novel treatment options. Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant Prunella vulgaris L., which exhibits an anti-cancer effect in multiple types of tumors. However, the therapeutic effect and underlying mechanism of morin in treating GC remains elusive. The study aims to explore the therapeutic effect and underlying molecular mechanisms of morin in GC. METHODS: For in vitro experiments, the proliferation inhibition of morin was measured by cell counting kit-8 assay and colony formation assay in human GC cell line MKN45, human gastric adenocarcinoma cell line AGS, and human gastric epithelial cell line GES-1; for apoptosis analysis, microscopic photography, Western blotting, ubiquitination analysis, quantitative polymerase chain reaction analysis, flow cytometry, and RNA interference technology were employed. For in vivo studies, immunohistochemistry, biomedical analysis, and Western blotting were used to assess the efficacy and safety of morin in a xenograft mouse model of GC. RESULTS: Morin significantly inhibited the proliferation of GC cells MKN45 and AGS in a dose- and time-dependent manner, but did not inhibit human gastric epithelial cells GES-1. Only the caspase inhibitor Z-VAD-FMK was able to significantly reverse the inhibition of proliferation by morin in both GC cells, suggesting that apoptosis was the main type of cell death during the treatment. Morin induced intrinsic apoptosis in a dose-dependent manner in GC cells, which mainly relied on B cell leukemia/lymphoma 2 (BCL-2) associated agonist of cell death (BAD) but not phorbol-12-myristate-13-acetate-induced protein 1. The upregulation of BAD by morin was due to blocking the ubiquitination degradation of BAD, rather than the transcription regulation and the phosphorylation of BAD. Furthermore, the combination of morin and BCL-2 inhibitor navitoclax (also known as ABT-737) produced a synergistic inhibitory effect in GC cells through amplifying apoptotic signals. In addition, morin treatment significantly suppressed the growth of GC in vivo by upregulating BAD and the subsequent activation of its downstream apoptosis pathway. CONCLUSION Morin suppressed GC by inducing apoptosis, which was mainly due to blocking the ubiquitination-based degradation of the pro-apoptotic protein BAD. The combination of morin and the BCL-2 inhibitor ABT-737 synergistically amplified apoptotic signals in GC cells, which may overcome the drug resistance of the BCL-2 inhibitor. These findings indicated that morin was a potent and promising agent for GC treatment. Please cite this article as: Wang Y, Sun XY, Ma FQ, Ren MM, Zhao RH, Qin MM, Zhu XH, Xu Y, Cao ND, Chen YY, Dong TG, Pan YF, Zhao AG. Morin inhibits ubiquitination degradation of BCL-2 associated agonist of cell death and synergizes with BCL-2 inhibitor in gastric cancer cells. J Integr Med. 2025; 23(3): 320-332.
Humans ; Flavonoids/therapeutic use* ; Stomach Neoplasms/pathology* ; Animals ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Cell Line, Tumor ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Ubiquitination/drug effects* ; Mice ; Drug Synergism ; Mice, Inbred BALB C ; Mice, Nude ; Xenograft Model Antitumor Assays ; Flavones

Objective:To evaluate the diagnostic value of the vesical imaging-reporting and data system（VI-RADS）for determining muscle invasion in variant histology urothelial carcinoma（VUC）of the bladder.Methods:A retrospective analysis was performed on the pathological and imaging data of 518 bladder cancer patients admitted to Jiangsu Province Hospital between January 2013 and January 2023. Patients were stratified into pure urothelial carcinoma（PUC）group（ n = 457）and variant urothelial carcinoma（VUC）group（ n = 61）based on the presence of histological variants. In the PUC group，there were 390 males（85.3%）and 67 females（14.7%），with a mean age of（66.9 ± 11.2）years. Tumor characteristics included maximum diameter ≥ 30 mm in 149（32.6%），< 30 mm in 308（67.4%），multiple tumors in 147（32.2%），solitary in 310（67.8%），pedunculated morphology in 143（31.3%）and non-pedunculated in 314（68.7%）. Histological grading identified high-grade tumors in 319 patients（69.8%）and low-grade tumors in 138（30.2%）. Pathological stage distribution included 191 of T a（41.8%），127 of T 1（27.8%），76 of T 2（16.6%），47 of T 3（10.3%），and 16 of T 4（3.5%）patients. The VUC group included 61 patients，comprising 51 males（83.6%）and 10 females（16.4%），with a mean age of（65.8 ± 11.4）years. Tumor characteristics were maximum diameter ≥ 30 mm in 38（62.3%），< 30 mm in 23（37.7%），multiple tumors in 16（26.2%），solitary in 45（73.8%），pedunculated morphology in 11（18.0%）and non-pedunculated in 50（82.0%）. Histological grading identified high-grade tumors in 59 patients（96.7%）and low-grade tumors in 2（3.3%）. Pathological stage distribution included 3 of T a（4.9%），15 of T 1（24.6%），15 of T 2（24.6%），20 of T 3（32.8%），and 8 of T 4（13.1%）patients. No statistically significant differences were found between the two groups in gender，age，or tumor multiplicity（ P > 0.05）. Statistically significant differences were found in pathological grade，pathological stage，maximum tumor diameter，and pedunculated morphology（ P < 0.05）. Furthermore，an external validation cohort of 278 bladder cancer patients treated between February 2023 and February 2024 from multiple centers（Jiangsu Provincial People’s Hospital，The First Affiliated Hospital of Zhengzhou University，Union Hospital Tongji Medical College Huazhong University of Science and Technology，Jiangsu Provincial Hospital of Traditional Chinese Medicine，Suzhou Municipal Hospital，Huaian First People’s Hospital，Yixing People’s Hospital）was retrospectively analyzed to externally validate the performance of VI-RADS scoring in predicting muscle invasion of VUC. This cohort included a PUC subgroup of 241 patients，comprising 196 males（81.3%）and 45 females（18.7%），with a mean age of（68.0 ± 10.7）years. Tumor characteristics were maximum diameter ≥ 30 mm in 85（35.3%），< 30 mm in 156（64.7%），multiple tumors in 65（27.0%），solitary in 176（73.0%），pedunculated morphology in 76（31.5%）and non-pedunculated in 165（68.5%）. Histological grading identified high-grade tumors in 175 patients（72.6%）and low-grade tumors in 66（27.4%）. Pathological staging comprised 107 patients of T a（44.4%），78 of T 1（32.4%），22 of T 2（9.1%），22 of T 3（9.1%），and 12 of T 4（5.0%）. The VUC subgroup consisted of 37 patients，comprising 29 males（78.4%）and 8 females（21.6%），with a mean age of（70.5 ± 9.5）years. Tumor characteristics were maximum diameter ≥ 30 mm in 23（62.2%），< 30 mm in 14（37.8%），multiple tumors in 9（24.3%），solitary in 28（75.7%），pedunculated morphology in 7（18.9%）and non-pedunculated in 30（81.1%）. Histological grading identified high-grade tumors in 36 patients（97.3%）and low-grade tumors in 1（2.7%）. Pathological staging comprised 1 patient of T a（2.7%），9 of T 1（24.3%），7 of T 2（18.9%），19 of T 3（51.4%），and 1 of T 4（2.7%）. In this validation cohort，no significant differences were found in gender，age，tumor multiplicity，or pedunculated morphology between the PUC and VUC subgroups（ P > 0.05）. Significant differences were observed in pathological grade，pathological stage，and maximum tumor diameter（ P < 0.05）. Three radiologists independently reviewed and scored the multiparametric MRI（mp-MRI）in a blinded manner. Inter-reader agreement was assessed using the weighted kappa statistic. Differences in variables between the two groups were compared using t-tests，chi-square tests，or Fisher’s exact test. The diagnostic performance of VI-RADS for muscle invasion in VUC and PUC was comprehensively evaluated using receiver operating characteristic（ROC）curves，the area under the curve（AUC），and cut-off values determined by the Youden’s index. The DeLong test was used to assess whether the diagnostic performance of VI-RADS differed between VUC and PUC. Results:In the retrospective single-center cohort，the AUC of VI-RADS for assessing muscle invasion was 0.895（95% CI 0.864?0.922）in the PUC group，with a cut-off value of > 3，and the AUC was 0.896（95% CI 0.791-0.960）in the VUC group，with a cut-off value of > 3. The difference between the two groups was not statistically significant（ P = 0.986）. Using a VI-RADS score > 3 as the cut-off value，the accuracy，sensitivity，specificity，positive predictive value（PPV），and negative predictive value（NPV）for diagnosing muscle invasion status in the PUC group were 85.8%（392/457），70.5%（98/139），92.5%（294/318），80.3%（98/122），and 87.8%（294/335），respectively. The corresponding values for the VUC group were 82.0%（50/61），76.7%（33/43），94.4%（17/18），97.1%（33/34），and 63.0%（17/27）.In the retrospective multicenter cohort，the AUC of VI-RADS for assessing muscle invasion was 0.891（95% CI 0.845?0.927）in the PUC group，with a cut-off value of > 2，and the AUC was 0.898（95% CI 0.754?0.973）in the VUC group，with a cut-off value of > 3. The difference between the two groups was not statistically significant（ P = 0.897）. Using a VI-RADS score > 3 as the cut-off value，the accuracy，sensitivity，specificity，PPV，and NPV for diagnosing muscle invasion status in the PUC group were 85.9%（207/241），58.9%（33/56），94.1%（174/185），75.0%（33/44），and 88.3%（174/197），respectively. The corresponding values for the VUC group were 81.1%（30/37），77.8%（21/27），90.0%（9/10），95.5%（21/22），and 60.0%（9/15）.In the single-center cohort，the Kappa values for inter-reader agreement in assessing muscle invasion status using VI-RADS were 0.881（ P < 0.01）for the PUC group and 0.941（ P < 0.01）for the VUC group among the three readers. In the multicenter cohort，the Kappa values were 0.858（ P < 0.01）for the PUC group and 0.838（ P < 0.01）for the VUC group. Conclusions:VI-RADS demonstrates similarly high diagnostic performance for assessing muscle invasion in both PUC and VUC，which is applicable for diagnosing muscle invasion status in VUC，and shows good inter-reader agreement.

Background:Rhei Radix et Rhizoma has been traditionally used as a potent laxative for centuries due to its remarkable efficacy.Raw pieces of Rhei Radix et Rhizoma(RP)are known for their strong laxative effects,often accompanied by side effects,while steamed Rhei Radix et Rhizoma pieces(SP)possess a milder laxative effect and are widely used clinically.However,there is a lack of comprehensive evidence examining the mechanisms underlying SP's effectiveness,particularly from a bioavailability perspective.Objective:This study aimed to investigate the impact of the steaming process on the in vivo disposition of RP and SP through pharmacokinetics,tissue distribution,and excretion assays.Methods:An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous quantitative analysis of prototype anthraquinones and their glucuronide metabolites.Pharmacokinetic,tissue distribution,and excre-tion assays were conducted in constipation rats following oral administration of RP and SP.Blood,tissue,urine,and fecal samples were collected and analyzed to compare the absorption,distribution,metabolism,and excretion profiles of anthraquinones,high-lighting differences in bioavailability and safety between RP and SP.Results:Compared with the RP group,the SP group showed significantly reduced area under the plasma concentration-time curve,mean residence time,and half-life time values for rhein-8-O-β-D-glucopyranoside,rhein,emodin,aloe-emodin,and their glucuronide metabolites.The clearance values were significantly increased in the SP group.These results demonstrate that SP led to lower exposure levels and higher elimination rates of these components compared with RP.Additionally,these compo-nents were primarily distributed in the large intestine,where they exerted their laxative effects.Glucuronide metabolites were mainly excreted through urination,while prototype components were excreted in both urine and feces.Notably,the cumulative excretion of aloe-emodin,emodin,rhein,and their glucuronide metabolites was significantly higher in both urine and feces after SP administra-tion,indicating that SP enhances the excretion of these components compared with RP.Conclusion:The findings suggest that SP reduced anthraquinone exposure levels while enhancing their excretion,demonstrating that the steaming process significantly promotes the elimination of key components.This study provides a comprehensive analysis of how steaming alters the in vivo disposition of Rhei Radix et Rhizoma,offering a scientific basis for the improved safety and clinical use of SP.These insights not only clarify the mechanistic differences between RP and SP but also contribute to a broader understanding of processing-induced modifications in Chinese medicines.This research paves the way for optimizing Chinese medicine processing techniques to enhance the safety and efficacy of herbal therapies.

Objective:Based on the analysis of the challenges faced by universities in establishing off-site scientific research institutions, this study draws on the practical experience of Peking University Health Science Center to provide insights for standardizing the development of such institutions, enhancing university-local government collaboration, and facilitating the transformation of scientific and technological achievements.Methods:The institutional framework, development progress and practical experience of off-site scientific research institutions affiliated with Peking University Health Science Center were systematically summarized.Results:These institutions had made initial success in establishing research platforms, developing teams of talent, promoting technology transfer, and contributing to local industrial development.Conclusions:It is recommended that universities continue to focus on standardizing establishment procedures, enhancing university-local government collaboration, strengthening interdepartmental support, and building teams of talent, to advance the high-quality development of off-site scientific research institutions.