Novel role for Ddx39 in differentiation and telomere length regulation of embryonic stem cells.

Erk signaling is indispensable for the self-renewal and differentiation of mouse embryonic stem cells (ESCs), as well as telomere homeostasis. But how Erk regulates these biological processes remains unclear. We identified 132 Erk2 interacting proteins by co-immunoprecipitation and mass spectrometric analysis, and focused on Ddx39 as a potential Erk2 substrate. We demonstrated that Erk2 phosphorylates Ddx39 on Y132 and Y138. Ddx39 knockout (KO) ESCs are defective in differentiation, due to reduced H3K27ac level upon differentiation. Phosphorylation of Ddx39 promotes the recruitment of Hat1 to acetylate H3K27 and activate differentiation genes. In addition, Ddx39 KO leads to telomere elongation in ESCs. Ddx39 is recruited to telomeres by the telomere-binding protein Trf1, consequently disrupting the DNA loop formed by Trf1 and suppressing the alternative lengthening of telomeres (ALT). Phosphorylation of Ddx39 weakens its interaction with Trf1, releasing it from telomeres. Thus, ALT activity is enhanced, and telomeres are elongated. Altogether, our studies reveal an essential role of Ddx39 in the differentiation and telomere homeostasis of ESCs.

Enhancing Localized Electron Density over Pd1.4Cu Decorated Oxygen Defective TiO2-x Nanoarray for Electrocatalytic Nitrite Reduction to Ammonia.

Electrocatalytic nitrite (NO2 -) reduction to ammonia (NH3) is a promising method for reducing pollution and aiding industrial production. However, progress is limited by the lack of efficient selective catalysts and ambiguous catalytic mechanisms. This study explores the loading of PdCu alloy onto oxygen defective TiO2-x, resulting in a significant increase in NH3 yield (from 70.6 to 366.4 µmol cm-2 h-1 at -0.6 V vs reversible hydrogen electrode) by modulating localized electron density. In situ and operando studies illustrate that the reduction of NO2 - to NH3 involves gradual deoxygenation and hydrogenation. The process also demonstrated excellent selectivity and stability, with long-term durability in cycling and 50 h stability tests. Density functional theory (DFT) calculations elucidate that the introduction of PdCu alloys further amplified electron density at oxygen vacancies (Ovs). Additionally, the Ti─O bond is strengthened as the d-band center of the Ti 3d rising after PdCu loading, facilitating the adsorption and activation of *NO2. Moreover, the presence of Ovs and PdCu alloy lowers the energy barriers for deoxygenation and hydrogenation, leading to high yield and selectivity of NH3. This insight of controlling localized electron density offers valuable insights for advancing sustainable NH3 synthesis methods.

The Gut Microbial Lipid Metabolite 14(15)- EpETE Inhibits Substance P Release by Targeting GCG/PKA Signaling to Relieve Cisplatin-Induced Nausea and Vomiting in Rats.

Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect related to activation of substance P (SP). SP activation can result from dysregulation of the gut-brain axis, and also from activation of protein kinase A signaling (PKA) signaling. In this study, we connected these factors in an attempt to unveil the mechanisms underlying CINV and develop new therapeutic strategies. Female rats were injected with cisplatin to induce pica. Fecal samples were collected before/after injection, and subjected to lipid metabolomics analysis. In another portion of pica rats, the PKA inhibitor KT5720 was applied to investigate the involvement of PKA signaling in CINV, while fecal microbiota transplantation (FMT) was implemented to verify the therapeutic effect of the lipid metabolite 14(15)-EpETE. Pica symptoms were recorded, followed by ileal histological examination. The targeting relationship between 14(15)-EpETE and glucagon was determined by bioinformatics. SP and glucagon/PKA signaling in rat ileum, serum, and/or brain substantia nigra were detected by immunohistochemistry, enzyme-linked immunosorbent assay, and/or western blot. The results showed a significantly lower level of 14(15)-EpETE in rat feces after cisplatin injection. KT5720 treatment alleviated cisplatin-induced pica symptoms, ileal injury, SP content increase in the ileum, serum, and brain substantia nigra, and ileal PKA activation in rats. The ileal level of glucagon was elevated by cisplatin in rats. FMT exerted an effect similar to that of KT5720 treatment, relieving the cisplatin-induced changes, including ileal glucagon/PKA activation in rats. Our findings demonstrate that FMT restores 14(15)-EpETE production, which inhibits SP release by targeting GCG/PKA signaling, ultimately mitigating CINV.

Carbon footprint analysis of wastewater treatment processes coupled with sludge in situ reduction.

The goal of this study was to assess the impacts or benefits of sludge in situ reduction (SIR) within wastewater treatment processes with relation to global warming potential in wastewater treatment plants, with a comprehensive consideration of wastewater and sludge treatment. The anaerobic side-stream reactor (ASSR) and the sludge process reduction activated sludge (SPRAS), two typical SIR technologies, were used to compare the carbon footprint analysis results with the conventional anaerobic - anoxic - oxic (AAO) process. Compared to the AAO, the ASSR with a typical sludge reduction efficiency (SRE) of 30 % increased greenhouse gas (GHG) emissions by 1.1 - 1.7 %, while the SPRAS with a SRE of 74 % reduced GHG emissions by 12.3 - 17.6 %. Electricity consumption (0.025 - 0.027 kg CO2-eq/m3), CO2 emissions (0.016 - 0.059 kg CO2-eq/m3), and N2O emissions (0.009 - 0.023 kg CO2-eq/m3) for the removal of secondary substrates released from sludge decay in the SIR processes were the major contributor to the increased GHG emissions from the wastewater treatment system. By lowering sludge production and the organic matter content in the sludge, the SIR processes significantly decreased the carbon footprints associated with sludge treatment and disposal. The threshold SREs of the ASSR for GHG reduction were 27.7 % and 34.6 % for the advanced dewatering - sanitary landfill and conventional dewatering - drying-incinerating routes, respectively. Overall, the SPRAS process could be considered as a cost-effective and sustainable low-carbon SIR technology for wastewater treatment.

A bibliometric analysis on laparoscopic pelvic floor surgery from 1996-2022.

INTRODUCTION: Pelvic organ prolapse is a common condition in middle-aged and older women. Laparoscopic pelvic floor surgery is frequently researched as a treatment for this issue. However, the effectiveness of this procedure has only been the subject of a few studies. METHODS: To quantitatively evaluate and display the relevant literature from the Web of Science database, we set the publication period of the literature from 1996 to 2022 and used VOSviewer and CiteSpace for visual analysis. RESULTS: Laparoscopic pelvic floor surgery research has increased year-on-year, with 1003 publications identified from 63 countries and published in 210 journals. In the global ranking of studies, the United States was the leader (n = 306; 30.5 %), with the most published authors being Campagna, Giuseppe (n = 17) and Scambia, Giovanni (n = 17). The International urogynecology journal included the most significant articles (n = 173; 17.2 %). Keyword analysis suggests that complications, rectal prolapse, native tissue repair, and warranty may have become hotspots in recent years. CONCLUSIONS: This bibliometric study shows that the depth and breadth of research on pelvic floor laparoscopic surgery have expanded rapidly over the last twenty-five years and that laparoscopic surgery has been recognized by different scholars or countries as an essential modality for the treatment of pelvic floor organ prolapse.

Platelets promote primary hepatocellular carcinoma metastasis through TGF-ß1-mediated cancer cell autophagy.

Previous research has revealed that platelets promote tumor metastasis by binding to circulating tumor cells (CTCs). However, the role of platelets in epithelial-mesenchymal transition (EMT) of cancer cells at the primary tumor site, the crucial initial step of tumor metastasis, remains to be elucidated. Here, we found that platelet releasate enhanced EMT and motility of hepatocellular carcinoma (HCC) cells via AMPK/mTOR-induced autophagy. RNA-seq indicated that platelet releasate altered TGF-ß signaling pathway of cancer cells. Inhibiting TGFBR or deleting platelet TGF-ß1 suppressed AMPK/mTOR pathway activation and autophagy induced by platelet releasate. Compared with Pf4cre-; Tgfb1fl/fl mice, HCC orthotopic models established on Pf4cre+; Tgfb1fl/fl mice showed reduced TGF-ß1 in primary tumors, which corresponded with decreased cancer cell EMT, autophagy, migration ability and tumor metastasis. Inhibition of autophagy via Atg5 knockdown in cancer cells negated EMT and metastasis induced by platelet-released TGF-ß1. Clinically, higher platelet count correlated with increased TGF-ß1, LC3 and N-cad expression in primary tumors of HCC patients, suggesting a link between platelets and HCC progression. Our study indicates that platelets promote cancer cell EMT in the primary tumor and HCC metastasis through TGF-ß1-induced HCC cell autophagy via the AMPK/mTOR pathway. These findings offer novel insights into the role of platelets in HCC metastasis and the potential therapeutic targets for HCC metastasis.

A preliminary study of contrast-enhanced ultrasound guided capsule-preserving hydrodilatation in shoulder adhesive capsulitis.

Background: Capsule-preserving hydrodilatation is a common treatment for adhesive capsulitis (AC), and ultrasound (US) has recently become the most popular adjuvant tool for image-guided glenohumeral joint injection. However, traditional US is hardly adequate to assess extracapsular fluid leakage, which may decide the treatment outcomes. In this study, we explored the value of contrast-enhanced ultrasound (CEUS) guided capsule-preserving hydrodilatation with steroids and ultrasonic contrast agents for treatment of AC. Methods: A total of 40 consecutive patients with AC were prospectively enrolled and received CEUS-guided capsule-preserving hydrodilatation. The number of injection attempts, injection volume, and fluid leakage were recorded, and the correlations with clinical features were analyzed by Pearson or Spearman correlation coefficients. Outcome measures including visual analog scale (VAS) score, passive range of motion (ROM), and shoulder pain and disability index (SPADI) score were evaluated at baseline and 4 weeks after treatment. Comparisons between patients with good and poor clinical outcomes were performed with independent t-test, Mann-Whitney U test, and chi-square test. Logistic regression was used to identify predictors of good clinical outcomes. A P value <0.05 defined significance. Results: Access to the glenohumeral joint was successful in 87.5% patients on the first attempt. The infused fluid volume was 21.0±3.40 mL. Longer symptom duration (r=-0.676, P<0.001), greater SPADI (r=-0.148, P=0.007), and decreased ROM in abduction (r=0.38, P=0.016) were associated with a decreased volume of infused fluid. CEUS detected massive fluid leakage in 5 (12.5%) patients, with 4 capsule ruptures confirmed by magnetic resonance imaging (MRI). Longer symptom duration (r=0.485, P=0.001), decreased ROM in the direction of abduction (r=-0.33, P=0.037), and external rotation (r=-0.34, P=0.032) were correlated with an increased incidence of massive fluid leakage. Moreover, patients with good outcomes had significantly shorter symptom duration (5.7±2.09 vs. 11.2±3.89 months, P=0.002) and greater initial VAS score (6.9±1.04 vs. 6.3±0.50, P=0.022) than those with poor outcomes. Absence of massive fluid leakage was an independent predictor of clinical good outcomes at 4 weeks after treatment [odd ratio (OR) =0.05, 95% confidential interval (CI): 0.003-0.882, P=0.041]. Conclusions: CEUS-guided capsule-preserving hydrodilatation allows real-time visualization of capsule dilatation, accurate detection of extracapsular fluid leakage, and identification of risks for capsule rupture. It provides an effective treatment for AC, and is useful to predict patients' clinical outcomes.

Socioeconomic Status Plays a Moderating Role in the Association Between Multimorbidity and Health-Related Quality of Life Among Cancer Patients.

This study aimed to explore the moderating role of socioeconomic status (SES) in the association between multimorbidity and health-related quality of life (HRQOL) among cancer patients in Anhui China. A total of 560 cancer patients were recruited for the cross-section study. Socio-demographic and clinical characteristics were analyzed using descriptive statistics. Tobit regression analysis was employed to investigate the relationship between multimorbidity and HRQOL as well as to assess the moderating effect of SES. The research findings indicated that 76.61% of cancer patients experienced multimorbidity, with psychological multimorbidity being the most prevalent (45.54%), followed by physical-psychological multimorbidity (20.89%). Moreover, physical-psychological multimorbidity had the most substantial adverse effect on HRQOL (P < .001). The presence of multimorbidity was correlated with a significant decline in HRQOL, with a 17.5% (P < .001) decrease in HRQOL for each additional multimorbidity. Additionally, SES played a significant role in moderating the impact of multimorbidity on HRQOL in cancer patients. (Marginal effect = -0.022, P < .01). The high SES group exhibited a higher overall HRQOL than the low SES group (Marginal effect = 0.068, P < .001). And with the increase of multimorbidity, HRQOL in the higher SES showed a more pronounced downward trend, compared with the lower SES (ß = -.270 vs ß = -.201, P < .001). Our findings underscore the importance of preventing and managing multimorbidity in cancer patients, particularly those with low SES. Furthermore, it is essential to consider the impact of the rapid decline in HRQOL as the number of multimorbidity increases in individuals with higher SES. It is imperative to explore interdisciplinary and continuous collaborative management models.

Promotion and Mechanism of Acupotomy on Chondrocyte Autophagy in Knee Osteoarthritis Rabbits.

OBJECTIVE: To explore the effect of acupotomy intervention on autophagy of chondrocytes in rabbits with knee osteoarthritis (KOA), and to determine the possible mechanisms of acupotomy to alleviate cartilage degeneration. METHODS: The modified Videman method was used to construct a KOA rabbit model. After modeling, 40 rabbits were randomly divided into 4 groups by a random number table: control; KOA (model); KOA + acupotomy (acupotomy), and KOA + sham acupotomy (sham), 10 in each group. After a 3-week treatment course, the knee joint activity was determined by the modified Lequesne MG index. Hematoxylin-eosin staining staining was used to examine the morphological changes of chondrocytes. Autophagy of chondrocytes was observed by transmission electron microscopy. The surface morphology of cartilage tissue was observed by scanning electron microscope. The mRNA and protein levels of AMP kinase/mammalian target of rapamycin/Unc-51 (AMPK/mTOR/ULK1) signal pathway key proteins, autophagy-related factor Beclin-1 and microtubule-associated protein 1A/1B light chain 3 (LC3) in rabbit knee cartilage were assessed by real-time fluorescence quantitative polymerase chain reaction and Western blot, respectively. RESULTS: The modified Lequesne MG score of acupotomy group was significantly lower than that of model group (P<0.05). Pathological results showed that chondrocyte autophagy decreased and cartilage surface was rough in the model group, which recovered after acupotomy treatment. The mRNA expressions of AMPK, ULK1, Beclin-1 and the protein levels of p-AMPK, p-ULK1, Beclin-1, and LC3 II/LC3 I were decreased in the model group, while the mRNA and protein expressions of mTOR were increased (P<0.01). However, acupotomy treatment reversed these abnormal changes (P<0.05). CONCLUSIONS: Acupotomy could effectively up-regulate the expressions of AMPK, ULK1 and Beclin1, reduce the expression of mTOR, promote autophagy, and alleviate joint degeneration. Acupotomy is a promising complementary and alternative therapy for KOA.

Mediating roles of activities of daily living and depression on the relationship between sleep quality and health-related quality of life.

This study aimed to explore the mediating effects of ADL and depression on the relationship between sleep quality and HRQOL among older people in rural China, while also exploring the moderating impact of loneliness. The study gathered data from a household survey conducted among 1587 Chinese rural older adults (mean age = 73.63 years). The collected data was analyzed using SPSS version 23.0 software (IBM, New York, USA) and the PROCESS macro version 4.0 program. The findings indicated a significant correlation between sleep quality, ADL, depression, loneliness and HRQOL. ADL and depression exhibited a chain mediation effect on the relationship between sleep quality and HRQOL. Notably, the association between sleep quality and HRQOL was entirely mediated by ADL and depression. Additionally, loneliness acted as a moderator in the relationship between ADL and HRQOL. The findings of this study suggest that interventions focusing on sleep quality should prioritize strategies for enhancing older adults' ADL and depression as integral components of promoting older adults' HRQOL.

Microwave ablation with hydrodissection used for the treatment of vascular malformations: effectiveness and safety study.

Object: The aim of the study was to investigate the safety, effectiveness, and peripheral nerve protection in ultrasound-guided microwave ablation (US-guided-MWA) for vascular malformations (VMs) closely related to peripheral nerve. Materials and methods: From August 2019 to February 2022, 31 patients with 39 VMs received US-guided-MWA. All lesions were confirmed to be closely related to the peripheral nerve by imaging evaluation. Hydrodissection was applied to protect surrounding normal tissue, including peripheral nerves. The patients were followed up at 1day, 2 days, 3 days, 1 week, 1 month, 3 months after operation. Measurements of lesion volume, volume reduction ratio (VRR), sensory and functional abnormalities of adjacent nerves, number of treatments, complication details, personal satisfaction, recurrence, and symptom improvement were recorded. Results: Among the 39 VMs, the maximum volume is 128.58ml, while the minimum volume is 0.99ml. After a mean follow-up of 13.06 ± 4.83 months, the mean numerical rating scale (NRS) score decreased from 5.13 ± 1.65 to 0.53 ± 0.83 (P<0.0001). The mean mass volume was reduced from 18.34 ± 24.68 ml to 1.35 ± 2.09 ml (P=0.0001). The VRR of all lesions was 92.06%. However, the mean number of treatments was only 1.64 ± 0.87. All patients were satisfied with the technique, with a mean satisfaction score (SC) of 9.23 ± 1.13. There were no motor function abnormalities of the related nerves. 10 patients felt numbness in the ablation area after ablation, and gradually recovered after 1 month. Conclusion: US-guided-MWA serves as a novel alternative approach for patients with VMs. Preoperative evaluation of the relationship between VMs and peripheral nerves combined with intraoperative hydrodissection is an effective and safe method to prevent nerve injury.

An ultrasound based method for predicting the malignant potential of primary gastrointestinal stromal tumors preoperatively.

OBJECTIVE: Gastrointestinal stromal tumors (GISTs) are difficult to identify the risk level accurately without surgical pathological confirmation. The purpose of our study was to propose a noninvasive prediction method for predicting the malignant potential of GISTs preoperatively by using contrast-enhanced ultrasound (CEUS) with gastric distention. METHODS: We reviewed 47 GISTs who underwent CEUS from April 2017 to August 2023 retrospectively, all the lesions were certificated by pathology after surgery. The age of the patient, size of the lesion, shape, necrosis, calcification in the lesion, perfusion parameters including arrival time (AT), peak intensity (PI), time to peak (TTP), and area under the curve (AUC) of the lesion and surrounding normal tissue were analyzed. Logistic regression analyses were performed. Of the 47 GISTs, 26 were high-risk and 21 low-risk tumors respectively. RESULTS: Compared with low-risk GISTs, high-risk GIST had faster AT (7.7s vs. 11.5s, p < 0.05), higher PI (15.2dB vs. 12.5dB, p < 0.05), and larger size (4.4 cm vs. 2.2 cm, p < 0.001). In multivariate logistic regression, AT, PI, and size were significant features. The corresponding regression equation In (p/(1-p)=-5.9 + 4.5 size + 4.6 PI + 4.0 AT). CONCLUSION: The size, AT, and PI of the GISTs on CEUS can be used as parameters for a noninvasive risk level prediction model of GISTs. This model may help identify the different risk levels of GISTs before surgery.

Exosomal PD-L1 in cancer and other fields: recent advances and perspectives.

PD-1/PD-L1 signaling is a key factor of local immunosuppression in the tumor microenvironment. Immune checkpoint inhibitors targeting PD-1/PD-L1 signaling have achieved tremendous success in clinic. However, several types of cancer are particularly refractory to the anti-PD-1/PD-L1 treatment. Recently, a series of studies reported that IFN-γ can stimulate cancer cells to release exosomal PD-L1 (exoPD-L1), which possesses the ability to suppress anticancer immune responses and is associated with anti-PD-1 response. In this review, we introduce the PD-1/PD-L1 signaling, including the so-called 'reverse signaling'. Furthermore, we summarize the immune treatments of cancers and pay more attention to immune checkpoint inhibitors targeting PD-1/PD-L1 signaling. Additionally, we review the action mechanisms and regulation of exoPD-L1. We also introduce the function of exoPD-L1 as biomarkers. Finally, we review the methods for analyzing and quantifying exoPD-L1, the therapeutic strategies targeting exoPD-L1 to enhance immunotherapy and the roles of exoPD-L1 beyond cancer. This comprehensive review delves into recent advances of exoPD-L1 and all these findings suggest that exoPD-L1 plays an important role in both cancer and other fields.

Network Pharmacology Combined with Animal Models to Investigate the Mechanism of ChangPu YuJin Tang in the Treatment of Tourette Syndrome.

BACKGROUND: ChangPu YuJin Tang (CPYJT) is a Chinese herbal formula that has been shown to be an effective therapeutic strategy for pediatric patients with Tourette Syndrome (TS). Using an integrated strategy of network pharmacology and animal model, the aim of this study was to investigate the mechanism of CPYJT in the treatment of TS. METHODS: Compound libraries of CPYJT were established using databases, such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The TCMSP database and Swiss Target Prediction database were used to predict the targets. The above results were constructed into a CPYJT-Drug-Component-Target network. Moreover, TS targets were predicted using GeneCards and other databases. The targets corresponding to the potential ingredients in CPYJT and the targets corresponding to TS were taken as the intersections to construct the CPYJT-TS network. The target network was analysed by PPI using the string database. GO and KEGG enrichment analyses were performed on the target network. The whole process was performed using Cytoscape 3.7.2 to make visual network diagrams of the results. CPYJT was characterised by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS). Transmission Electron Microscopy (TEM) was used to observe the structural changes of CPYJT on the neuronal cells of the IDPN model rats. RT-PCR and Western Blot were used to analyse the changes in the mRNA and protein expression levels of BDNF, TrkB, PI3K, and AKT in the cortex, striatum, and thalamus brain regions after CPYJT administration in IDPN model rats. RESULTS: Network pharmacology and UHPLC-MS studies revealed that CPYJT acted on the TS through multiple neurotransmitters and the BDNF/TrkB and PI3K/AKT signalling pathways. CPYJT ameliorated neurocellular structural damage in the cortex, striatum, and thalamus of TS model rats. Additionally, CPYJT up-regulated the levels of BDNF, TrkB, PI3k, and AKT in the cortex, striatum, and thalamus of TS model rats. CONCLUSION: It was found that CPYJT protected neuronal cells from structural damage in multiple brain regions and affected the expression levels of BDNF, TrkB, PI3K, and Akt in the cortex, striatum, and thalamus during TS treatment.

Microwave ablation for painful chest wall metastases from gastrointestinal stromal tumor: a case report.

Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract, with the potential to metastasize. Metastases to bone and soft tissue are more frequent in advanced cases, where targeted therapy is the standard treatment. However, around 10-15% of patients develop disease progression despite treatment. Studies have shown the efficacy of ablation in managing bone and soft tissue metastases (1, 2), but there are no reports of ablation for treating GIST bone or soft tissue metastases. Case presentation: In 2022, a 58-year-old man complaining of left back pain was admitted to Sichuan Cancer Hospital. He had undergone radical resection of the primary gastric GIST and vertebral metastases in 2014 and 2018, respectively. In 2019, rib metastases still occurred despite the use of targeted therapy. During the course of radiotherapy, targeted therapy, and immunotherapy, he experienced persistent chest wall pain. In addition, new lesions occurred in the lungs and chest wall in 2022. After a thorough assessment, microwave ablation (MWA) was recommended in response to his demand for immediate pain relief. The large rib metastasis constricted the spleen, so we completed the ablation in two sessions to reduce the risk of complications. He had 17 months of follow-up until September 2023, during which time his discomfort was considerably reduced. Conclusion: For GIST patients with soft tissue and bone metastases, MWA may offer substantial immediate pain alleviation. When other treatment procedures fail to achieve adequate efficacy, it provides an option.

[Mechanism of acupotomy on chondrocyte ferroptosis in rabbits with knee osteoarthritis based on HSPA5/GPX4 signaling pathway].

OBJECTIVE: To observe the effect of acupotomy on heat shock protein A family member 5 (HSPA5)/glutathione peroxidase 4 (GPX4) signaling pathway in the chondrocytes of the rabbits with knee osteoarthritis (KOA) and explore the mechanism of acupotomy on chondrocyte ferroptosis in KOA. METHODS: Twenty-seven New Zealand rabbits were randomly divided into a normal group, a model group and an acupotomy group, with 9 rabbits in each group. The left hind limb was fixed by the modified Videman method for 6 weeks to establish KOA model. After modeling, acupotomy was given in the acupotomy group, once a week and for consecutive 3 weeks. Using Lequesne MG score, the local symptoms, physical signs and functions of knee joint were evaluated. With HE staining and saffrane-solid green staining adopted, the morphology of chondrocytes and cartilage tissue was observed. Under transmission electron microscope, the mitochondrial structure of chondrocytes was observed. The iron content of cartilage tissue was detected by iron ion kit. The mitochondrial membrane potential (Δψm) and the reactive oxygen species (ROS) level in cartilage tissue were determined by flow cytometry, and the mitochondrial damage rate was calculated. The mRNA expression of HSPA5, GPX4, type Ⅱ collagen α1 chain (COL2A1), matrix metalloproteinases (MMP) 3 and MMP13 was detected by the real-time quantitative PCR; and the protein expression of HSPA5, GPX4, type Ⅱ collagen (COL-Ⅱ), MMP3 and MMP13 was detected by Western blot. The mean flourscence intensity of HSPA5 and GPX4 in cartilage tissue was determined by immunofluorescence. RESULTS: Before intervention, compared with the normal group, the Lequesne MG scores were increased in the model group and the acupotomy group (P<0.01). After intervention, the Lequesne MG score in the acupotomy group was decreased when compared with that in the model group. In comparison with that in the normal group, the number of chondrocytes was reduced and the cells were disarranged; the layers of cartilage structure were unclear, the tide lines disordered and blurred; the mitochondria were wrinkled and the mitochondrial crista decreased or even disappeared in the model group. Compared with the model group, the number of chondrocytes was increased, the layers of cartilage structure were clear, the tide lines recovered, the number of mitochondria elevated, with normal structure and more crista in the acupotomy group. The iron content of cartilage tissue was increased (P<0.01), the Δψm of chondrocytes was declined, the mitochondrial damage rate was increased (P<0.01), the average fluorescence intensity of ROS was increased (P<0.01); the mRNA and corresponding protein expression of HSPA5, GPX4 and COL2A1 was decreased (P<0.01), the mRNA and protein expression of MMP3 and MMP13 was increased (P<0.01) and the average fluorescence intensity of HSPA5, GPX4 was decreased (P<0.01) in the model group when compared with those in the normal group. Compared with the model group, the iron content in cartilage tissue was reduced (P<0.01), the Δψm of chondrocytes was increased, the mitochondrial damage rate was decreased (P<0.01), and the average fluorescence intensity of ROS was decreased (P<0.01); the mRNA and corresponding protein expression of HSPA5, GPX4 and COL2A1 was higher (P<0.01), and the mRNA and protein expression of MMP3 and MMP13 was lower, and the average fluorescence intensity of HSPA5, GPX4 was increased (P<0.01) in the acupotomy group. CONCLUSION: Acupotomy can alleviate cartilage injury of KOA rabbits, and its mechanism may be related to the regulation of HSPA5/GPX4 signaling pathway to maintain iron homeostasis in articular cartilage, thus inhibiting chondrocyte ferroptosis and relieving extracellular matrix degradation.

Thermal ablation with and without adjuvant systemic therapy: a nationwide multicenter observational cohort study of solitary colorectal liver metastases.

BACKGROUND: Thermal ablation is routinely used for solitary colorectal liver metastases (SCLM), but the added value of adjuvant systemic therapy in SCLM remains unclear. This study aimed to compare the long-term outcomes for SCLM treated by ablation alone (AB) versus ablation plus systemic therapy (AS). METHODS: This multicenter retrospective study using nationwide data from fourteen institutions between October 2010 and May 2023, 369 patients with initial SCLM smaller than 5 cm, no extrahepatic metastases, and colorectal cancer R0 resection treated by thermal ablation were included. The crude analysis was used to analyze eligible cases between the two groups. The propensity score matching to control for potential confounders in each matched group. Subgroup analyses were performed to identify specific survival benefits. RESULTS: 61.2% (226/369) of eligible patients were treated with AS and 38.8% (143/369) with AB. During the median follow-up period of 8.8 years, 1-/3-/5-year DFS/OS rates did not differ between the two groups, when analyzed via propensity score matching ( P =0.52/0.08). Subgroup analysis revealed that AS was significantly associated with better OS than AB in patients with plasma CEA >5 ug/l ( P =0.036), T (III-IV) category of primary cancer ( P =0.034), or clinical risk score (1-2) ( P =0.041). In each matched group, the authors did find a significant difference in drug-related adverse events ( P <0.001) between AS group (24.1%, 28/116) and AB group (0.0%, 0/116). CONCLUSIONS: For patients with plasma CEA >5 ug/l, T (III-IV) category of primary cancer, or clinical risk score (1-2), thermal ablation plus systemic therapy appeared to be associated with improved overall survival. Thermal ablation was equally effective in disease-free survival for treating SCLM, whether with or without adjuvant systemic therapy.

Clinical relevance and therapeutic predictive ability of hypoxia biomarkers in head and neck cancer tumour models.

Tumour hypoxia promotes poor patient outcomes, with particularly strong evidence for head and neck squamous cell carcinoma (HNSCC). To effectively target hypoxia, therapies require selection biomarkers and preclinical models that can accurately model tumour hypoxia. We established 20 patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models of HNSCC that we characterised for their fidelity to represent clinical HNSCC in gene expression, hypoxia status and proliferation and that were evaluated for their sensitivity to hypoxia-activated prodrugs (HAPs). PDX models showed greater fidelity in gene expression to clinical HNSCC than cell lines, as did CDX models relative to their paired cell lines. PDX models were significantly more hypoxic than CDX models, as assessed by hypoxia gene signatures and pimonidazole immunohistochemistry, and showed similar hypoxia gene expression to clinical HNSCC tumours. Hypoxia or proliferation status alone could not determine HAP sensitivity across our 20 HNSCC and two non-HNSCC tumour models by either tumour growth inhibition or killing of hypoxia cells in an ex vivo clonogenic assay. In summary, our tumour models provide clinically relevant HNSCC models that are suitable for evaluating hypoxia-targeting therapies; however, additional biomarkers to hypoxia are required to accurately predict drug sensitivity.

Insomnia among coronavirus disease 2019 survivors: A single-center cross-sectional study.

Since the coronavirus disease 2019 (COVID-19) epidemic, insomnia has become one of the longer COVID-19 symptoms. This study aimed to investigate insomnia among COVID-19 survivors and explore the occurrence and influencing factors of insomnia. A cross-sectional study was performed from December 2022 to February 2023 through an online questionnaire star survey with 8 questions. The insomnia severity index scale (ISI) was used to assess the severity of insomnia. Univariate analysis was used to analyze the factors related to COVID-19 infection. A total of 564 participants (183 males and 381 females) were surveyed in the present study. The prevalence of insomnia was 63.12%. Among these insomnia patients, there were 202 (35.82%) with sub-threshold symptoms, 116 (20.57%) with moderate symptoms, and 38 (6.74%) with severe symptoms. Univariate analysis indicated that there were statistically significant differences in the prevalence of insomnia among COVID-19 survivors of different ages, occupations, and educational levels (P < .05). Of the 356 insomnia patients, 185 (51.97%) did not take any measures against insomnia, while those who took drugs only, physical exercise only, drugs and physical exercise, and other measures were 90 (25.28%), 42 (11.80%), 17 (4.78%), and 22 (6.18%), respectively. Additionally, of the 107 insomnia patients with drug therapy, 17 (15.89%) took estazolam, 16 (14.95%) took alprazolam, 39 (36.45%) took zopiclone, and 35 (32.71%) took other drugs to improve insomnia symptoms. The prevalence of insomnia symptoms remains high among COVID-19 survivors in China. Education level and occupation may be the influencing factors. Unfortunately, most patients with insomnia do not take corresponding treatment measures.