Mesenchymal stem cells-derived IL-6 promotes invasion and metastasis of oral squamous cell carcinoma via JAK-STAT3 signalling.

OBJECTIVES: Oral squamous cell carcinoma (OSCC) is often diagnosed with cervical lymph node metastasis. Mesenchymal stem cells (MSCs) and interleukin-6 (IL-6) signalling are considered to play important roles in promoting tumour malignancy. The detailed biological interaction of MSCs and IL-6 and the subsequent effect on OSCC metastasis remain largely unclear. This study aimed to determine the effects and molecular mechanism of MSCs-derived IL-6 on tumour invasion and metastasis. SUBJECTS AND METHODS: The effects of MSC-derived IL-6 and tocilizumab on the proliferation, mobility, and epithelial-mesenchymal transition (EMT) of OSCC cells and potential pathways were detected in vitro. In addition, a murine xenograft model was generated to verify the biological mechanism in vivo. RESULTS: The results showed that the expression of MSCs and EMT-related signals was increased in poorly differentiated OSCC tissues. MSCs released a higher level of IL-6 and promoted the proliferation, invasion, and metastasis of OSCC cells and solid neoplasms, which were activated by the downstream molecules JAK and STAT3. CONCLUSIONS: The results indicated that MSCs-derived IL-6-promoted tumour invasion and metastasis via JAK-STAT3 signalling. Blockade of this pathway by tocilizumab may be a potential treatment to improve the prognosis and survival rate of patients with OSCC.

Effects of Ferroptosis on Cardiovascular Diseases.

Ferroptosis is a novel form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides, which causes membrane injury. Under the catalysis of iron ions, cells deficient in glutathione peroxidase (GPX4) cannot preserve the balance in lipid oxidative metabolism, and the buildup of reactive oxygen species on the membrane lipids leads to cell death. An increasing body of evidence suggests that ferroptosis plays a significant role in the development and occurrence of cardiovascular diseases. In this paper, we mainly elaborated on the molecular mechanisms regulating ferroptosis and its impact on cardiovascular disease to lay the groundwork for future studies on the prophylaxis and treatment of this patient population.

Saikosaponin D Alleviates DOX-induced Cardiac Injury In Vivo and In Vitro.

ABSTRACT: As a highly efficient anticancer agent, doxorubicin (DOX) is used for treatment of various cancers, but DOX-induced oxidative damages contribute to a degenerative irreversible cardiac toxicity. Saikosaponin D (SSD), which is a triterpenoid saponin with many biological activities including anti-inflammatory effects and antioxidant properties, provides protection against pathologic cardiac remodeling and fibrosis. In the present study, we investigated the work of SSD for DOX-induced cardiotoxicity and the involved mechanisms. We observed that DOX injection induced cardiac injury and malfunction and decreased survival rate. Besides, DOX treatment increased lactate dehydrogenase leakage, cardiomyocyte apoptosis, and myocardium fibrosis and decreased the size of cardiomyocytes. Meanwhile, all the effects were notably attenuated by SSD treatment. In vitro, we found that 1 µM SSD could enhance the proliferation of H9c2 cells and inhibit DOX-induced apoptosis. It was found that the levels of malondialdehyde (MDA) and reactive oxygen species were significantly reduced by improving the activities of the endogenous antioxidative enzymes including catalase and glutathione peroxidase. Furthermore, SSD treatment could downregulate the DOX-induced p38 phosphorylation. Our results suggested that SSD efficiently protected the cardiomyocytes from DOX-induced cardiotoxicity by inhibiting the excessive oxidative stress via p38-MAPK (mitogen-activated protein kinase, MAPK) signaling pathway.

Oral reactive capillary hemangiomas induced by SHR-1210 in the treatment of non-small cell lung cancer: a case report and literature review.

BACKGROUND: Antibodies to PD-1 and PD-L1 have remarkably improved the overall survival of many patients with advanced solid tumors. SHR-1210 is an anti-PD-1 monoclonal antibody. Dermatologic reactive capillary hemangiomas (RCH) were the most common and unique drug-related AEs of SHR-1210, but rare on oral mucosa and gastrointestinal mucosa. Herein we report a case of RCH occurred in oral mucosa during the clinical trials of SHR-1210 in the treatment of non-small cell lung cancer. CASE PRESENTATION: A male in his 60 s with a history of non-small cell lung cancer received injection of anti-PD-1 monoclonal antibodies SHR-1210. The patient developed drug-related RCH on skin after the first injection and began to have gingival hyperplasia one year after the first injection which gradually increased in size and affect eating and speaking. Anti-PD-1 treatments were continued. After periodontal treatment, two oral lesions and one skin lesion were surgically removed. Similar histological manifestation was found in all three lesions as reactive capillary hemangiomas. All lesions had a good prognosis without recurrence on oral mucosa within one year after surgery. CONCLUSIONS: Oral reactive capillary hemangiomas could be induced by SHR-1210 in the treatment of non-small cell lung cancer. Surgical resection is an effective treatment with a good prognosis.

Clinical Research of Lupus Retinopathy: Quantitative Analysis of Retinal Vessels by Optical Coherence Tomography Angiography in Patients with Systemic Lupus Erythematosus.

BACKGROUND: Lupus retinopathy, an ocular manifestation of systemic lupus erythematosus (SLE), is the major pathology attributed to retinal vasculopathy. Our study is to analyze the changes in retinal vessels in patients with SLE by optical coherence tomography angiography. METHODS: A total of 61 SLE patients without obvious retinal manifestation and 71 healthy people were included. The SLE patients were further divided into a lupus nephritis (LN) group and a non-LN group. The changes in central macular thickness (CMT) and the retinal vessel densities were compared between the two groups, and the correlation between retinal vascular changes and disease activity was analyzed. RESULTS: Compared with healthy control, the CMT and the retinal vascular densities in both superficial and deep retina were decreased significantly in SLE patients. There was no significant difference in retinal vascular densities between LN groups and non-LN groups. CONCLUSION: The CMT and retinal vessel densities were decreased in SLE patients without clinical manifestations, which might serve as a sensitive biomarker for early changes of lupus retinopathy in SLE patients.

The Interval of Two-Stage Bilateral Total Hip Arthroplasty under Enhanced Recovery Affects Perioperative Complications and Cost of Hospitalization: A Retrospective Study.

OBJECTIVES: Perioperative enhanced recovery after surgery (ERAS) protocols can improve the quality of healthcare and reduce hospitalization for patients who underwent total hip arthroplasty (THA). The interval of staged bilateral THA under ERAS is still unclear. We attempt to ascertain the optimal interval of staged bilateral THA for reducing the perioperative complications and the cost of hospitalization. METHODS: We retrospectively reviewed patients who received staged bilateral THA under ERAS performed at West China Hospital of Sichuan University from 2018 to 2021. The staged time was divided into two groups using four different cutoff points: (1) ≤3 months versus >3 months, (2) ≤4 months versus >4 months, (3) ≤5 months versus >5 months and (4) ≤6 months versus >6 months. Primary outcomes included the rate of perioperative complications and the cost of hospitalization. The secondary outcomes were the length of hospital stay (LOS), the rates of transfusion and albumin (Alb) administration, hemoglobin (Hb) decrease and serum Alb decrease. The categorical variables were compared using chi-squared and/or two-tailed Fisher's exact tests, whereas continuous variables were compared using two-tailed independent t-tests, the continuous variables which were asymmetrical distributions used a Kruskal-Wallis test. RESULTS: With the application of ERAS, the rate of perioperative complications in the >5 months group was significantly lower than that in the ≤5 months group (13/195 vs. 45/307, p < 0.05). Concerning the cost of hospitalization, the >5 monthly intervals spent significantly less than the ≤5 monthly intervals ($ 8695.91 vs. $ 8919.71, p < 0.05). However, no significant difference was found for secondary outcomes such as the rate of transfusions and Alb administrations or decreases of Hb and Alb in the 5 months threshold. CONCLUSIONS: More than 5 months maybe a reasonable period to perform the first contralateral THA under ERAS regarding the rate of perioperative complications and the cost of hospitalization. However, more high-quality research will include a larger sample size in the future to validate the appropriate time of staged bilateral THA.

Radiographic bone volume alteration after jaw cyst enucleation with or without simultaneous bone grafts: A prospective randomized study.

OBJECTIVE: This study was aimed to evaluate bone healing after jaw cyst enucleation with or without bone substitutes by cone beam computed tomography, and to analyze potential influence factors for bone formation as well. MATERIALS AND METHODS: Sixty seven jaw cyst patients were randomly assigned to two groups. Thirty three patients in control group accepted cystectomy without any filling material. The rest 34 bone cavities which filled with xenograft (DBBM, Bio-Oss®) and covered by absorbable membrane (Bio-Gide®) were included in the guided bone regeneration (GBR) group. All patients were examined with cone bean computerized tomography before operation, 3 and 6 months after surgery. Linear regression analysis was applied to evaluate the influence factors of bone healing. RESULTS: There was no significant difference in bone formation rate at 3 months after enucleation, with shrinkage rate (SR) of cystic lesion in control group and GBR group of 26.43 ± 14.98% and 20.78 ± 10.80%, respectively (p > 0.05). Larger shrinkage area in GBR group was detected on postoperative radiographs after 6 months with SR of 60.11 ± 19.23%, when compared to those in patients without filling (6 months SR: 48.63 ± 19.39%, p = 0.018, <0.05). Linear regression analysis showed that cyst size was negatively correlated with bone formation. CONCLUSION: GBR with bovine xenograft and absorbable membrane showed considerable bone regeneration property in the healing of jaw cystic defects after enucleation of radicular cysts. Cyst size showed a suppressive influence on bone formation.

What Is the Normal Trajectory of C-Reactive Protein, Erythrocyte Sedimentation Rate, Plasma Fibrinogen and D-Dimer after Two-Stage Exchange for Periprosthetic Joint Infection?

OBJECTIVE: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), plasma fibrinogen and D-Dimer are used as diagnostic biomarkers of prosthetic joint infection (PJI) after total joint arthroplasty (TJA). The purpose of the study was to investigate the normal trajectory of CRP, ESR, plasma fibrinogen and D-Dimer at different time points after two-stage exchange arthroplasty for PJI. METHODS: We studied 53 patients undergoing two-stage exchange for PJI at five time points: preoperatively (T0), duration of hospital stays (T1), 30 days (T2), 30-90 days (T3), and 90-180 days (T4) after surgery. The medical records of all patients were well documented and carefully reviewed. The Shapiro-Wilk test was utilized to compare the normal distribution for continuous variables, and the nonnormally distributed data were used for Friedmann's one-way repeat measures analysis of variances. Post hoc Dunnett's test was used to compare each pair of data to find differences from baseline. RESULTS: Compare with T0 point, the levels of CRP and ESR increased significantly and reached peak values at T1 point (all P < 0.001), with median values of 56.40 mg/L (range, 5.54-161.0 mg/L) and 49.00 mm/h (range, 13.00-113.0 mm/h), respectively. In addition, the levels of plasma fibrinogen and D-Dimer increased significantly and reached peak values at T1 point (all P < 0.001), with median values of 4.13g/L (range, 2.27-6.80 mg/L) and 4.00 mg/L (range, 0.19-14.01 mg/L), respectively. CRP and ESR rapidly declined at the T2 point with significantly compared with T0 point (P = 0.001 and P < 0.001). The levels of CRP, ESR, plasma fibrinogen and D-Dimer returned to preoperative levels of 5.23 mg/L (range, 1.01-21.70 mg/L), 19.00 mm/h (range, 6.00-60.00 mm/h), 3.38g/L (range, 1.71-5.10 g/L) and 2.33 mm/h (range, 0.19-6.87 mg/L) at T4 point, and there was no significant difference compared with T0 point (all P > 0.05). CONCLUSIONS: The study demonstrated the normal trajectory of CRP, ESR, plasma fibrinogen and D-Dimer at five time points in patients who underwent two-stage exchange for PJI. Thus, the results have the possibility of providing signs of infection after the patient receives two-stage exchange arthroplasty for PJI, which can benefit from early treatment.

Core-Shell Structured Porous Calcium Phosphate Bioceramic Spheres for Enhanced Bone Regeneration.

Adequate new bone regeneration in bone defects has always been a challenge as it requires excellent and efficient osteogenesis. Calcium phosphate (CaP) bioceramics, including hydroxyapatite (HA) and biphasic calcium phosphates (BCPs), have been extensively used in clinical bone defect filling due to their good osteoinductivity and biodegradability. Here, for the first time, we designed and fabricated two porous CaP bioceramic granules with core-shell structures, named in accordance with their composition as BCP@HA and HA@BCP (core@shell). The spherical shape and the porous structure of these granules were achieved by the calcium alginate gel molding technology combined with a H2O2 foaming process. These granules could be stacked to build a porous structure with a porosity of 65-70% and a micropore size distribution between 150 and 450 µm, which is reported to be good for new bone ingrowth. In vitro experiments confirmed that HA@BCP bioceramic granules could promote the proliferation and osteogenic ability when cocultured with bone marrow mesenchymal stem cells, while inhibiting the differentiation of RAW264.7 cells into osteoclasts. In vivo, 12 weeks of implantation in a critical-sized femoral bone defect animal model showed a higher bone volume fraction and bone mineral density in the HA@BCP group than in the BCP@HA or pure HA or BCP groups. From histological analysis, we discovered that the new bone tissue in the HA@BCP group was invading from the surface to the inside of the granules, and most of the bioceramic phase was replaced by the new bone. A higher degree of vascularization at the defect region repaired by HA@BCP was revealed by 3D microvascular perfusion angiography in terms of a higher vessel volume fraction. The current study demonstrated that the core-shell structured HA@BCP bioceramic granules could be a promising candidate for bone defect repair.

Clinicopathology and Recurrence Analysis of 44 Jaw Aneurysmal Bone Cyst Cases: A Literature Review.

In the past half-century, considerable attention has been paid to oral and maxillofacial skeletal cyst, however, aneurysmal bone cyst (ABC), unlike other common bone diseases, still contours numerous unanswered questions in terms of classification, etiology and pathological mechanism. The purpose of this article was to evaluate the proportion of primary ABC and secondary ABC, and to assess the recurrence of ABC and related factors. A methodical search of Embase, MEDLINE, Cochrane Library, Web of Science was conducted for well-documented jaw aneurysmal bone cyst (JABC) cases. One hundred thirty-one articles were identified after database searching and 31 of them were included in our study for further research with 44 JABC cases. All the articles were analyzed by two separate authors. About 25% of the reported jaw aneurysmal bone cyst was secondary. Both the pathological classification and surgical treatment had a significant influence on recurrence rate (P = 0.0082, P = 0.0022), while patients' age or radiographic features rarely affected prognosis. Jaw aneurysmal bone cysts can present variable clinical and histological presentations. Recurrence may be attributed to omittance of underlying potential blood supply or conservative surgical protocol.

GEF-independent Ran activation shifts a fraction of the protein to the cytoplasm and promotes cell proliferation.

Ran (Ras-related nuclear protein) plays several important roles in nucleo-cytoplasmic transport, mitotic spindle formation, nuclear envelope/nuclear pore complex assembly, and other functions in the cytoplasm, as well as in cellular transformation when switched on. Unlike other members of the GTPase superfamily, Ran binds more tightly to GDP than to GTP due to the presence of an auto-inhibitory C-terminal tail. Multiple missense mutations in the C-terminus of Ran occur in cancers, but their biological significance remains unclear. Here, the quantitative GDP/GTP binding preference of four engineered mutations with unstable C-termini was analyzed using a devised mant-GDP dissociation assay. The results showed that the impact of different C-terminal mutations depends on multiple factors. Although these mutants were more GTP-loaded in human cells, they were shown to be more cytoplasmic, and to support nuclear transport with minimally or partially reduced efficiency. Further, several Ran cancer mutants were compromised in autoinhibition, slightly more GTP-bound, more cytoplasmic, and enhanced the proliferation of A549 and HeLa cells in vitro. Thus, our work reveals a new route of Ran activation independent of guanine nucleotide exchange factor (GEF), which may account for the hyper-proliferation induced by Ran cancer mutations.

Distinct RanBP1 nuclear export and cargo dissociation mechanisms between fungi and animals.

Ran binding protein 1 (RanBP1) is a cytoplasmic-enriched and nuclear-cytoplasmic shuttling protein, playing important roles in nuclear transport. Much of what we know about RanBP1 is learned from fungi. Intrigued by the long-standing paradox of harboring an extra NES in animal RanBP1, we discovered utterly unexpected cargo dissociation and nuclear export mechanisms for animal RanBP1. In contrast to CRM1-RanGTP sequestration mechanism of cargo dissociation in fungi, animal RanBP1 solely sequestered RanGTP from nuclear export complexes. In fungi, RanBP1, CRM1 and RanGTP formed a 1:1:1 nuclear export complex; in contrast, animal RanBP1, CRM1 and RanGTP formed a 1:1:2 nuclear export complex. The key feature for the two mechanistic changes from fungi to animals was the loss of affinity between RanBP1-RanGTP and CRM1, since residues mediating their interaction in fungi were not conserved in animals. The biological significances of these different mechanisms in fungi and animals were also studied.