Chimeric antigen receptor-based immunotherapy in breast cancer: Recent progress in China.

Breast cancer (BC) is the fourth most prevalent cancer in China. Despite conventional treatment strategies, BC patients often have poor therapeutic outcomes, leading to significant global cancer mortality rates. Chimeric antigen receptor (CAR)-based immunotherapy is a promising and innovative approach for cancer treatment that redirects immune cells to attack tumor cells expressing selected tumor antigens (TAs). T cells, natural killer (NK) cells, and macrophages, key components of the immune system, are used in CAR-based immunotherapies. Although remarkable progress has been made with CAR-T cells in hematologic malignancies, the application of CAR-based immunotherapy to BC has lagged. This is partly due to obstacles such as tumor heterogeneity, which is further associated with the TA and BC subtypes, and the immunosuppressive tumor microenvironment (TME). Several combinatorial approaches, including the use of immune checkpoint inhibitors, oncolytic viruses, and antitumor drugs, have been proposed to overcome these obstacles in BC treatment. Furthermore, several CAR-based immunotherapies for BC have been translated into clinical trials. This review provides an overview of the recent progress in CAR-based immunotherapy for BC treatment, including targeting of TAs, consideration of BC subtypes, assessment of the TME, and exploration of combinatorial therapies. The authors focused on preclinical studies and clinical trials of CAR-T cells, CAR-NK cells, and CAR-macrophages especially conducted in China, followed by an internal comparison and discussion of current limits. In conclusion, this review elucidates China's contribution to CAR-based immunotherapies for BC and provides inspiration for further research. PLAIN LANGUAGE SUMMARY: Despite conventional treatment strategies, breast cancer (BC) patients in China often have poor therapeutic outcomes. Chimeric antigen receptor (CAR)-based immunotherapy, a promising approach, can redirect immune cells to kill tumor cells expressing selected tumor antigens (TAs). However, obstacles such as TA selection, BC subtypes, and immunosuppressive tumor microenvironment still exist. Therefore, various combinatorial approaches have been proposed. This article elucidates several Chinese CAR-based preclinical and clinical studies in BC treatment with comparisons of foreign research, and CAR-immune cells are analyzed, providing inspiration for further research.

Bispherical metal augment improved biomechanical stability in severe acetabular deficiency reconstruction: a comparative finite element analysis.

BACKGROUND: This study used finite element analysis (FEA) to compare the biomechanical stability of bispherical metal augment (BA) and wedge-shaped trabecular-metal augment (TA) in different acetabular defect reconstruction models, thereby explaining the application value of this novel bispherical augment in complex hip revision. METHODS: Three different acetabular defect pelvis models originating from three representative patients with different types of severe acetabular defects (Paprosky IIC, IIIA, and IIIB) were constructed and reconstruction with BA and TA technique was simulated. Based on the FEA models, the displacement of reconstruction implants, relative displacement of bone implants, and hemi-pelvic von Mises stress were investigated under static loads. RESULTS: BA acquired smaller reconstruction system displacement, less relative displacement of bone implants, and lower pelvic von Mises stress than TA in all Paprosky IIC, IIIA, and IIIB defect reconstructions. CONCLUSION: The FEA results show that BA could acquire favourable biomechanical stability in severe acetabular defect reconstruction. This technique is a reliable method in complex hip revision.

Modular revision strategy with bispherical augments in severe acetabular deficiency reconstruction.

PURPOSE: Reconstruction of severe acetabular deficiency is extremely challenging in total hip arthroplasty (THA) revisions. Novel bispherical augments were designed to fill acetabular bone loss and facilitate restoration of hip center of rotation (HCOR). Current study aims to compare the outcomes of bispherical augments and tantalum augments. METHODS: Between July 2017 and December 2018, bispherical augments (BA group) were implanted in 25 patients (25 hips) and 22 patients (22 hips) underwent porous tantalum augments (TA group) reconstruction in revision THA. Clinical and radiographic results were evaluated for 25 hips in BA group and 20 hips in TA group at the final follow-up. The mean duration of follow-up was 2.9 years (range, 2.2 ~ 3.7) in BA group and 2.9 years (range, 2.3 ~ 3.8) in TA group. RESULTS: Harris hip scores, HCOR, and leg length discrepancy (LLD) correction did not differ between the treatment groups. The bispherical augments were located more closer to the medial-superior part (zone II) of acetabular shell while the majority of tantalum augments were located at the lateral-superior part (zone I) (P = 0.010). More screws were used in the BA group for augment fixation (mean 2.1 vs. 1.3) (P = 0.000). There was no evidence of loosening or migration in all hips. Only one dislocation occurred in BA group and treated with closed reduction, no recurrence of instability up to the final follow-up. CONCLUSION: The clinical and radiological outcomes of bispherical augments were comparable with tantalum augments; this technique was a reliable alternative method in severe acetabular deficiency reconstruction.

The role of carbonic anhydrase III and autophagy in type 2 diabetes with cardio-cerebrovascular disease.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases among the elderly people. The T2DM increases the risk of cardio-cerebrovascular disease (CCD), and the main pathological change of the CCD is atherosclerosis (AS). Meanwhile, the carbonic anhydrases (CAs) are involved in the formation and progression of plaques in AS. However, the exact physiological mechanism of carbonic anhydrase III (CAIII) has not been clear yet, and there are also no correlation study between CAIII protein and T2DM with CCD. The 8-week old diabetic mice (db/db-/- mice) and wild-type mice (wt mice) were feed by a normal diet till 32 weeks, and detected the carotid artery vascular opening angle using the method of biomechanics; The changes of cerebral cortex and myocardium were watched by the ultrastructure, and the autophagy were observed by electron microscope; The tissue structure, inflammation and cell injury were observed by Hematoxylin and eosin (HE) staining; The apoptosis of cells were observed by TUNEL staining; The protein levels of CAIII, IL-17, p53 were detected by immunohistochemical and Western Blot, and the Beclin-1, LC3, NF-κB were detected by Western Blot. All statistical analysis is performed using PRISM software. Compared with wt mice, db/db-/- mice' carotid artery open angle increased significantly. Electron microscope results indicated that autophagy in db/db-/- mice cerebral cortex and heart tissue decreased and intracellular organelle ultrastructure were damaged. HE staining indicated that, db/db-/- mice' cerebral cortex and heart tissue stained lighter, inflammatory cells infiltration, cell edema were obvious, myocardial fibers were disorder, and myocardial cells showed different degrees of degeneration. Compared with wt mice, TUNEL staining showed that there was obviously increase in db/db-/- mice cortex and heart tissue cell apoptosis. The results of immunohistochemistry and Western Blot indicated that CAIII, Beclin-1 and LC3II/I expression levels conspicuously decreased in cortex and heart tissue of db/db-/- mice, and the expression level of IL-17, NF-κB and p53 obviously increased. The carotid artery' vascular stiffness was increased and which was probably related with formation of AS in diabetic mice. And the autophagy participated in the occurrence and development of diabetic CCD. CAIII protein might somehow be involved in the regulation of autophagy probably through affecting cell apoptosis and inflammation, but the underlying mechanism remains to be further studied.

Percutaneous endoscopic lumbar discectomy and microsurgical laminotomy : A prospective, randomized controlled trial of patients with lumbar disc herniation and lateral recess stenosis.

BACKGROUND: Sufficient decompression of the nerve root canal is still regarded as the method of choice when operating on patients with lumbar disc herniation (LDH) with lumbar lateral recess stenosis; however, tissue-sparing procedures are becoming more popular. Endoscopic techniques offer advantages and the benefits of rehabilitation, which have become the standard in many surgical operations when operating on the spine. A significant issue has been the upgrading of instruments to provide enough bone resection under continuous visual control. MATERIAL AND METHODS: We examined patients who had LDH with lateral recess stenosis and compared the results of nerve root canal decompression using percutaneous endoscopic lumbar discectomy (PELD) with a microsurgical laminotomy (ML) technique. In this study 40 patients with full endoscopic decompression or microsurgery were followed up for 2 years. In addition to general and specific parameters, the following two parameters were also used for the investigation: the Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI). RESULTS: Except for 1 patient in whom repair was done by fusion and 1 who was lost to follow-up, 38 patients remained in the study over the 2 years. The mean operating time in the PELD group was longer (p < 0.05), but intraoperative and postoperative blood loss was less than in the ML group (p < 0.05). The postoperative results were better than before surgery, and the VAS and ODI parameters indicated a clear improvement in leg pain and daily activities in both groups (p > 0.05). Of the patients three suffered increasing back pain (2 ML, 1 PELD). CONCLUSION: The results indicated that the PELD can provide an effective supplement and serve as an alternative for LDH with lateral recess stenosis compared with the ML technique when the indication criteria are fulfilled. The PELD also has the advantage of being a minimally invasive intervention.

Chondroprotective Effects of Hyaluronic Acid-Chitosan Nanoparticles Containing Plasmid DNA Encoding Cytokine Response Modifier A in a Rat Knee Osteoarthritis Model.

BACKGROUND/AIMS: Interleukin (IL)-1ß plays an essential role in the pathophysiology of osteoarthritis (OA). Cytokine response modifier A (CrmA) can prevent the generation of active IL-1ß. This study aimed to explore the chondroprotective effects of hyaluronic acid-chitosan nanoparticles containing plasmid DNA encoding CrmA (HA/CS-CrmA) in a rat OA model. METHODS: HA/CS-CrmA nanoparticles were synthesized through the complex coacervation of cationic polymers. The characteristics, toxicity, and transfection of the nanoparticles were investigated. Furthermore, the potential effects of HA/CS-CrmA nanoparticles were evaluated via a rat anterior cruciate ligament transection (ACLT) model of OA. Cartilage damage and synovial inflammation were assessed by safranin O/fast green and hematoxylin and eosin staining. Type II collagen in cartilage was measured by immunohistochemistry, and the expression levels of IL-1ß, matrix metalloproteinase (MMP)-3, and MMP-13 in synovial tissue were detected by western blot. RESULTS: The HA/CS-CrmA nanoparticles, which effectively entrapped plasmid DNA, showed an adequate size (100-300 nm) and a regular spherical shape. The nanoparticles safely transfected synoviocytes and released plasmid DNA in a sustained manner over 3 weeks. Additionally, HA/CS-CrmA nanoparticles significantly inhibited cartilage damage, synovial inflammation, and the loss of type II collagen induced by ACLT. The expression levels of IL-1ß, MMP-3, and MMP-13 in synovial tissue were dramatically down-regulated by HA/CS-CrmA nanoparticles. CONCLUSIONS: These results suggested that HA/CS-CrmA nanoparticles could attenuate cartilage destruction and protect against early OA by inhibiting synovial inflammation via inhibition of IL-1ß generation.

EGb761 improves the cognitive function of elderly db/db-/- diabetic mice by regulating the beclin-1 and NF-κB signaling pathways.

To assess whether EGb761 could protect elderly diabetic mice with cognitive disorders and explore the role of beclin-1-mediated autophagy in these protective effects. Two-month-old male db/db-/- mice and wild-type C57/BL6 mice were randomly divided into six groups: db/db-/- control, db/db-/- 50 mg, db/db-/- 100 mg, wild-type (WT) control, WT 50 mg, and WT 100 mg. EGb761 (50 mg/kg or 100 mg/kg of bodyweight) was given by gavage once a day for 1 month from the age of 6 months. Y-maze and social choice tests were performed at 8th months. The blood pressure was measured. The imaging changes in the brain were measured using magnetic resonance imaging (MRI). The expression and distribution of beclin-1, LC3, and NF-κB were detected using immunohistochemistry staining and western blotting. Ultrastructure alterations in the hippocampus were observed using transmission electron microscopy. Compared with WT mice, the learning ability, memory and overall cognitive function of db/db-/- mice decreased (P < 0.05), and EGb761 could significantly improve the learning and memory function of db/db-/- mice (P < 0.05). EGb761 significantly improved systolic blood pressure in db/db-/- mice (P < 0.01). In addition, fMRI-bold showed a decline in the hippocampus of mice in the db/db-/- group compared with WT. EGb761 could improve these above changes. Immunohistochemistry staining and western blotting confirmed that EGb761 significantly increased beclin-1 and reduced LC3-II/I levels in the brains of db/db-/- mice (P < 0.05). NF-κB levels were obviously higher in the db/db-/- group than that in the WT group, and EGb761 significantly reduced NF-κB levels in db/db-/- mice (P < 0.05). There was a trend of increased autophagosomes in db/db-/- mice, but EGb761 did not change obviously the number of autophagosomes. Compared with normal aged WT mice, aging db/db-/- mice had more common complications of cerebral small vessel disease and cognitive dysfunction. EGb761 could significantly improve the cognitive function of aging db/db-/- mice via a mechanism that may involve the regulation of beclin-1, LC3, and NF-κB.

Impact of Physician-Coordinated Intensive Follow-Up on Long-Term Medical Costs in Patients with Unstable Angina Undergoing Percutaneous Coronary Intervention.

BACKGROUND: To investigate the impact of professional physician-coordinated intensive follow-up on long-term expenditures after percutaneous coronary intervention (PCI) in unstable angina (UA) patients. METHODS: In this study, there were 669 UA patients who underwent successful PCI and followed up for 3 years, then divided into the intensive follow-up group (N = 337), and the usual follow-up group (N = 332). Patients were provided with detailed discharge information and individualized follow-up schedules. The intensive group received the extra follow-up times and medical consultations, and all patients were followed up for approximately 3 years. RESULTS: At the 3-year mark after PCI, the cumulative major adverse cardiac events (MACE), recurrence of myocardial ischemia, cardiac death, all-cause death and revascularization in the intensive group were lower than in the usual group. Additionally, the proportion of good medication adherence was significantly higher than in the usual group (56.4% vs. 46.1%, p < 0.001). The hospitalization daytime, total hospitalization cost and total medical cost in the intensive group were lower. Multiple linear regression showed that diabetes, hypertension, intensive follow-up and good medication adherence were associated with emergency and regular clinical cost (p < 0.05), the re-hospitalization cost (p < 0.05) and the total medical cost (p < 0.05) of patient care. Intensive follow-up and good adherence were negatively correlated with the cost of re-hospitalization (standardized coefficients = -0.132, -0.128, p < 0.05) and total medical costs (standardized coefficients = -0.072, -0.086, p < 0.05). CONCLUSIONS: Intensive follow-up can reduce MACE, improve medication adherence and save long-term total medical costs, just by increasing the emergency and regular clinical visits cost in UA patients after PCI.

High-level expression of periostin is significantly correlated with tumour angiogenesis and poor prognosis in osteosarcoma.

Periostin (PN), originally named as osteoblast-specific factor-2 (OSF-2), has been involved in regulating adhesion and differentiation of osteoblasts. Recently many studies have shown that high-level expression of PN is correlated significantly with tumour angiogenesis and prognosis in many kinds of human cancer. However, whether and how periostin expression influences prognosis in osteosarcoma remains unknown. This study aimed to examine the expression of PN in patients with osteosarcoma and explore the relationship of PN expression with clinicopathologic factors, tumour angiogenesis and prognosis. Immunohistochemistry was performed to determine the expression of PN in osteosarcoma and osteochondroma respectively. Vascular endothelial growth factor (VEGF) and CD34 were also examined in tissues from the osteosarcoma patients mentioned above. The results showed that PN expression was significantly (P < 0.05) higher in osteosarcoma (80.9%) than in osteochondroma (14.7%). Increased PN protein expression was associated with histological subtype (P = 0.000), Enneking stage (P = 0.027) and tumour size (P = 0.009). The result also showed that high expression of PN correlated with VEGF expression (r = 0.285; P = 0.019) and that tumours with PN-positive expression significantly had higher microvessal density (44.6 ± 13.7 vs. 20.6 ± 6.5; P = 0.000) compared to those in normal bone tissues. Additionally, the expression of PN was found to be an independent prognostic factor in osteosarcoma patients. In conclusion, our findings suggest that PN may have an important role in tumour progression and may be used as a prognostic biomarker for patients with osteosarcoma.

Clinical and MRI outcomes of HA injection following arthroscopic microfracture for osteochondral lesions of the talus.

PURPOSE: The purpose of this study was to compare the clinical and magnetic resonance imaging (MRI) outcomes of arthroscopic microfracture surgery alone or in combination with hyaluronic acid (HA) injection in the treatment of osteochondral lesions of the talus. METHODS: Thirty-five patients with osteochondral lesions of the talus who underwent arthroscopic microfracture were included and followed up for at least 9 months post-operatively. The patients were randomly divided into non-injection group (n = 17) who received treatment with microfracture surgery alone and injection group (n = 18) who also accepted intra-articular injection of HA post-operatively. Quantitative MRI was used to evaluate the cartilage repair after surgery. American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hind foot Scale scores and Visual Analogue Scale (VAS) scores were used to evaluate clinical outcomes. RESULTS: After operation, the MRI outcomes showed that the thickness index was higher (0.8 ± 0.1 vs. 0.7 ± 0.1) and the T2 index was lower (1.2 ± 0.1 vs. 1.4 ± 0.1) in the injection group than in the non-injection group (P < 0.01). As for the volumes of subchondral bone marrow oedema, there are no significant differences between groups (n.s.). Compared with the non-injection group, the AOFAS score and the VAS score yielded a higher level of improvement in injection group at final follow-up post-operatively (P < 0.05). CONCLUSIONS: Arthroscopic microfracture is a safe and effective procedure for osteochondral lesions of the talus. Intra-articular HA injection as an adjunct to arthroscopic microfracture might offer better functional recovery than microfracture alone. LEVEL OF EVIDENCE: II.

Cementless Total Hip Arthroplasty With a High Hip Center for Hartofilakidis Type B Developmental Dysplasia of the Hip: Results of Midterm Follow-Up.

BACKGROUND: Acetabular reconstruction in adults with Hartofilakidis type B developmental dysplasia of the hip is a major technical challenge. The purpose of this retrospective study was to evaluate hip function and radiographic outcomes regarding high hip center at midterm follow-up. METHODS: From January 1, 2007 to December 31, 2009, 37 patients who had Hartofilakidis type B developmental dysplasia of the hip underwent a primary total hip arthroplasty using a high hip center technique. Functional, radiographic, and survivorship outcomes were evaluated. RESULTS: Of the 37 patients, 31 patients (83.8%) were available for the mean follow-up of 6.1 years (range, 1.5-7.6 years). Thirty-one cementless cups were located at an average vertical distance of 38.1 ± 3.3 mm and at a mean horizontal distance of 35.5 ± 3.4 mm. The mean ratio of the height of the hip center was 2.4% (range, 2.0%-2.9%). The Harris Hip Scores were improved from 50.3 points (range, 38-63 points) preoperatively to 92.3 points (range, 85-100 points) at the final follow-up (P < .001). Four patients continued to present with Trendelenburg gait pattern at the last follow-up. With use of revision for any reason and aseptic loosening as the end point, the 5-year survival rates were 90.3% (95% CI, 79.9%-100%) and 93.3% (95% CI, 84.3%-100%), respectively. CONCLUSIONS: The high hip center technique in conjunction with a cementless acetabular component seems to be a valuable alternative to achieve satisfactory midterm outcomes for Hartofilakidis type B developmental dysplasia of the hip.

Surgical treatment for young adult hip dysplasia: joint-preserving options.

Developmental dysplasia of the hip (DDH) is a spectrum of disorders that results in anatomic abnormalities leading to increased contact stress in the joint and, eventually, secondary osteoarthritis. However, many patients with DDH become symptomatic before the severe degenerative changes of the hip because of abnormal hip biomechanics, mild hip instability, impingement, or associated intra-articular pathology. Early diagnosis and appropriate treatment for DDH are of the utmost importance. With the modification of techniques like pelvic osteotomy and capsular arthroplasty, and the introduction of intracapsular procedures such as arthroscopy and femoral head-neck junction osteochondroplasty, many young patients with symptomatic hip dysplasia may benefit from joint preservation procedures. We review the current development of these concepts and the associated surgical techniques.

High expression of periostin is dramatically associated with metastatic potential and poor prognosis of patients with osteosarcoma.

BACKGROUND: Recent studies have found that periostin (PN), as a kind of secreted glycoprotein, is closely related to the metastatic potential and prognosis of many kinds of tumors. This study aimed to examine the expression of PN in patients with osteosarcoma and explore the relationship of PN expression with clinicopathologic factors and prognosis. METHODS: PN was detected by histopathological and immunohistochemical methods in 62 cases of osteosarcoma and 62 of osteochondroma. Detailed pathological and clinical data were collected by reviewing medical records. RESULTS: The results showed that increased PN protein expression was prevalent in osteosarcoma and was significantly associated with pathologic subtype (P =0.000), tumor size (P =0.016) and Enneking stage (P =0.047). Additionally, expression of PN was found to be an independent prognostic factor in osteosarcoma patients. High expression of PN protein is closely correlated to the tumor progression and poor survival of osteosarcoma. CONCLUSIONS: Our data suggest that PN is a promising biomarker for identifying individuals with poor prognostic potential and suggests its possible use as a prognostic marker in patients with osteosarcoma.

Impact of surgical types on overall survival in patients with ductal carcinoma in situ: an analysis based on the SEER database.

Background: Breast cancer, as one of the most common malignancies among women globally, presents a concerning incidence rate, underscoring the importance of addressing the treatment of its precursor lesion, ductal carcinoma in situ (DCIS). Treatment decisions for DCIS, involving the balance between breast-conserving surgery (BCS) and mastectomy, remain an area requiring further investigation. This study aimed to compare influence of different surgical types on overall survival (OS) of patients with DCIS and identify specific subgroups with improved OS to develop an effective survival nomogram for patients. Methods: Patient data from the Surveillance, Epidemiology, and End Results (SEER) database for DCIS cohort from 2010 to 2020 were retrieved. Kaplan-Meier (K-M) survival curves were utilized to compare prognostic OS of patients with different surgical methods. Cox regression analysis was employed to determine prognostic factors and establish a nomogram to predict 3-, 5-, and 10-year survival rates. The model was confirmed by Concordance Index (C-index), calibration curves, and receiver operating characteristic (ROC) curves. Results: A total of 71,675 patients with DCIS were included. Patients who underwent subcutaneous mastectomy (SM) demonstrated the best OS compared to other surgical types. Additionally, adjuvant radiotherapy or chemotherapy in combination with surgery significantly improved OS compared to surgery alone. Among DCIS patients aged ≤74 years, those who underwent SM benefited the most in terms of OS, while in the age group of 63-74 years, patients who underwent BCS had significantly higher OS than those who underwent total (simple) mastectomy (TM)/modified radical mastectomy (MRM). Multiple factors were associated with improved OS in DCIS patients, and these factors were integrated into the nomogram to establish OS predictions. The C-index, calibration curves, and ROC curves indicated that the nomogram was suitable for assessing patient prognosis. Conclusions: This study demonstrated that SM treatment yielded the best survival rates for DCIS patients, providing important guidance for future surgical decision-making. Moreover, identifying multiple independent factors related to survival and establishing reliable survival nomograms can assist physicians in developing personalized treatment plans and prolonging patient survival.

Prognostic value of EIF5A2 in solid tumors: A meta-analysis and bioinformatics analysis.

Aims: In cancer biology, the aberrant overexpression of eukaryotic translation initiation factor 5A2 (EIF5A2) has been correlative with an ominous prognosis, thereby underscoring its pivotal role in fostering metastatic progression. Consequently, EIF5A2 has garnered significant attention as a compelling prognostic biomarker for various malignancies. Our research endeavors were thus aimed at elucidating the utility and significance of EIF5A2 as a robust indicator of cancer outcome prediction. Method: An exhaustive search of the PubMed, EMBASE, and Web of Science databases found relevant studies. The link between EIF5A2 and survival prognosis was examined using hazard ratios and 95% confidence intervals. Subsequently, The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases were employed to validate EIF5A2 expression across various cancer types. Results: Through pooled analysis, we found that increased EIF5A2 expression was significantly associated with decreased overall survival (OS) and disease-free survival/progression-free survival/relapse-free survival (DFS/PFS/RFS). Moreover, TCGA analysis revealed that EIF5A2 was significantly upregulated in 27 types of cancer, with overexpression being linked to shorter OS in three, worse DFS in two, and worse PFS in six types of cancer. GEPIA showed that patients with EIF5A2 overexpression had reduced OS and DFS. Conclusions: In solid tumors, EIF5A2 emerges as a reliable prognostic marker. Our meta-analysis comprehensively analyzed the prognostic value of EIF5A2 in solid tumors and assessed its efficacy as a predictive marker.

Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: new insights and therapeutic implications.

The tumor microenvironment (TME) is a highly intricate milieu, comprising a multitude of components, including immune cells and stromal cells, that exert a profound influence on tumor initiation and progression. Within the TME, angiogenesis is predominantly orchestrated by endothelial cells (ECs), which foster the proliferation and metastasis of malignant cells. The interplay between tumor and immune cells with ECs is complex and can either bolster or hinder the immune system. Thus, a comprehensive understanding of the intricate crosstalk between ECs and immune cells is essential to advance the development of immunotherapeutic interventions. Despite recent progress, the underlying molecular mechanisms that govern the interplay between ECs and immune cells remain elusive. Nevertheless, the immunomodulatory function of ECs has emerged as a pivotal determinant of the immune response. In light of this, the study of the relationship between ECs and immune checkpoints has garnered considerable attention in the field of immunotherapy. By targeting specific molecular pathways and signaling molecules associated with ECs in the TME, novel immunotherapeutic strategies may be devised to enhance the efficacy of current treatments. In this vein, we sought to elucidate the relationship between ECs, immune cells, and immune checkpoints in the TME, with the ultimate goal of identifying novel therapeutic targets and charting new avenues for immunotherapy.

Mechanism of YAP1 in the senescence and degeneration of endplate chondrocytes induced by intermittent cyclic mechanical tension.

BACKGROUND: This study aimed to investigate the potential mechanism of YAP1 in the senescence and degeneration of endplate chondrocytes induced by intermittent cyclic mechanical tension (ICMT). METHODS: According to the Pfirrmann grade evaluation classification, 30 human endplate cartilage tissues were divided into the lumbar vertebra fracture (LVF) group and lumbar disc herniation (LDH) group. Then, quantitative reverse transcription polymerase chain reaction, western blot, flow cytometry, hematoxylin-eosin staining, and senescence-associated ß-galactosidase staining were performed. The difference in extracellular matrix expression between LVF and LDH endplate cartilage was detected. Second, the effect of ICMT on endplate chondrocytes degeneration was observed. Finally, the key regulatory role of YAP1 in ICMT-induced endplate cartilage degeneration was further verified. RESULTS: In degraded human endplate cartilage and tension-induced degraded endplate chondrocytes, the expression of YAP1, COL-2A, and Sox9 was decreased. Conversely, the expression of p53 and p21 was increased. By regulating YAP1 in vivo and in vitro, we can achieve alleviation of ICMT-induced senescence of endplate chondrocytes and effective treatment of disc degeneration. CONCLUSIONS: ICMT could induce senescence and degeneration of endplate chondrocytes, and ICMT-induced senescence and degeneration of endplate chondrocytes could be alleviated by regulating YAP1 expression.

Long head of biceps tendon transposition for massive and irreparable rotator cuff tears: A systematic review and meta-analysis.

BACKGROUND: Superior capsular reconstruction (SCR) with long head of biceps tendon (LHBT) transposition was developed to massive and irreparable rotator cuff tears (MIRCTs); however, the outcomes of this technique remain unclear. AIM: To perform a systematic review of biomechanical outcomes and a meta-analysis of clinical outcomes after LHBT transposition for MIRCTs. METHODS: We performed a systematic electronic database search on PubMed, EMBASE, and Cochrane Library. Studies of SCR with LHBT transposition were included according to the inclusion and exclusion criteria. Biomechanical studies were assessed for main results and conclusions. Included clinical studies were evaluated for quality of methodology. Data including study characteristics, cohort demographics, and outcomes were extracted. A meta-analysis was conducted of the clinical outcomes. RESULTS: According to our inclusion and exclusion criteria, a total of six biomechanical studies were identified and reported an overall improvement in subacromial contact pressures and prevention of superior humeral migration without limiting range of motion (ROM) after LHBT transposition for MIRCTs. A total of five clinical studies were included in the meta-analysis of LHBT transposition outcomes, consisting of 253 patients. The results indicated that compared to other surgical methods for MIRCTs, LHBT transposition had advantages of more significant improvement in ROM (forward flexion mean difference [MD] = 6.54, 95% confidence interval [CI]: 3.07-10.01; external rotation [MD = 5.15, 95%CI: 1.59-8.17]; the acromiohumeral distance [AHD] [MD = 0.90, 95%CI: 0.21-1.59]) and reducing retear rate (odds ratio = 0.27, 95%CI: 0.15-0.48). No significant difference in American Shoulder and Elbow Surgeons score, visual analogue scale score, and University of California at Los Angles score was demonstrated between these two groups for MIRCTs. CONCLUSION: In general, SCR with LHBT transposition was a reliable and economical technique for treating MIRCTs, both in terms of biomechanical and clinical outcomes, with comparable clinical outcomes, improved ROM, AHD, and reduced the retear rates compared to conventional SCR and other established techniques. More high-quality randomized controlled studies on the long-term outcomes of SCR with LHBT transposition are required to further assess.

Treatment Outcomes in COVID-19 Patients with Brucellosis: Case Series in Heilongjiang and Systematic Review of Literature.

Objective: Clinical characteristics and outcome in COVID-19 with brucellosis patients has not been well demonstrated, we tried to analyze clinical outcome in local and literature COVID-19 cases with brucellosis before and after recovery. Methods: We retrospectively collected hospitalization data of comorbid patients and prospectively followed up after discharge in Heilongjiang Infectious Disease Hospital from January 15, 2020 to April 29, 2022. Demographics, epidemiological, clinical symptoms, radiological and laboratory data, treatment medicines and outcomes, and follow up were analyzed, and findings of a systematic review were demonstrated. Results: A total of four COVID-19 with brucellosis patients were included. One patient had active brucellosis before covid and 3 patients had nonactive brucellosis before brucellosis. The median age was 54.5 years, and all were males (100.0%). Two cases (50.0%) were moderate, and one was mild and asymptomatic, respectively. Three cases (75.0%) had at least one comorbidity (brucellosis excluded). All 4 patients were found in COVID-19 nucleic acid screening. Case C and D had only headache and fever on admission, respectively. Four cases were treated with Traditional Chinese medicine, western medicines for three cases, no adverse reaction occurred during hospitalization. All patients were cured and discharged. Moreover, one case (25.0%) had still active brucellosis without re-positive COVID-19, and other three cases (75.0%) have no symptoms of discomfort except one case fell fatigue and anxious during the follow-up period after recovery. Conducting the literature review, two similar cases have been reported in two case reports, and were both recovered, whereas, no data of follow up after recovery. Conclusion: These cases indicate that COVID-19 patients with brucellosis had favorable outcome before and after recovery. More clinical studies should be conducted to confirm our findings.

Association between MTHFR C677T polymorphism and osteonecrosis of the femoral head: a meta-analysis.

The results of studies on association between the C677T polymorphism of the 5,10-methylene-tetrahydrofolate reductase (MTHFR) gene and osteonecrosis of the femoral head (ONFH) are controversial. To derive a more precise estimation of the relationship between the MTHFR C677T polymorphism and ONFH, a meta-analysis was performed. Eight studies on MTHFR C677T association with ONFH were searched up to April 2011, and the genotype frequencies in control group were consistent with Hardy-Weinberg equilibrium. The effect summary odds ratio (OR) and 95% confidence intervals were obtained. Publication bias was tested by funnel plot, Egger's regression test, and heterogeneity was assessed. Eight studies containing 778 cases and 1,162 controls were included. Heterogeneity was observed (χ(2) = 18.58, P = 0.01). Under the random effects model, the common OR was 1.38 (95% CI: 0.92-2.08; P = 0.12). In the subgroup meta-analysis, there was an association between MTHFR C677T polymorphism and ONFH in non-Asian population for CT + TT vs. CC (OR = 1.72; 95% CI: 1.21-2.43; P = 0.002; I(2) = 37.9%, P = 0.17), but not for Asian population (OR = 0.88; 95% CI: 0.66-1.66; P = 0.35; I(2) = 45.4%, P = 0.16). There was heterogeneity between studies and no clear evidence of an association on a worldwide population. When stratifying for the race, this meta-analysis did not provide an evidence of confirming association between MTHFR C677T polymorphism and ONFH. The large sample and well-designed study based on different ethnic groups should be considered in future associated studies to clarify the association of MTHFR C677T polymorphism with ONFH susceptibility.