Pan-cancer and single-cell analysis of actin cytoskeleton genes related to disulfidptosis.

Disulfidptosis was recently reported to be caused by abnormal disulfide accumulation in cells with high SLC7A11 levels subjected to glucose starvation, suggesting that targeting disulfidptosis was a potential strategy for cancer treatment. We analyzed the relationships between gene expression and mutations and prognoses of patients. In addition, the correlation between gene expression and immune cell infiltration was explored. The potential regulatory mechanisms of these genes were assessed by investigating their related signaling pathways involved in cancer, their expression patterns, and their cellular localization. Most cancer types showed a negative correlation between the gene-set variation analysis (GSVA) scores and infiltration of B cells and neutrophils, and a positive correlation between GSVA scores and infiltration of natural killer T and induced regulatory T cells. Single-cell analysis revealed that ACTB, DSTN, and MYL6 were highly expressed in different bladder urothelial carcinoma subtypes, but MYH10 showed a low expression. Immunofluorescence staining showed that actin cytoskeleton proteins were mainly localized in the actin filaments and plasma membrane. Notably, IQGAP1 was localized in the cell junctions. In conclusion, this study provided an overview of disulfidptosis-related actin cytoskeleton genes in pan-cancer. These genes were associated with the survival of patients and might be involved in cancer-related pathways.

Inhibition of PFKFB3 Expression Stimulates Macrophage-Mediated Lymphangiogenesis Post-Acute Myocardial Infarction.

BACKGROUND: The dilation of lymphatic vessels plays a critical role in maintaining heart function, while a lack thereof could contribute to heart failure (HF), and subsequently to an acute myocardial infarction (AMI). Macrophages participate in the induction of lymphangiogenesis by secreting vascular endothelial cell growth factor C (VEGF-C), although the precise mechanism remains unclear. METHODS: Intramyocardial injections of adeno-associated viruses (AAV9) to inhibit the expression of VEGFR3 (VEGFR3 shRNA) or promote the expression of VEGFR3 (VEGFR3 ORF) in the heart; Myh6-mCherry B6 D2-tg mice and flow cytometry were used to evaluate the number of myocellular debris in the mediastinal lymph nodes; fluorescence staining and qPCR were used to evaluate fluorescence analysis; seahorse experiment was used to evaluate the level of glycolysis of macrophages; Lyz2𝐶𝑟𝑒, VEGFCfl/fl, and PFKFB3fl/fl mice were used as a model to knock out the expression of VEGF-C and PFKFB3 in macrophages. RESULTS: The escalation of VEGFR3 in cardiac tissue can facilitate the drainage of myocardial debris to the mediastinal lymph nodes, thereby improving cardiac function and reducing fibrosis after reperfusion injury. Conversely, myeloid VEGF-C deficiency displayed an increase in macrophage counts and inflammation levels following reperfusion injury. The inhibition of the critical enzyme PFKFB3 in macrophage glycolysis can stimulate the manifestation of VEGF-C in macrophages. A deficiency in myeloid PFKFB3 is associated with induced lymphangiogenesis following reperfusion injury. CONCLUSIONS: Our initial investigations suggest that the suppression of PFKFB3 expression in macrophages could potentially stimulate the production of VEGF-C in these immune cells, which in turn may facilitate lymphangiogenesis and mitigate the inflammatory effects of I/R injury.

GLUT1 Mediates the Metabolic Reprogramming and Inflammation of CCR2$

BACKGROUND: Macrophages expressing CC chemokine receptor 2 (CCR2) possess characteristics and performance akin to M1 polarized macrophages, which promote inflammation. Advanced heart failure (HF) patients with higher abundance of CCR2+ macrophages are more likely to experience adverse remodeling. The precise mechanism of CCR2+ macrophages in how they affect the progression of dilated cardiomyopathy remains unknown. METHODS: Cardiac biopsy samples from dilated cardiomyopathy patients (DCM) were used for immunohistochemistry and immunofluorescence staining. PCR is employed to identify the IL-1ß, IL-6, TNF-α, TGF-ß, MMP2, MMP9, PKM1, PKM1, GLUT1, GLUT2, GLUT3, GLUT4, PDK1, PFKFB3, PFK1 and HK2 mRNA expression of CCR2+ monocytes/macrophages from the peripheral blood of DCM patients. Seahorse was used to evaluate the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of CCR2+ monocytes/macrophages. 2-DG was used to simulate a lack of glucose. Lentivirus containing GLUT1 inhibitory sequence was used to knockdown GLUT1 gene expression of CCR2+ monocytes/macrophages. Western Blot and immunofluorescence staining was used to evaluate the expression of NLRP3. RESULTS: Immunostaining results of cardiac biopsy tissue from dilated cardiomyopathy (DCM) patients demonstrated that the progression to HF was associated with an increase in the number of CCR2+ macrophages. PCR results demonstrated that CCR2 monocytes and macrophages derived from the blood of DCM patients expressed elevated levels of inflammatory factors and up regulation of glycolysis related genes. In addition, OCR and glucose uptake experiments confirmed that increased glucose uptake of these cells was associated with greater inflammation and correlated with a worsening of cardiac function. limiting the glucose supply to CCR2+ monocytes and macrophages, or suppressing the activity of glucose transporter 1 (GLUT1) could reduce inflammation levels. CONCLUSIONS: These results suggest that CCR2+ monocytes and macrophages rely on metabolic reprogramming to trigger inflammatory response and contribute to myocardial injury and the progression of DCM.

Pan-cancer and single-cell analysis reveal the prognostic value and immune response of NQO1.

Background: Overexpression of the NAD(P)H: Quinone Oxidoreductase 1 (NQOI) gene has been linked with tumor progression, aggressiveness, drug resistance, and poor patient prognosis. Most research has described the biological function of the NQO1 in certain types and limited samples, but a comprehensive understanding of the NQO1's function and clinical importance at the pan-cancer level is scarce. More research is needed to understand the role of NQO1 in tumor infiltration, and immune checkpoint inhibitors in various cancers are needed. Methods: The NQO1 expression data for 33 types of pan-cancer and their association with the prognosis, pathologic stage, gender, immune cell infiltration, the tumor mutation burden, microsatellite instability, immune checkpoints, enrichment pathways, and the half-maximal inhibitory concentration (IC50) were downloaded from public databases. Results: Our findings indicate that the NQO1 gene was significantly upregulated in most cancer types. The Cox regression analysis showed that overexpression of the NQO1 gene was related to poor OS in Glioma, uveal melanoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma, and adrenocortical carcinoma. NQO1 mRNA expression positively correlated with infiltrating immune cells and checkpoint molecule levels. The single-cell analysis revealed a potential relationship between the NQO1 mRNA expression levels and the infiltration of immune cells and stromal cells in bladder urothelial carcinoma, invasive breast carcinoma, and colorectal cancer. Conversely, a negative association was noted between various drugs (17-AAG, Lapatinib, Trametinib, PD-0325901) and the NQO1 mRNA expression levels. Conclusion: NQO1 expression was significantly associated with prognosis, immune infiltrates, and drug resistance in multiple cancer types. The inhibition of the NQO1-dependent signaling pathways may provide a promising strategy for developing new cancer-targeted therapies.

Impact of intra-articular injection with tranexamic acid on total blood loss and postoperative pain after arthroscopic rotator cuff repair surgery.

Objectives: To evaluate the impact of intra-articular injection with tranexamic acid (TXA) on total blood loss (TBL) and postoperative pain after arthroscopic rotator cuff repair (ARCR). Methods: This study retrospectively included patients with full-thickness rotator cuff tears who underwent shoulder ARCR surgery in Taizhou hospital, China, between January 2018 and December 2020. Patients received 10 ml (100 mg/ml) of intra-articular TXA injection (TXA group) or 10 ml of normal saline (non-TXA group) after the incision was sutured. The primary variable was the type of drug injected into the shoulder joint at the end of the operation. The primary outcome were perioperative TBL and postoperative pain [measured by visual analog scale (VAS)]. The secondary outcomes were differences in red blood cell count, hemoglobin count, hematocrit, platelet count. Results: A total of 162 patients were included, 83 patients in TXA group and 79 patients in non-TXA group. Notably, patients in TXA group were more likely to have lower TBL volume [261.21 (175.13-506.67) ml vs. 382.41 (236.11-593.31), P = 0.025], and postoperative VAS score ≤ 2 within 24 h (P = 0.031) compared with those in non-TXA group. In addition, the median hemoglobin count difference was significantly lower in TXA group than that of in non-TXA group (P = 0.045), while, the differences in median counts of red blood cell, hematocrit, and platelet between the two groups were comparable (all P > 0.05). Conclusion: Intra-articular injection of TXA might reduce the TBL and degree of postoperative pain within 24 h after shoulder arthroscopy.

Comparison of risk assessment strategies incorporating coronary artery calcium score with estimation of pretest probability to defer cardiovascular testing in patients with stable chest pain.

BACKGROUND: The risk assessment of patients with stable chest pain (SCP) to defer further cardiovascular testing is crucial, but the most appropriate risk assessment strategy remains unknown. We aimed to compare current strategies to identify low risk SCP patients. METHODS: 5289 symptomatic patients who had undergone coronary artery calcium score (CACS) and coronary computed tomographic angiography scan were identified and followed. Pretest probability (PTP) of obstructive coronary artery disease (CAD) for every patient was estimated according to European Society of Cardiology (ESC)-PTP model and CACS-weighted clinical likelihood (CACS-CL) model, respectively. Based on the 2019 ESC guideline-determined risk assessment strategy (ESC strategy) and CACS-CL model-based risk assessment strategy (CACS-CL strategy), all patients were divided into low and high risk group, respectively. Area under receiver operating characteristic curve (AUC), integrated discrimination improvement (IDI) and net reclassification improvement (NRI) was used. RESULTS: CACS-CL model provided more robust estimation of PTP than ESC-PTP model did, with a larger AUC (0.838 versus 0.735, p < 0.0001), positive IDI (9%, p < 0.0001) and less discrepancy between observed and predicted probabilities. As a result, compared to ESC strategy which only applied CACS-CL model to patients with borderline ESC-PTP, CACS-CL strategy incorporating CACS with estimation of PTP to entire SCP patients indicated a positive NRI (19%, p < 0.0001) and a stronger association to major adverse cardiovascular events, with hazard ratios: 3.97 (95% confidence intervals: 2.75-5.72) versus 5.11 (95% confidence intervals: 3.40-7.69). CONCLUSION: The additional use of CACS for all SCP patients in CACS-CL strategy improved the risk assessment of SCP patients to identify individuals at low risk.

Hemorrhagic shock due to ruptured lower limb vascular malformation in a neurofibromatosis type 1 patient: A case report.

BACKGROUND: Neurofibromatosis type 1 (NF-1) is a common autosomal dominant genetic disorder. It is characterized by café-au-lait spots and cutaneous neurofibromas. Although NF-1 typically involves the skin, nerves, bones, and eyes, vascular manifestation in the form of devastating hemorrhage can occur rarely. CASE SUMMARY: We present the case of a 47-year-old female with NF-1 who had a ruptured right lower limb arterial malformation. She presented with sudden right lower limb swelling for two hours and symptoms of hemorrhagic shock on admission. The physical examination revealed a right lower limb presenting as elephantiasis and visible dark-brown pigmentation over a large area. Computed tomography angiography showed right lower limb arteriovenous malformation. Therefore, the patient underwent emergency right lower limb digital subtraction angiography (DSA) and vascular embolization after blood transfusions. However, after DSA, vascular embolization, and repeated blood transfusions, the anemia and right lower limb swelling and tenderness did not improve. As a result, the patient underwent right lower extremity above-knee amputation. After amputation, the patient's hemoglobin level improved significantly without blood transfusion, and she was discharged from the hospital after the incision healed. Postoperative pathological examination suggested neurogenic tumors. No other complications had occurred 1-year follow-up. CONCLUSION: Vascular malformation and rupture are fatal complications of NF-1. Embolization may not provide complete relief, the patient might need to undergo neurofibroma resection or amputation.

Clinical Outcomes of Arthroscopy-Assisted Modified Triple Endobutton Plate Fixation in Rockwood Type III Acute Acromioclavicular Joint Dislocation: A Retrospective Study.

OBJECTIVE: The common triple Endobutton plate (CTEP) fixation is a lengthy procedure that is associated with high failure rates. Therefore, we used arthroscopy to improve the Endobutton fixation method by shortening the duration of surgery and reducing operative complications. This study explored the safety and effectiveness of arthroscopy-assisted modified triple Endobutton plate (MTEP) fixation in Rockwood type III managing acute acromioclavicular joint (ACJ) dislocation. METHODS: This was a retrospective single-center study involving 73 patients with Rockwood type III acute ACJ dislocation treated between January 2016 and January 2021. The 73 patients were classified into three groups, the acromioclavicular hook plate (ACHP) group (22 cases), CTEP group (24 cases) and MTEP group (27 cases), based on the type of surgical treatment they received. Clinical outcome data from the patient records, including the Constant-Murley score (CMS), American Shoulder and Elbow Surgeons score (ASES) and University of California at Los Angeles shoulder rating scale score (UCLA), were retrospectively reviewed. The scores were assessed before surgery and at the third and twelfth month after surgery. The clavicle-coracoid (CC) distance on the affected side was estimated from imaging scans taken before surgery, on the second day after surgery, and within the third and twelfth month after surgery. The student's t-test was used to compare normally distributed data for independent samples, while homogeneity of variance test was used to compare normally distributed data among multiple groups. Non-normally distributed data were compared using Mann-Whitney rank-sum tests. RESULTS: There were no differences in age, gender, body mass index (BMI), dislocated side, trauma etiology, and duration of follow-up among the three groups. There was also no significant difference in the duration of surgery between the ACHP and MTEP groups, although the duration in the two groups was shorter than in the CTEP group (P < 0.05). The duration of hospitalization for the MTEP group was significantly shorter than for the CTEP group which was in turn shorter than for the ACHP group (both P < 0.05). There was no significant difference in postoperative CMS, ASES, and UCLA scores between the CTEP and MTEP groups but the score for the two groups differed significantly from those of the ACHP group (all Ps < 0.05). In addition, there was no significant difference in CC distance among the three groups after surgery (P > 0.05). CONCLUSION: Arthroscopic reconstruction of the coracoclavicular ligament using MTEP fixation to manage acute Rockwood type III ACJ dislocation is minimally invasive, and is associated with rapid functional recovery, few complications and satisfactory early clinical results.

Maffucci syndrome complicated by giant chondrosarcoma in the left ankle with an IDH1 R132C mutation: a case report.

BACKGROUND: Maffucci syndrome (MS) is a rare, nonhereditary congenital mesodermal dysplasia characterized by multiple enchondromas and hemangiomas, associated with an increased risk of developing malignant tumors. Given their rarity, the pathogenesis of these tumors has not been clarified, and there is no standard treatment. CASE PRESENTATION: We present a case of a 45-year-old man with MS to supplement the clinical manifestations and explore the molecular mechanism of MS. The patient underwent amputation surgery to inhibit tumor development and was diagnosed with MS with 1-2 grade giant chondrosarcoma in the left ankle. In addition, the whole exon analysis results revealed isocitrate dehydrogenase 1 (IDH1) R132C mutation in chondrosarcoma lesions but not in blood DNA. CONCLUSIONS: This case report showed MS complicated by giant chondrosarcoma in the left ankle with an IDH1 R132C mutation, which is appropriate to monitor the development of MS pathology and other concomitant lesions.

Validation and Comparison of PROMISE and CONFIRM Model to Predict High-Risk Coronary Artery Disease in Symptomatic and Diabetes Mellitus Patients.

BACKGROUND: The identification of high-risk coronary artery disease (HRCAD) is important in diabetes mellitus (DM) patients. However, the reliability of current models to predict HRCAD has not been fully investigated. Thus, we aimed to validate and compare CONFIRM and PROMISE high-risk model (CHM and PHM) in DM patients. METHODS: 5936 symptomatic DM patients who underwent coronary computed tomographic angiography (CCTA) were identified. Probability of HRCAD for each patient was estimated based on CHM and PHM, respectively. We used Area under the receiver operating characteristic curve (AUC), integrated discrimination improvement (IDI), net reclassification improvement (NRI) and Hosmer-Lemeshow (H-L) test to evaluate model's predictive accuracy. RESULTS: Overall, 470 (8%) patients had HRCAD on CCTA. There was no difference between the AUC for CHM and PHM (0.744 v.s. 0.721, p = 0.0873). Compared to CHM, PHM demonstrated a positive IDI (3.08%, p < 0.0001), positive NRI (12.50%, p < 0.0001) and less discrepancy between observed and predicted probabilities (H-L χ2 for CHM: 35.81, p < 0.0001; H-L χ2 for PHM: 23.75, p = 0.0025). CONCLUSIONS: Compared to CHM, PHM was associated with a more accurate prediction for HRCAD and might optimize downstream management strategy in symptomatic patients with DM. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT04691037).

Comparison of NICE and ESC strategy for risk assessment in women with stable chest pain: a coronary computed tomography angiography study.

BACKGROUND: For women presenting with stable chest pain (SCP), the appropriate risk assessment strategy to identify individuals unlikely to benefit from further cardiovascular imaging testing (CIT) is debatable. Thus, the present study intended to compare two risk assessment strategies in these individuals. METHODS: 2592 women with SCP who underwent coronary computed tomography angiography (CCTA) were divided into low and high risk group according to 2016 National Institute of Health and Care Excellence guideline-determined strategy (NICE strategy) and 2019 European Society of Cardiology guideline-determined strategy (ESC strategy), respectively. The associations of coronary artery disease (CAD), major adverse cardiovascular event (MACE) and other subsequent clinical outcomes with risk groups and net reclassification improvement (NRI) were evaluated to compare different strategies. RESULTS: Both NICE strategy which focused on symptom evaluation and ESC strategy which was based on pretest probability (PTP) determined by ESC-PTP model and coronary artery calcium score-weighted clinical likelihood (CACS-CL) model classified a proportion (34.49% and 63.97%, respectively) of individuals into the low risk group. Compared to NICE strategy, ESC strategy indicated stronger associations between risk groups and obstructive CAD (odds ratio: 27.63 versus 3.57), MACE (hazard ratios: 4.24 versus 1.91), more intensive clinical management as well as a positive NRI (27.71%, p < 0.0001). CONCLUSION: Compared to NICE strategy, ESC strategy which sequentially incorporated ESC-PTP model with CACS-CL model seemed to be associated with greater effectiveness in identifying individuals who may derive maximum benefit from further CIT in women presenting with SCP.

One-stage total hip arthroplasty for advanced hip tuberculosis combined with developmental dysplasia of the hip: A case report.

BACKGROUND: A patient with advanced tuberculosis of the hip joint combined with Crowe type IV developmental dysplasia of the hip (DDH) and a drainage sinus is a rare condition. There are no previous reports of this condition, and it is a complex challenge for surgeons to develop a treatment scheme. CASE SUMMARY: We report a 73-year-old male patient with severe hip pain and drainage sinus of the left hip for one month. Approximately 40 years ago, a drainage sinus occurred at the lateral left hip was healed at the local hospital with anti-infectious therapy. After the sinus healed, gradual pain occurred in the left hip for 40 years. Approximately one month prior, hip pain was sharply aggravated, and a drainage sinus reoccurred in the left hip. The X-ray and computed tomography examinations showed destruction of the head and neck of the left femur, as well as an acetabular deformity. The results of Mycobacterium tuberculosis antibody and Xpert were positive. Therefore, the patient was diagnosed with advanced TH combined with Crowe type IV DDH. After 22 d of treatment with anti-tuberculosis chemotherapy, the sinus healed, and the patient underwent one-stage total hip arthroplasty (THA) surgery consisting of debridement, osteotomy, and joint replacement. After surgery, the patient received anti-tuberculosis chemotherapy drugs for nine months, with no recurrent infection. After one year of follow-up, the Harris score of the patient increased from 21 pre-THA to 86. CONCLUSION: Although drainage sinuses are a contraindication to one-stage THA, one-stage THA is still an effective and safe surgical method after the sinus heals.

Arthroscopy-Assisted Treatment of Wear Debris Pseudotumor After Total Knee Arthroplasty: A Case Report.

BACKGROUND: Wear debris pseudotumors are a rare complication after total knee arthroplasty (TKA) and have seldom been reported in the recent literature. There is no consensus on the best therapeutic method, but the high quality curative treatment, safe, low invasive treatments are required for the patients. CASE PRESENTATION: In this paper, we present the case of a 74-year-old man with a wear debris pseudotumor after TKA with symptoms of severe pain and functional disability of his right knee. X-ray examination showed that the medial compartment of the right knee was narrowing. Magnetic resonance imaging (MRI) and Doppler ultrasound both revealed a polycystic mass at the posteromedial side of the patient's right knee. Considering the bad health condition and the minimally invasive surgery requirement of this senior patient, arthroscopic knee debridement and percutaneous cystic mass suction were carried out simultaneously. Video arthroscopy of the right knee showed visible inflammatory soft tissue, obvious polyethylene fragments, wear of the polyethylene prothesis, and a broken polyethylene insert. The intraarticular polyethylene wear debris was removed as much as possible, and inflammatory soft tissue was debrided and sent for pathology. Postoperative pathology showed polyethylene debris in the soft tissue with an apparent multinucleated giant cell response, which was consistent with foreign body granuloma. All clinical manifestation was improved and Lysholm scores were significantly better at one year with this treatment, increasing from 32 points to 71 points. CONCLUSION: After two years of follow-up, the patient's knee joint was significantly relieved from soreness and pain, and walking was not significantly restricted. Our treatment could not address the root cause of the wear debris pseudotumor, which was due to prosthesis failure, but sometimes, such an approach is the safest, most economical, and most effective choice for patients who are intolerant to reoperation.