Identifying specific TLS-associated genes as potential biomarkers for predicting prognosis and evaluating the efficacy of immunotherapy in soft tissue sarcoma.

Background: The tertiary lymphatic structure (TLS) is an important component of the tumor immune microenvironment and has important significance in patient prognosis and response to immune therapy. However, the underlying mechanism of TLS in soft tissue sarcoma remains unclear. Methods: A total of 256 RNAseq and 7 single-cell sequencing samples were collected from TCGA-SARC and GSE212527 cohorts. Based on published TLS-related gene sets, four TLS scores were established by GSVA algorithm. The immune cell infiltration was calculated via TIMER2.0 and "MCPcounter" algorithms. In addition, the univariate, LASSO, and multivariate-Cox analyses were used to select TLS-related and prognosis-significant hub genes. Single-cell sequencing dataset, clinical immunohistochemical, and cell experiments were utilized to validate the hub genes. Results: In this study, four TLS-related scores were identified, and the total-gene TLS score more accurately reflected the infiltration level of TLS in STS. We further established two hub genes (DUSP9 and TNFSF14) prognosis markers and risk scores associated with soft tissue sarcoma prognosis and immune therapy response. Flow cytometry analysis showed that the amount of CD3, CD8, CD19, and CD11c positive immune cell infiltration in the tumor tissue dedifferentiated liposarcoma patients was significantly higher than that of liposarcoma patients. Cytological experiments showed that soft tissue sarcoma cell lines overexpressing TNFSF14 could inhibit the proliferation and migration of sarcoma cells. Conclusion: This study systematically explored the TLS and related genes from the perspectives of bioinformatics, clinical features and cytology experiments. The total-gene TLS score, risk score and TNFSF14 hub gene may be useful biomarkers for predicting the prognosis and immunotherapy efficacy of soft tissue sarcoma.

Progress in extracellular vesicle homeostasis as it relates to cardiovascular diseases.

Extracellular vesicles (EVs) are involved in both physiological and pathological processes in many organ systems and are essential in mediating intercellular communication and maintaining organismal homeostasis. It is helpful to propose new strategies for disease treatment by elucidating the mechanisms of EV release and sorting. An increasing number of studies have shown that there is specific homeostasis in EVs, which is helpful for the human body to carry out physiological activities. In contrast, an EV homeostasis im-balance promotes or accelerates disease onset and development. Alternatively, regulating the quality of EVs can maintain homeostasis and even achieve the purpose of treating conditions. An analysis of the role of EV homeostasis in the onset and development of cardiovascular disease is presented in this review. This article also summarizes the methods that regulate EV homeostasis and their application in cardiovascular diseases. In particular, this study focuses on the connection between EV steady states and the cardiovascular system and the potential value of EVs in treating cardiovascular diseases.

Stepwise versus Concerted: Theoretical Insights into the Stereoselectivity in Aryl Imine Formation Assisted by Acid and Water.

The wide applications of the aryl Schiff base require extensive understanding of the mechanism of its formation, which remains unclear. In this work, the detailed formation mechanisms between benzaldehyde and aniline or 4-(9-anthryl) ethynyl aniline were investigated at the CCSD(T)//B3LYP level, and the influence of water molecules and acid catalysis and the stereoselectivity were addressed. The results show that the participation of explicit water molecules greatly accelerates the reactions by alleviating the ring tension of the transition states, and acid catalysis strongly favors the imine formation and provides driving force for the forward reaction. In acidic conditions, both N-protonated carbinolamine formations and imine formations are achieved under mild conditions with the assistance of water molecules, and the proton transfer is more advanced than the C-N and C═N bond formation, which is in good agreement with the experimental observations. In contrast, under neutral conditions, even with the assistance of two water molecules, the reaction is hard to take place at room temperature owing to the high Gibbs free energy barriers with the proton transfer and the C-N or C═N bond formation concerted. The analysis of stereoselectivity shows that the formation of trans imine is both kinetically and thermodynamically more favorable than the cis one under the acidic condition with the assistance of water molecules, and the presence of conjugated substituent 4-(9-anthryl) ethynyl of aniline marginally raises the energy barriers. This work provides a systematic view of the mechanism for the formation of aryl imine and is expected to offer insights for the control of the dynamic covalent chemistry and the synthesis of covalent organic frameworks.

Reconstructing avascular necrotic femoral head through a bioactive ß-TCP system: From design to application.

A variety of techniques have been used for treating avascular necrosis of the femoral head (ANFH), but have frequently failed. In this study, we proposed a ß-TCP system for the treatment of ANFH by boosting revascularization and bone regeneration. The angio-conductive properties and concurrent osteogenesis of the highly interconnected porous ß-TCP scaffold were revealed and quantified through an in vivo model that simulated the ischemic environment of ANFH. Mechanical test and finite element analysis showed that the mechanical loss caused by tissue necrosis and surgery was immediately partially compensated after implantation, and the strength of the operated femoral head was adaptively increased and eventually returned to normal bone, along with continuous material degradation and bone regeneration. For translational application, we further conducted a multi-center open-label clinical trial to assess the efficacy of the ß-TCP system in treating ANFH. Two hundred fourteen patients with 246 hips were enrolled for evaluation, and 82.1% of the operated hips survived at a 42.79-month median follow-up. The imaging results, hip function, and pain scores were dramatically improved compared to preoperative levels. ARCO stage Ⅱ disease outperformed stage Ⅲ in terms of clinical effectiveness. Thus, bio-adaptive reconstruction using the ß-TCP system is a promising hip-preserving strategy for the treatment of ANFH.

Research on the Relationship between Exosome Production and Atherosclerosis.

Atherosclerosis (AS) is the leading cause of cardiovascular disease, causing a major burden on patients as well as families and society. Exosomes generally refer to various lipid bilayer microvesicles originating from different cells that deliver various bioactive molecules to the recipient cells, exerting biological effects in cellular communication and thereby changing the internal environment of the body. The mechanisms of correlation between exosomes and the disease process of atherosclerosis have been recently clarified. Exosomes are rich in nucleic acid molecules and proteins. For example, the exosome miRNAs reportedly play important roles in the progression of atherosclerotic diseases. In this review, we focus on the composition of exosomes, the mechanism of their biogenesis and release, and the commonly used methods for exosome extraction. By summarizing the latest research progress on exosomes and atherosclerosis, we can explore the advances in the roles of exosomes in atherosclerosis to provide new ideas and targets for atherosclerosis prevention, diagnosis, and treatment.

Does joint-sparing tumor resection jeopardize oncologic and functional outcomes in non-metastatic high-grade osteosarcoma around the knee?

BACKGROUND: We previously reported joint-sparing tumor resection for osteosarcoma with epiphyseal involvement in which transepiphyseal osteotomy went through the in situ ablated epiphysis. However, we do not know whether this is a safe approach when compared with joint-sacrificed tumor resection. Our objective was to compare oncologic and functional outcomes between patients who underwent joint preservation (JP) and joint replacement (JR) tumor resection. Furthermore, we identified the risk factors of local recurrence, metastasis and survival. METHODS: Eighty-nine patients with non-metastatic high-grade osteosarcoma around the knee were treated with limb-salvage surgery (JP in 47 and JR in 42). Age, gender, tumor location, pathologic fracture, plain radiographic pattern, limb diameter change, perivascular space alteration, surgical margin, local recurrence, metastasis, death, and the Musculoskeletal Tumor Society (MSTS)-93 scores were extracted from the records. Univariate analysis was performed to compare oncologic and functional outcomes. Binary logistic and cox regression models were used to identify predicted factors for local recurrence, metastasis, and survival. RESULTS: Local recurrence, metastasis and overall survival were similar in the JP and JR group (p = 0.3; p = 0.211; p = 0.143). Major complications and limb survival were also similar in the JR and JP group (p = 0.14; p = 0.181). The MSTS score of 27.06 ± 1.77 in the JP group was higher than that of 25.88 ± 1.79 in the JR group (p = 0.005). The marginal margin of soft tissue compared with a wide margin was the only independent predictor of local recurrence (p = 0.006). Limb diameter increase and perivascular fat plane disappearance during neoadjuvant chemotherapy were independent predictors for metastasis (p = 0.002; p = 0.000) and worse survival (p = 0.000; p = 0.001). CONCLUSIONS: Joint-sparing tumor resection with the ablative bone margin offers advantage of native joint preservation with favorable functional outcomes while not jeopardizing oncologic outcomes compared with joint-sacrificed tumor resection. Surgeon should strive to obtain adequate soft tissue surgical margin decreasing risk of local recurrence. Novel drug regimens might be reasonable options for patients with obvious limb diameter increase and perivascular fat disappearance during chemotherapy.

Predicting chemosensitivity based on mini patient-derived xenografts in osteosarcoma patients: A retrospective study.

Context: The survival of patients diagnosed with osteosarcoma has not improved in the past three decades because of chemoresistance. Aim: This study aimed to improve the prognosis of patients with osteosarcoma. Settings and Design: From January 1, 2018, to June 30, 2019, a total of 14 patients with osteosarcoma were enrolled who underwent mini patient-derived xenograft (mini-PDX) assay in our hospital. Methods and Materials: We recruited 14 patients with osteosarcoma having acquirable lesions to establish PDX models and examine the sensitivity of nine drugs, including methotrexate (MTX), ifosfamide (IFO), epirubicin, and etoposide. Drug sensitivity was evaluated using the tumor relative proliferation rate (TRPR), and the patients' responses were assessed according to the RECIST 1.1 guidelines. Statistical Analysis Used: The difference in TRPR was analyzed using a paired t-test, while progression-free survival (PFS) was analyzed using the Kaplan-Meier method. Results: The mini-PDX results revealed that IFO had a lower tumor proliferation rate than MTX, indicating that IFO was more sensitive in patients with osteosarcoma (38.3% vs. 84.3%, P = 0.031). Thus, the regimen where IFO alternates with doxorubicin and cisplatin was recommended as adjuvant chemotherapy. MTX could replace IFO if the TRPR was better. Finally, 11 patients received adjuvant chemotherapy. A comparison of PFS revealed that sensitive patients with TRPR of <40% had a better prognosis (9.4 months vs. 3.7 months, P = 0.0324). Conclusions: Chemotherapy based on mini-PDX can improve the survival of patients with osteosarcoma whose TRPR was <40%, and that chemotherapy without MTX could be an alternative for osteosarcoma.

Redefining the Incidence and Profile of Fluoropyrimidine-Associated Cardiotoxicity in Cancer Patients: A Systematic Review and Meta-Analysis.

AIM: The cardiac toxicity that occurs during administration of anti-tumor agents has attracted increasing concern. Fluoropyrimidines have been used for more than half a century, but their cardiotoxicity has not been well clarified. In this study, we aimed to assess the incidence and profile of fluoropyrimidine-associated cardiotoxicity (FAC) comprehensively based on literature data. METHODS: A systematic literature search was performed using PubMed, Embase, Medline, Web of Science, and Cochrane library databases and clinical trials on studies investigating FAC. The main outcome was a pooled incidence of FAC, and the secondary outcome was specific treatment-related cardiac AEs. Random or fixed effects modeling was used for pooled meta-analyses according to the heterogeneity assessment. PROSPERO registration number: (CRD42021282155). RESULTS: A total of 211 studies involving 63,186 patients were included, covering 31 countries or regions in the world. The pooled incidence of FAC, by meta-analytic, was 5.04% for all grades and 1.5% for grade 3 or higher. A total of 0.29% of patients died due to severe cardiotoxicities. More than 38 cardiac AEs were identified, with cardiac ischemia (2.24%) and arrhythmia (1.85%) being the most frequent. We further performed the subgroup analyses and meta-regression to explore the source of heterogeneity, and compare the cardiotoxicity among different study-level characteristics, finding that the incidence of FAC varied significantly among different publication decades, country/regions, and genders. Patients with esophagus cancer had the highest risk of FAC (10.53%), while breast cancer patients had the lowest (3.66%). The treatment attribute, regimen, and dosage were significantly related to FAC. When compared with chemotherapeutic drugs or targeted agents, such a risk was remarkably increased (χ2 = 10.15, p < 0.01; χ2 = 10.77, p < 0.01). The continuous 5-FU infusion for 3-5 consecutive days with a high dosage produced the highest FAC incidence (7.3%) compared with other low-dose administration patterns. CONCLUSIONS: Our study provides comprehensive global data on the incidence and profile of FAC. Different cancer types and treatment appear to have varying cardiotoxicities. Combination therapy, high cumulative dose, addition of anthracyclines, and pre-existing heart disease potentially increase the risk of FAC.

Evaluation of Anlotinib Combined with Adriamycin and Ifosfamide as Conversion Therapy for Unresectable Soft Tissue Sarcomas.

(1) Background: This study investigated the safety and efficiency of adriamycin and ifosfamide combined with anlotinib (AI/AN) as a neoadjuvant conversion therapy in uSTS. (2) Methods: Patients with uSTS were eligible to receive AI/An, including adriamycin (20 mg/m2/d) and ifosfamide (3 g/m2/d) for the first to the third day combined with anlotinib (12 mg/d) for 2 weeks on/1 week off, all of which combine to comprise one cycle. Surgery was recommended after four cycles of treatment. (3) Results: A total of 28 patients were enrolled from June 2018 to December 2020. The best tumor responses included eight patients with partial responses and 20 with a stable disease. Patients with synovial sarcoma and liposarcoma had a significant decrease in the number of tumors compared with fibrosarcoma (p = 0.012; p = 0.042). The overall response rate and disease control rate were 28.57% and 100%, respectively. In total, 24 patients received surgery, while the rates of limb salvage and R0 resection were 91.67% (n = 22/24) and 87.50% (n = 21/24), respectively. Until the last follow-up visit, the mean PFS and RFS were 21.70 and 23.97 months, respectively. During drug administration, 67.87% of patients had grade ≥3 AEs. No treatment-related death occurred. (4) Conclusions: AI/AN followed by surgery showed favorable efficiency and manageable safety in patients with uSTS. A randomized controlled study with a large cohort should be performed for further investigations.

The clinical value of Aspergillus-specific IgG antibody test in the diagnosis of nonneutropenic invasive pulmonary aspergillosis.

OBJECTIVES: Aspergillus-specific IgG antibody (Asp IgG) has been successfully applied in the diagnosis of chronic pulmonary aspergillosis. We explored its value in nonneutropenic invasive pulmonary aspergillosis (IPA) by a multicenter, prospective, and controlled study. METHODS: We enrolled 372 clinically suspected nonneutropenic patients with IPA from February 2015 to August 2022. After excluding 4 cases with Aspergillus colonization, the remaining 368 cases were finally confirmed as patients with IPA (n = 99), or non-IPA patients (n = 269) consisting of community-acquired pneumonia (n = 206), tuberculosis (n = 22), nontuberculous mycobacteria (n = 5), lung abscess (n = 6), or noninfectious diseases (n = 30). Asp IgG in plasma samples was tested by enzyme-linked immunosorbent assay. RESULTS: At cut-off value of ≥80 AU/mL, Asp IgG had much higher sensitivity (59.6% vs. 19.2%, p < 0.0001), but lower specificity (77.0% vs. 96.3%, p < 0.0001) than serum galactomannan (GM) (cut-off value of ≥1.0), and similar sensitivity (59.6% vs. 55.6%, p = 0.611) but lower specificity (77.0% vs. 91.2%, p = 0.001) than bronchoalveolar lavage fluid (BALF) GM (cut-off value of ≥1.0), respectively. Combination diagnosis of either positive for Asp IgG or BALF GM had higher sensitivity (81.0% vs. 55.6%, p = 0.002), but lower specificity (75.2% vs. 91.2%, p = 0.001) than BALF GM alone. The receiver operating characteristic curve showed that Asp IgG had an optimal diagnostic value when the cut-off value was 56.6 AU/ml, and the sensitivity and specificity were 77.8% and 63.9%, respectively. DISCUSSIONS: The diagnostic value of Asp IgG for IPA is superior to serum GM, and a little inferior to BALF GM in nonneutropenic patients with IPA. Considering the convenience of taking blood samples, it is a good screening and diagnostic method for nonneutropenic patients with IPA, especially for those who cannot bear invasive procedures.

A classification system of joint-salvage tumor resection in osteosarcoma of the knee: A retrospective cohort study.

BACKGROUND: Joint-preserving surgery is possible for patients with juxta-articular osteosarcoma of the knee, even when the tumor invades the epiphysis. Oncologic and functional outcomes may vary due to the extent of tumor invasion, the amount of epiphysis preservation, and reconstruction methods. We aimed to introduce a novel classification facilitating clinical evaluation of different surgical treatments. METHODS: We identified 52 patients with osteosarcoma of the knee undergoing joint-preserving tumor resection and intercalary reconstruction. We classified procedures into two types and six subtypes based on the tumor location and adjuvant treatment employed. Oncologic outcomes, limb function and complications were compared among different types. RESULTS: None of the patients had a local recurrence in the preserved epiphysis apart from three (5.7 %) who had local recurrence in soft tissue. Overall survival rate of the patients was 82.7 % at 5 and 10 years. There was no difference in survival rate (P = 0.909), local recurrence (P = 0.642) between type I (tumor not invading epiphysis) and type II (tumor invading epiphysis). In addition to one skin necrosis in the 3D-printed prosthesis reconstruction and one infection in Capanna reconstruction, all complications necessitating additional surgery occurred in allograft. The Musculoskeletal Tumor Society (MSTS) scores ranged from 21 to 30 with a median of 26. There were differences in the MSTS scores among six subgroups (P = 0.015), with the highest in type Ia and the lowest in type IIc. The less of the viable epiphysis retained, the worse the knee function was at long-term follow up. CONCLUSIONS: The suggested classification can guide surgical strategy and is convenient for comparison of the functional results.

Identification of a polyamine-related signature and six novel prognostic biomarkers in oral squamous cell carcinoma.

Elevated polyamine levels are required for tumor transformation and development; however, expression patterns of polyamines and their diagnostic potential have not been investigated in oral squamous cell carcinoma (OSCC), and its impact on prognosis has yet to be determined. A total of 440 OSCC samples and clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Consensus clustering was conducted to classify OSCC patients into two subgroups based on the expression of the 17 polyamine regulators. Polyamine-related differentially expressed genes (PARDEGs) among distinct polyamine clusters were determined. To create a prognostic model, PARDEGs were examined in the training cohorts using univariate-Lasso-multivariate Cox regression analyses. Six prognostic genes, namely, "CKS2," "RIMS3," "TRAC," "FMOD," CALML5," and "SPINK7," were identified and applied to develop a predictive model for OSCC. According to the median risk score, the patients were split into high-risk and low-risk groups. The predictive performance of the six gene models was proven by the ROC curve analysis of the training and validation cohorts. Kaplan-Meier curves revealed that the high-risk group had poorer prognosis. Furthermore, the low-risk group was more susceptible to four chemotherapy drugs according to the IC50 of the samples computed by the "pRRophetic" package. The correlation between the risk scores and the proportion of immune cells was calculated. Meanwhile, the tumor mutational burden (TMB) value of the high-risk group was higher. Real-time quantitative polymerase chain reaction was applied to verify the genes constructing the model. The possible connections of the six genes with various immune cell infiltration and therapeutic markers were anticipated. In conclusion, we identified a polyamine-related prognostic signature, and six novel biomarkers in OSCC, which may provide insights to identify new treatment targets for OSCC.

Silk Fibroin-Based Tough Hydrogels with Strong Underwater Adhesion for Fast Hemostasis and Wound Sealing.

Rapid and strong adhesion of hydrogel adhesives is required for instant wound closure and hemostasis. However, in situ hydrogel formation and sufficient adhesion at target tissue sites in biological environments are severely compromised by the presence of blood and body fluids. In this work, an underwater adhesive hydrogel (named SHCa) is fabricated with rapid in situ gelation, enhanced mechanical toughness, and robust underwater adhesion. The SHCa can undergo rapid UV irradiation-induced gelation under water within 5 s and adhere firmly to underwater surfaces for 6 months. The synergistic effects of crystalline ß-sheet structures and dynamic energy-dissipating mechanisms enhance the mechanical toughness and cohesion, supporting the balance between adhesion and cohesion in wet environments. Importantly, the SHCa can achieve rapid in situ gelation and robust underwater adhesion at various tissue surfaces in highly dynamic fluid environments, substantially outperforming the commercially available tissue adhesives. The lap shear adhesion strength and wound closure strength of SHCa on blood-covered substrates are 7.24 and 12.68 times higher than those of cyanoacrylate glue, respectively. Its fast hemostasis and wound sealing performance are further demonstrated in in vivo animal models. The proposed hydrogel with strong underwater adhesion provides an effective tool for fast wound closure and hemostasis.

Construction of m6A-based prognosis signature and prediction for immune and anti-angiogenic response.

Background: Increasing evidence illustrated that m6A regulator-mediated modification plays a crucial role in regulating tumor immune and angiogenesis microenvironment. And the combination of immune checkpoint inhibitor and anti-angiogenic therapy has been approved as new first-line therapy for advanced HCC. This study constructed a novel prognosis signature base on m6A-mediated modification and explored the related mechanism in predicting immune and anti-angiogenic responses. Methods: Gene expression profiles and clinical information were collected from TCGA and GEO. The ssGSEA, MCPCOUNT, and TIMER 2.0 algorithm was used to Estimation of immune cell infiltration. The IC50 of anti-angiogenic drugs in GDSC was calculated by the "pRRophetic" package. IMvigor210 cohort and Liu et al. cohort were used to validate the capability of immunotherapy response. Hepatocellular carcinoma single immune cells sequencing datasets GSE140228 were collected to present the expression landscapes of 5 hub genes in different sites and immune cell subpopulations of HCC patients. Results: Three m6A clusters with distinct immune and angiogenesis microenvironments were identified by consistent cluster analysis based on the expression of m6A regulators. We further constructed a 5-gene prognosis signature (termed as m6Asig-Score) which could predict both immune and anti-angiogenic responses. We illustrated that high m6Asig-Score is associated with poor prognosis, advanced TNM stage, and high TP53 mutation frequency. Besides, the m6Asig-Score was negatively associated with immune checkpoint inhibitors and anti-angiogenic drug response. We further found that two of the five m6Asig-Score inner genes, B2M and SMOX, were associated with immune cell infiltration, immune response, and the sensitivity to sorafenib, which were validated in two independent immunotherapy cohorts and the Genomics of Drug Sensitivity in Cancer (GDSC) database. Conclusion: We constructed a novel prognosis signature and identified B2M and SMOX for predicting immune and anti-angiogenic efficacy in HCC, which may guide the combined treatment strategies of immunotherapy and anti-angiogenic therapy in HCC.

Therapeutic drug monitoring and safety evaluation of voriconazole in the treatment of pulmonary fungal diseases.

Aims: The gene polymorphism of voriconazole metabolism-related liver enzyme is notable in East Asia population. It casts a significant influence on the rational use of voriconazole. We conducted this study to investigate the relationship between steady-state voriconazole trough concentration (Ctrough) and adverse effects (AEs), especially hepatotoxicity. Methods: We conducted a real-world study in the Jinling Hospital from January 2015 to June 2020. A total of 140 patients receiving voriconazole were enrolled in this study. The determination and scoring of voriconazole-associated hepatotoxicity were performed according to the Roussel Uclaf Causality Assessment Method scoring scale and the severity of hepatotoxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE). Results: Elevated steady-state voriconazole Ctrough with concomitant AEs are the most common reason for dose adjustments during treatment. Compared with the group without any AEs, voriconazole Ctrough was significantly higher in the hepatotoxicity and neurotoxicity groups, and the incidence of both events showed an overall increasing trend with increasing voriconazole Ctrough. Hepatotoxicity occurred in 66.7% of patients within 7 days of the first dose of voriconazole and 94.4% within 15 days of the dose. Steady-state voriconazole Ctrough >3.61 mg/l was associated with an increased incidence of hepatotoxicity (area under the curve = 0.645, p = 0.047). Logistic regression analysis showed that timely voriconazole dose adjustment was a predictor of attenuated hepatotoxicity after adjustment for confounders, but hepatotoxicity was not associated with voriconazole Ctrough measured at a single time point. Conclusion: Hepatotoxicity and neurotoxicity correlate with voriconazole Ctrough, and dose reduction in patients with elevated steady-state voriconazole Ctrough may prevent hepatotoxicity. In patients with early occurrence of hepatotoxicity, initial therapeutic drug monitoring (TDM) might predict the risk of hepatotoxicity. Follow-up TDM may be necessary to predict late onset hepatotoxicity. Plain Language Summary: Safety of voriconazole for the treatment of pulmonary fungal diseases Introduction: Several studies have suggested an association between the concentration of voriconazole in the blood and liver damage, but the evidence is weak. This study aimed to investigate relationships between voriconazole drug concentration and side effects and to analyze the factors affecting liver damage caused by voriconazole.Methods: We conducted a study at the Jinling Hospital from January 2015 to June 2020, in which a total of 140 patients were finally enrolled.Results: Voriconazole doses were adjusted in 44 patients due to abnormal voriconazole drug concentration or side effects, 32 patients reduced the dose and 8 patients increased the dose. An elevated liver enzyme level was the most common cause for dose adjustment. After the first dose adjustment, most patients achieved the target drug concentration. A total of 18 patients were determined as probable or highly probable to have drug-induced liver injury from voriconazole. Voriconazole drug concentration was significantly higher in the liver damage and nervous system damage groups as compared with the group without any side effects, and most liver damage events occurred within 14 days of the first dose. Voriconazole drug concentration >3.61 mg/l was associated with an increased incidence of liver damage.Conclusion: In this study, approximately one-third of patients with pulmonary fungal disease needed to adjust their dose after the standard dose of voriconazole treatment. The incidence of liver damage and nervous system damage showed an overall increasing trend with increasing voriconazole baseline concentrations. Initial therapeutic drug monitoring may be predictive of liver damage. Follow-up monitoring of liver enzymes may be needed.

Advanced bioactive hydrogels for the treatment of myocardial infarction.

Myocardial infarction (MI) is the leading cause of cardiovascular disease-related deaths. Local ischemia and cardiomyocyte death lead to a series of pathological remodeling events of the infarcted extracellular matrix (ECM) that are significantly different from normal cardiac tissues. These pathological characteristics have inspired the development of microenvironment-responsive therapeutic strategies for MI. Bioactive hydrogels attract great attention because of their unique physicochemical features to induce specific biological responses upon interacting with cells, ECMs, and signal molecules. They exhibit physicochemical-responsive activities to regulate interactions between hydrogels and the biological system. Many bioactive hydrogels with intelligent properties have been used to repair infarcted myocardium and restore the cardiac function after MI. Current research studies ensure that bioactive hydrogels have a high clinical importance and application prospects. This review summarizes the advances of bioactive hydrogels in the field of on-demand treatment of MI and evaluates their key physicochemical characteristics. A range of bioactive hydrogels and their biomedical applications are discussed in repairing injured hearts and restoring cardiac functions, providing insights into the development of intelligent therapeutic approaches for MI.

NPC1 Deficiency Contributes to Autophagy-Dependent Ferritinophagy in HEI-OC1 Auditory Cells.

Niemann-Pick type C disease (NPCD) is a rare genetic syndrome characterized by cholesterol accumulation in multiple organelles. NPCD is mainly caused by gene deficiency of NPC intracellular cholesterol transporter 1 (NPC1). It has been reported that some of the NPCD patients exhibit clinical features of progressive hearing loss at high frequency and iron disorder, but the underlying relationship is unknown. A recent study has reported that ferroptosis contributes to the impairment of cochlear hair cells that are related to sensory hearing. In this study, we generated NPC1-deficient HEI-OC1 cells to show the effect of NPC1 deficiency on cochlear outer hair cells. We found that NPC1 deficiency enhances autophagy-dependent ferritinophagy to release Fe (II). Our work provides important insights into the effect of NPC1 deficiency in auditory cells, indicating that it induces ferroptosis and results in hearing loss.

The Incidence and Severity of Post-ERCP Pancreatitis in Patients Receiving Standard Administration of NSAIDs: a Systematic Review and Meta-analysis.

BACKGROUND: Routine rectal administration of 100 mg of diclofenac or indomethacin was demonstrated to be an effective prevention method to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. The systematic review and meta-analysis aimed to estimate the incidence and severity of post-ERCP pancreatitis (PEP) and explore the discrepancies of PEP incidences among different subgroups. METHODS: The PubMed, Web of Science, and Ovid EMBASE databases were searched for studies published until December 2020. Only randomized controlled trials (RCTs) reported rectal administration of 100 mg or higher doses of diclofenac or indomethacin, with PEP as the primary outcomes were eligible for inclusion. The overall and severity of PEP were estimated. Subgroup analysis was performed based on geographic regions, risk level, study beginning time, type of NSAIDs, administration time, and sample size. RESULTS: There were 26 randomized controlled trials (RCTs) with 7954 patients in 31 NSAIDs arms. The pooled incidences were 7.2% for overall PEP (95% confidence interval (CI) 5.9-8.5%), 5.0% for mild PEP (95% CI, 4.0-6.0%), and 1.5% for moderate and severe PEP (0.8-2.3%). PEP rate were higher in patients receiving rectal indomethacin than that of patients receiving rectal diclofenac (7.8% (95% CI, 6.4-9.3%) vs 3.8% (95% CI, 2.2-5.3%), p = 0.009). The PEP rates of high-risk patients and average-risk patients were 8.9% (95% CI, 5.6-12.2%) and 6.4% (95% CI, 5.1-7.6%), respectively (p = 0.160). CONCLUSIONS: The incidence of PEP was higher in patients receiving 100 mg rectal indomethacin than patients receiving 100 mg diclofenac. The effect of 100 mg diclofenac versus indomethacin on preventing PEP requires further study.

Intercalary tibial reconstruction with frozen tumor-bearing autograft in combination with ipsilateral fibula in limb-salvage surgery.

PURPOSE: The purpose of this study was to examine whether the results of a reconstruction using frozen autograft in combination with vascularized fibula are comparable to other reconstructive methods in limb-salvage surgery for tibial sarcoma with regard to the functional outcome and complications. METHODS: Between 2008 and 2012, nine patients with bone sarcoma of the tibia underwent excision of the affected segment that was then frozen and reimplanted with an ipsilateral vascularized fibular graft within it. Patients were examined clinically and radiographically. RESULTS: The mean follow-up was 48.8 months. The mean time to full weight-bearing was 6.2 months and to complete radiological union 6.8 months at the conjunction. One patient required a mid-thigh amputation due to local recurrence in soft tissue. No local recurrence arising from the frozen autograft was detected. Complications included wound dehiscence in 1, clawed toes in 1, temporary peroneal nerve palsy in 1, and stress fracture in 1. The average musculoskeletal tumor society functional score was 94.5%. CONCLUSIONS: Combination of a frozen tumor-bearing autograft and ipsilateral pedicled fibula is an effective reconstruction for massive bone defect arising from resection of bone sarcoma in tibia. This approach has the advantage of combining the biological properties offered by the vascularized bone graft with the mechanical endurance of the frozen autograft. The method is best indicated for intercalary defects of the tibia for selected patients. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Treatment-Related Coronary Disorders of Fluoropyrimidine Administration: A Systematic Review and Meta-Analysis.

Background: Coronary disorders are recognized as the most common manifestation of fluoropyrimidine-related cardiotoxicity in clinical practice. However, there are limited and conflicting data on the incidence and profiles of fluoropyrimidine-related coronary disorders. In this meta-analysis, we aimed to systematically assess the incidence of all-grade and grade 3 or higher fluoropyrimidine-related coronary disorders, and further explore the factors that influence its occurrence. Methods: Studies reporting the fluoropyrimidine-related coronary disorders were retrieved from a systematic search of English literature in the PubMed, Web of Science, Medline, and Cochrane database from 1 Jan 2001, to 1 Jan 2022. The NIH assessment tool was used to evaluate the quality of each study. The data of basic study characteristics, treatment details, and results of coronary toxicities were extracted. According to the results of the heterogeneity test (I2 and p-value statistic), a random-effect model or fixed-effect model was selected for the pooled analysis of the incidence of adverse coronary events. Subgroup analysis was conducted to further explore the risks influencing the occurrence of fluoropyrimidine-related coronary disorders. The stability and publication bias of our results were evaluated by sensitivity analysis and Egger test, respectively. Results: A total of 63 studies were finally included in our pooled analysis, involving 25,577 patients. The pooled cumulative incidence of all-grade and grade 3 or higher coronary disorders was 2.75% (95% CI 1.89%-3.76%) and 1.00% (95% CI 0.62%-1.47%), respectively. The coronary disorders were most reported as myocardial ischemia (1.28%, 95% CI 0.42%-2.49%) and angina/chest pain (1.1%, 95% CI 0.54%-1.81%). Subgroup analysis revealed that studies in the female-only population seemed to have a lower incidence of fluoropyrimidine-related coronary disorders. The occurrence of adverse coronary events varied among different tumor types. Patients with esophageal cancer have the highest coronary toxicity (6.32%), while those with breast cancer have a relatively lower incidence (0.5%). Coronary disorders induced by 5-FU monotherapy are more frequent than that induced by capecitabine (3.31% vs. 1.21%, p < 0.01). Fluoropyrimidine combination therapy, whether combined with other chemotherapy drugs, targeted therapy drugs, or radiotherapy, significantly increased the incidence of coronary complications (p < 0.01). Conclusion: This meta-analysis has defined the incidence of fluoropyrimidine-related coronary disorders and depicted its epidemiological profiles for the first time, which may provide a reference for clinical practice in cancer management.