Beneficial effects of maintaining liver function during hepatic arterial infusion chemotherapy combined with tyrosine kinase and programmed cell death protein-1 inhibitors on the outcomes of patients with unresectable hepatocellular carcinoma.

BACKGROUND AND AIM: Combination therapy is the primary treatment for unresectable hepatocellular carcinoma (u-HCC). The hepatic functional reserve is also critical in the treatment of HCC. In this study, u-HCC was treated with combined hepatic arterial infusion chemotherapy (HAIC), tyrosine kinase inhibitors (TKIs), and programmed cell death protein-1 (PD-1) inhibitors to analyze the therapeutic response, progression-free survival (PFS), and safety. METHODS: One hundred sixty-two (162) patients with u-HCC were treated by combination therapy of HAIC, TKIs, and PD-1 inhibitors. PFS was assessed by Child-Pugh (CP) classification subgroups and the change in the CP score during treatment. RESULTS: The median PFS was 11.7 and 5.1 months for patients with CP class A (CPA) and CP class B (CPB), respectively (p = 0.013), with respective objective response rates of 61.1 and 27.8% (p = 0.002) and conversion rates of 16 and 0% (p = 0.078). During treatment, the CP scores in patients with CPA worsened less in those with complete and partial response than in those with stable and progressive disease. In the CP score 5, patients with an unchanged CP score had longer PFS than those with a worsened score (Not reached vs. 7.9 months, p = 0.018). CPB was an independent factor negatively affecting treatment response and PFS. Patients with CPA responded better to the combination therapy and had fewer adverse events (AEs) than those with CPB. CONCLUSIONS: Thus, triple therapy is more beneficial in patients with good liver function, and it is crucial to maintain liver function during treatment.

Innovative Bio-based Hydrogel Microspheres Micro-Cage for Neutrophil Extracellular Traps Scavenging in Diabetic Wound Healing.

Neutrophil extracellular traps (NETs) seriously impede diabetic wound healing. The disruption or scavenging of NETs using deoxyribonuclease (DNase) or cationic nanoparticles has been limited by liberating trapped bacteria, short half-life, or potential cytotoxicity. In this study, a positive correlation between the NETs level in diabetic wound exudation and the severity of wound inflammation in diabetic patients is established. Novel NETs scavenging bio-based hydrogel microspheres 'micro-cage', termed mPDA-PEI@GelMA, is engineered by integrating methylacrylyl gelatin (GelMA) hydrogel microspheres with cationic polyethyleneimine (PEI)-functionalized mesoporous polydopamine (mPDA). This unique 'micro-cage' construct is designed to non-contact scavenge of NETs between nanoparticles and the diabetic wound surface, minimizing biological toxicity and ensuring high biosafety. NETs are introduced into 'micro-cage' along with wound exudation, and cationic mPDA-PEI immobilizes them inside the 'micro-cage' through a strong binding affinity to the cfDNA web structure. The findings demonstrate that mPDA-PEI@GelMA effectively mitigates pro-inflammatory responses associated with diabetic wounds by scavenging NETs both in vivo and in vitro. This work introduces a novel nanoparticle non-contact NETs scavenging strategy to enhance diabetic wound healing processes, with potential benefits in clinical applications.

Functional 2D Nanoplatforms Alleviate Eosinophilic Chronic Rhinosinusitis by Modulating Eosinophil Extracellular Trap Formation.

The therapeutic outcomes of patients with eosinophilic chronic rhinosinusitis (ECRS) remain unsatisfactory, largely because the underlying mechanisms of eosinophilic inflammation are uncertain. Here, it is shown that the nasal secretions of ECRS patients have high eosinophil extracellular trap (EET) and cell-free DNA (cfDNA) levels. Moreover, the cfDNA induced EET formation by activating toll-like receptor 9 (TLR9) signaling. After demonstrating that DNase I reduced eosinophilic inflammation by modulating EET formation, linear polyglycerol-amine (LPGA)-coated TiS2 nanosheets (TLPGA) as functional 2D nanoplatforms with low cytotoxicity, mild protein adsorption, and increased degradation rate is developed. Due to the more flexible linear architecture, TLPGA exhibited higher cfDNA affinity than the TiS2 nanosheets coated with dendritic polyglycerol-amine (TDPGA). TLPGA reduced cfDNA levels in the nasal secretions of ECRS patients while suppressing cfDNA-induced TLR9 activation and EET formation in vitro. TLPGA displayed exceptional biocompatibility, preferential nasal localization, and potent inflammation modulation in mice with eosinophilic inflammation. These results highlight the pivotal feature of the linear molecular architecture and 2D sheet-like nanostructure in the development of anti-inflammation nanoplatforms, which can be exploited for ECRS treatment.

The Mechanism of miR-29 in Bladder Cancer Released by Exosomes into Brain Microglia to Promote M2 Polarization and Angiogenesis in Brain Metastasis of Bladder Cancer.

Objective: To explore the role of miR-29 in bladder cancer, released by exosomes into brain microglia to influence its polarization and promote angiogenesis. This, in turn, would help design therapeutic strategies for brain metastasis caused by bladder cancer. Methods: The relative expression of miR-29 in normal bladder and bladder cancer cells was compared by qPCR technology, and the difference of specific binding between PI3K and has-miR-29a in the NC group and mimic group was verified by luciferase activity. Bladder cancer cells T24 were transfected with miR-29 NC, mimic, or neferine and divided into miR-29-NC group, miR-29-mimic group, miR-29-NC-neferine group, and miR-29-mimic-neferine group. Then they were co-cultured with microglia BV2 in a 1% hypoxia environment. The protein expressions of p-PI3K, p-AKT, p-AMPK, p-PGC-1α, p-PPARγ, CD206, and HIF1α in glial cells BV2 were detected by Western blot. The effect of each group on angiogenesis was observed by the tube formation experiment. A glioma mouse model was established, and the number of blood vessels and tumor proliferation were observed by pathological section H&E staining, to assess the effect of miR-29 on angiogenesis. Results: qPCR and dual-luciferase reporter assay showed that miR-29 was highly expressed in bladder cancer compared with normal bladder cells. The binding of miR-29 to PI3K led to the degradation of PI3K mRNA. Protein expression analysis showed that miR-29 inhibited PI3K and p-AKT in bladder cancer cells, and promoted the expression of p-AMPK, p-PGC-1α, p-PPARγ, CD206, and HIF1α. In vivo experiments demonstrated that miR-29 could promote the cell volume of bladder cancer cells and increase the number of blood vessels in bladder cancer cells, while neferine could inhibit the above effects. Conclusion: miR-29 can regulate PI3K/AMPK/PGC-1α/PPAR-γ signaling in microglial cells, promote their polarization to M2, and ultimately promote neovascularization in bladder cancer.

Tackling Severe Neutrophilic Inflammation in Airway Disorders with Functionalized Nanosheets.

Severe airway inflammatory disorders impose a significant societal burden, and the available treatments are unsatisfactory. High levels of neutrophil extracellular trap (NET) and cell-free DNA (cfDNA) were detected in the inflammatory microenvironment of these diseases, which are closely associated with persistent uncontrolled neutrophilic inflammation. Although DNase has proven to be effective in mitigating neutrophilic airway inflammation in mice by reducing cfDNA and NET levels, its clinical use is hindered by severe side effects. Here, we synthesized polyglycerol-amine (PGA) with a series of hydroxyl/amine ratios and covered them with black phosphorus (BP) nanosheets. The BP nanosheets functionalized with polyglycerol-50% amine (BP-PGA50) efficiently lowered cfDNA levels, suppressed toll-like receptor 9 (TLR9) activation and inhibited NET formation in vitro. Importantly, BP-PGA50 nanosheets demonstrated substantial accumulation in inflamed airway tissues, excellent biocompatibility, and potent inflammation modulation ability in model mice. The 2D sheet-like structure of BP-PGA50 was identified as a crucial factor for the therapeutic efficacy, and the hydroxyl/amine ratio was revealed as a significant parameter to regulate the protein resistance, cfDNA-binding efficacy, and cytotoxicity. This study shows the promise of the BP-PGA50 nanosheet for tackling uncontrolled airway inflammation, which is also significant for the treatment of other neutrophilic inflammatory diseases. In addition, our work also highlights the importance of proper surface functionalization, such as hydroxyl/amine ratio, in therapeutic nanoplatform construction for inflammation modulation.

Cuproptosis Regulates Microenvironment and Affects Prognosis in Prostate Cancer.

Current immunotherapy for prostate cancer is still in the stage of clinical trials. This delay is thought to be caused by an unclear regulatory mechanism of the immune microenvironment, which makes it impossible to distinguish patients suitable for immunotherapy. Cuprotosis may be related to the heterogeneity of immune microenvironment, which was regarded as a new copper-dependent cell death mode, was proposed, and gain attention. We explored for the first time the relationship between cuprotosis and the immune microenvironment of prostate cancer and constructed cuprotosis score. RNA sequencing data sets for prostate cancer were downloaded from public databases. Consensus clustering was applied to distinguish cuprotosis phenotype based on the expression of cuproptosis-related genes (CRGs) identified as prognostic factors. Genomic phenotypes of CRG clusters were depicted via consensus clustering. Cuprotosis score was established on the basis of differentially expressed genes (DEGs) identified as prognostic factors via principal component analysis. Cuprotosis score = the first principal component of prognostic factors + the second principal component of prognostic factors. The value of cuproptosis score in predicting prognosis and immunotherapy response was evaluated. PDHA1 (HR = 3.86, P < 0.001) and GLS (HR = 1.75, P = 0.018) were risk factors for prognosis of prostate cancer patients, while DBT (HR = 0.66, P = 0.048) was a favorable factor for prognosis of prostate cancer patients. CRG clusters had different prognosis and immune cell infiltration. So as gene clusters. Prostate cancer patients with low cuprotosis score showed better prognosis for biochemical relapse-free survival. Cuprotosis score is accompanied with high immune score and Gleason score. As cuprotosis genes, PDHA1, GLS, and DBT were identified as independent prognostic factors of prostate cancer. Cuprotosis score was established via principal component analysis of PDHA1, GLS, and DBT, which can be used as a predictor of prognosis and immunotherapy response of prostate cancer patients, and can characterize immune cells infiltration in tumors. Cuproptosis was involved in the regulation of immune microenvironment, which may depend on the effect of tricarboxylic acid cycle. Our study provided clues to reveal the relationship between copper death and immune microenvironment, highlighted the clinical significance of cuproptosis, and provided a reference for the development of personalized immunotherapy.

Multifunctional Cationic Hyperbranched Polyaminoglycosides that Target Multiple Mediators for Severe Abdominal Trauma Management.

Trauma and its associated complications, including dysregulated inflammatory responses, severe infection, and disseminated intravascular coagulation (DIC), continue to pose lethal threats worldwide. Following injury, cell-free nucleic acids (cfNAs), categorized as damage-associated molecular patterns (DAMPs), are released from dying or dead cells, triggering local and systemic inflammatory responses and coagulation abnormalities that worsen disease progression. Harnessing cfNA scavenging strategies with biomaterials has emerged as a promising approach for treating posttrauma systemic inflammation. In this study, the effectiveness of cationic hyperbranched polyaminoglycosides derived from tobramycin (HPT) and disulfide-included HPT (ss-HPT) in scavenging cfNAs to mitigate posttrauma inflammation and hypercoagulation is investigated. Both cationic polymers demonstrate the ability to suppress DAMP-induced toll-like receptor (TLR) activation, inflammatory cytokine secretion, and hypercoagulation by efficiently scavenging cfNAs. Additionally, HPT and ss-HPT exhibit potent antibacterial efficacy attributed to the presence of tobramycin in their chemical composition. Furthermore, HPT and ss-HPT exhibit favorable modulatory effects on inflammation and therapeutic outcomes in a cecal ligation puncture (CLP) mouse abdominal trauma model. Notably, in vivo studies reveal that ss-HPT displayed high accumulation and retention in injured organs of traumatized mice while maintaining a higher biodegradation rate in healthy mice, contrasting with findings for HPT. Thus, functionalized ss-HPT, a bioreducible polyaminoglycoside, holds promise as an effective option to enhance therapeutic outcomes for trauma patients by alleviating posttrauma inflammation and coagulation complications.

Pretreatment Neutrophil-to-Lymphocyte Ratio as Prognostic Biomarkers in Patients with Unresectable Hepatocellular Carcinoma Treated with Hepatic Arterial Infusion Chemotherapy Combined with Lenvatinib and Camrelizumab.

Purpose: This study aimed to assess the prognostic significance of the neutrophil-lymphocyte ratio (NLR) in patients with unresectable hepatocellular carcinoma (u-HCC) treated with hepatic artery infusion chemotherapy (HAIC) combined with lenvatinib and camrelizumab. Patients and Methods: We conducted a retrospective cohort study involving patients diagnosed with u-HCC who underwent HAIC combined with lenvatinib and camrelizumab. Patients were stratified into two cohorts using the median NLR as the cutoff point. We then assessed treatment response, overall survival (OS), progression-free survival (PFS), and adverse events in these patient groups. Results: Between October 2020 and April 2022, a total of 88 patients were enrolled in the study. The overall cohort exhibited a median PFS of 7.9 months, while the median OS was not reached, and a median NLR of 3.46. Notably, the group with NLR<3.46 demonstrated significantly superior OS (not reached vs 9.6 months, p = 0.017) and PFS (18.3 vs 5.3 months, p = 0.0015) compared to the NLR≥3.46 group. Furthermore, multivariate analysis revealed that an alpha-fetoprotein (AFP) ≥ 400 ng/mL [hazard ratio (HR), 2.133; 95% confidence interval (CI), 1.102-4.126; p = 0.024], Barcelona Clinical Hepatocellular Carcinoma (BCLC) stage C (HR, 2.319; 95% CI, 1.128-4.764; p = 0.022), and NLR ≥3.46 (HR, 2.35; 95% CI, 1.239-4.494; p = 0.009) were identified as independent risk factors for OS. Additionally, multivariate analysis demonstrated that AFP ≥ 400 ng/mL, BCLC stage C, and NLR ≥ 3.46 were independent negative factors of PFS. Conclusion: NLR can be associated with outcomes in patients with u-HCC treated with HAIC combined with lenvatinib and camrelizumab.

Rare benign liver tumors that require differentiation from hepatocellular carcinoma: focus on diagnosis and treatment.

BACKGROUND/AIM: Recently, an increase in the number of asymptomatic rare benign liver tumors (BLTs) has been reported during health check-ups. It is difficult to determine the nature of partial rare BLTs and not easy to distinguish from malignant liver tumors. This study aimed to analysis clinical features, diagnosis and treatment of rare BLTs to reduce misdiagnosis and provide reference for clinical practice. METHODS: From January 2012 to January 2021, we treated 112 rare BLTs by hepatectomy, including 54 focal nodular hyperplasias, 14 hepatocellular adenomas, 28 hepatic angiomyolipomas, 3 hepatic granulomas, 2 inflammatory pseudotumors of the liver, 2 nodular regenerative hyperplasia, 2 hepatic lipomas, 1 solitary fibrous tumor of the liver, 1 hepatic schwannoma and 1 hepatic myelolipoma. RESULTS: The majority of patients were middle-aged female and asymptomatic. Single tumors were dominant. The diagnostic accuracies of computed tomography (CT) and magnetic resonance imaging (MRI) were 32.5% and 44.2%, respectively. The majority of tumors were likely to be misdiagnosed as hepatocellular carcinoma (HCC) or difficult to distinguish from HCC. All patients underwent surgical treatment. Postoperative pathological and immunohistochemical examination can confirm the diagnosis. No patients without tumor recurrence or metastasis during follow-up period. CONCLUSION: Altogether, the clinical symptoms of rare BLTs lack specificity, and their preoperative diagnosis largely depends on imaging examination, with a low diagnostic accuracy rate and high chances of misdiagnosis as HCC. Diagnosis is confirmed by pathological and immunohistochemical examination. Surgical resection for rare BLT is safe and effective, regular postoperative follow-up is necessary.

Hepatectomy After Conversion Therapy for Initially Unresectable HCC: What is the Difference?

Purpose: Conversion therapy gives some patients with initially unresectable hepatocellular carcinoma (HCC) access to surgery. The purpose of this study was to evaluate the safety and efficacy of hepatectomy after conversion therapy and how it differed from those who undergoing direct hepatectomy. Patients and Methods: From January 2018 to April 2022, 745 patients underwent hepatectomy for HCC were enrolled. Among them, 41 patients of unresectable HCC underwent hepatectomy after conversion therapy. A demographically and clinically comparable cohort was created from the remaining patients in a 1:1 ratio using propensity score matching. Results: The median duration of conversion therapy was 108 (42-298) days, 8 patients achieved complete response (CR) and 33 achieved partial response (PR). Conversion therapy resulted in some degree of myelosuppression, but liver function index remained good. Compared with the direct hepatectomy group, the conversion group had more blood loss (600 mL vs 400 mL, p=0.015), longer operative time (270 min vs 240 min, p=0.02), higher blood transfusion rates, and longer hospital stay (8 days vs 11 days, p<0.001). Patients in the conversion group had significantly more complications of any grade (82.9% vs 51.2%, p=0.002) and grade 3/4 (26.8% vs 4.9%, p=0.013), and 6 patients developed post-hepatectomy liver failure (PHLF). There were no deaths in either group. All patients achieved R0 resection, 6 (6/41, 14.6%) achieved pathological complete response (pCR), 14 achieved major pathologic responses (MPR). During a median follow-up of 12.8 months, 14 patients in the conversion group experienced recurrence or metastasis, no deaths. Conclusion: Hepatectomy after conversion therapy was more difficult than direct hepatectomy, but accurate preoperative assessment could ensure the safety of the surgery. The damage of liver function after conversion therapy was more severe than expected, PHLF should be prevented and treated. Hepatectomy was effective and necessary, postoperative pathological examination could provide guidance for adjuvant therapy.

Hepatic arterial infusion chemotherapy combined with PD-1 inhibitors and tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: A tertiary medical center experience.

Background: Unresectable hepatocellular carcinoma (u-HCC) still accounts for the majority of newly diagnosed HCC which with poor prognosis. In the era of systemic therapy, combination therapy with programmed cell death protein-1 (PD-1) inhibitors and tyrosine kinase inhibitors (TKIs) has become mainstream. Hepatic arterial infusion chemotherapy (HAIC) as a local treatment has also shown a strong anti-tumor effect. This study aimed to investigate the efficacy and safety of HAIC, PD-1 inhibitors plus TKIs for u-HCC. Methods: This retrospective study included patients with initially u-HCC between October 2020 to April 2022 who had received at least one cycle of therapy with HAIC, PD-1 inhibitors plus TKIs. The primary outcome included overall response rate (ORR), the disease control rate (DCR), surgical conversion rate, progression-free survival (PFS) and treatment-related adverse events. Results: A total of 145 patients were included in the study. The median treatment cycle of HAIC and PD-1 inhibitors were 3 and 4, respectively. According to the modified RECIST criteria, the best ORR was 57.2% (83/145), 9 had achieved complete response (CR), DCR was 89.7% (130/145). Median time to achieve CR or PR was 65 days. Surgical conversion rate was 18.6% (27/145), seven patients (7/27,25.9%) achieved pathological complete response (pCR). The median follow-up was 12.5 months (4.5-20 months), and the median PFS was 9.7 months. Subgroup analysis showed that Child-pugh A patients had higher DCR (92.2% vs 79.3%, p=0.041) than Child-pugh B patients, as well as increased successful conversion rate (22.4% vs 3.4%, p=0.019). Patients without vascular invasion and extrahepatic metastases showed higher PR (63.4% vs 43.3%, p<0.05) and ORR (73.2% vs 50.0%, p<0.05) than those with vascular invasion. The ORR (73.2% vs 45.5%, p<0.05) and DCR (95.1% vs 78.8%, p<0.05) were also significantly better than those of patients with extrahepatic metastases. HAIC regimen was not related to efficacy (All p>0.05). The incidence rate of grade 3/4 treatment-related AEs was 17.7% without fatal events. Conclusion: The triple combination therapy of HAIC and PD-1 inhibitors plus TKIs for patients with initially unresectable HCC exhibited satisfactory efficacy with tolerable toxicity.

Clinical status of hospitalized keloid cases from 2013 to 2018.

OBJECTS: Keloids are intractable scar diseases and sometimes undergo hospitalization. This study aims to represent current status of keloid management in a national sample of hospitalized scar cases. METHODS: Data of scar-diagnosed cases admitted in 1064 China's tertiary hospitals between 2013 and 2018, were obtained from the Hospital Quality Monitoring System (HQMS) database. Variables analyzed include sex, age, nationality, occupation, hospital department, accompanied symptoms at admission, surgical treatment, length of stay (LOS), and hospitalization cost. The potential risk factors of keloid diagnosis among scar cases were preliminarily identified through the Cochran-Mantel-Haenszel tests and univariate regression analyses. RESULTS: This study identified 177,586 scar cases including 21,777 keloid cases and 155,809 non-keloid scar cases. The prevalence of scars in the HQMS database was gradually decreased from 0.123% in 2013 to 0.075% in 2018. We found a preponderances of males (54.32%), adults (61.52%), Han nationality (93.38%), and students (17.35%) in scar cases, among whom keloid cases accounted for growing proportions increasing from 9.2% in 2013 to 15.1% in 2018. Comparing non-keloid scar cases, keloid cases consisted of more women (59.1% VS 43.8%), office staffs (13.08% VS 6.75%) and retirees (5.16% VS 2.65%), and less Zhuang (0.79% VS 1.40%) and Hui nationalities (0.76% VS 1.00%), and showed lower incidence of accompanied symptoms (4.51% VS 47.96%) and higher rate of receiving operations (57.96% VS 50.28%, P < 0.001). Both the LOS and cost per hospitalization were lower in keloid cases. Furthermore, the adult and older women, Han and Uyghur nationalities, office staffs and retirees, and admitted in otolaryngology and dermatology departments, were potential predictors of keloid diagnosis among hospitalized scar cases. CONCLUSION: When viewed at the national level, keloid occupies an important part in scar management in Chinese tertiary hospitals. Demographic and clinical differences between keloids and other scars facilitate understanding and promoting of individualized anti-scar therapeutic strategies.

Combination of ablative fractional carbon dioxide laser and platelet-rich plasma treatment to improve hypertrophic scars: a retrospective clinical observational study.

BACKGROUND: Hypertrophic scars are one of the main complications that affect the quality of life of patients after burns. Many methods have been shown to be effective in the treatment of hypertrophic scars, such as ablative fractional CO2 laser (AFCL) and platelet-rich plasma (PRP). However, there are few studies on the effect of the combined application of these measures. The purpose of this study was to explore the therapeutic effect of AFCL combined with PRP on hypertrophic burn scars. METHODS: A retrospective clinical observation study was conducted on 50 patients with hypertrophic burn scars. The AFCL+PRP group included 31 patients who received AFCL combined with PRP treatment; the AFCL group included 19 patients who received AFCL treatment only. The University of North Carolina 4P Scar Scale (UNC4P) and the Vancouver Scar Scale (VSS) scores that were collected before each treatment were used as indicators of the effectiveness of the previous treatment. The scores recorded at the second, fourth and seventh months were analysed. RESULTS: The demographic data of the 2 groups were not significantly different. Before treatment, there was no difference in the UNC4P and VSS scores between the 2 groups. There was a significant decline in the UNC4P and VSS total scores over 6 months in both groups (p < 0.05) and scores in the 2 groups were comparable after 3 and 6 months (p < 0.05). UNC4P scores in the AFCL+PRP group decreased from a mean of 8.26 to 2.61 (p < 0.05) with a concomitant drop in VSS scores from a mean of 11.74 to 6.06 (p < 0.01). In the AFCL group UNC4P and VSS scores decreased from 7.68 to 4.63 (p < 0.05) and from 10.89 to 8.16 (p < 0.05), respectively. The sub-items of these 2 assessments were analysed and the results suggest that AFCL combined with PRP can comprehensively improve scarring. CONCLUSIONS: This study shows that PRP is an effective adjunct for AFCL in the treatment of hypertrophic burn scars and that the combination of PRP and AFCL proved to be more useful than AFCL alone. This combination may be a new and effective clinical practice for the treatment of scars. However, larger and higher-level clinical studies are still needed to determine its efficacy and possible mechanisms.

Comorbidities of scars in China: a national study based on hospitalized cases.

BACKGROUND: Scar comorbidities seriously affect the physical and mental health of patients, but few studies have reported the exact epidemiological characteristics of scar comorbidities in China. This study aimed to investigate the prevalence of scar comorbidities in China. METHODS: The data of 177,586 scar cases between 2013 and 2018 were obtained from the Hospital Quality Monitoring System based on the 10th edition of the International Classification of Diseases coding system. The total distribution of scar comorbidities and their relationship with age, aetiology and body regions were analysed. RESULTS: Six comorbidities (contracture, malformation, ocular complications, adhesion, infection and others) were the main focus. In general, male patients outnumbered females and urban areas outnumbered rural areas. The proportion of contractures was the highest at 59,028 (33.24%). Students, workers and farmers made up the majority of the occupation. Han Chinese accounted for the majority of the ethnic. The highest proportion of scar contracture occurred at 1-1.9 years of age (58.97%), after which a significant downward trend was observed. However, starting from 50 years of age, ocular complications increased gradually and significantly, eventually reaching a peak of 34.49% in those aged >80 years. Scar contracture was the most common comorbidity according to aetiology, and the highest proportion was observed in patients who were scalded (29.33%). Contractures were also the most frequent comorbidity in hands (10.30%), lower limbs (6.97%), feet (6.80%) and upper limbs (6.02%). The mean and median hospitalization durations were 12.85 and 8 days, respectively. CONCLUSIONS: Contractures were the most common comorbidities, and different comorbidities tended to occur at different ages and with different causative factors.

Prevalence and predictors of scar contracture-associated re-hospitalisation among burn inpatients in China.

Scar contracture, a common destructive complication causing increased re-hospitalisation rate of burn survivors and aggravated burden on the medical system, may be more seriously in Chinese population because of their higher susceptibility to scar formation. This study aims to evaluate the prevalence and predictors of scar contracture-associated re-hospitalisation among Chinese burn inpatients. This cross-sectional study screened burn inpatients hospitalised during 2013 to 2018 through the Hospital Quality Monitoring System database, among whom re-hospitalised for scar contracture were identified. Variables including sex, age, occupations, burn area, burn site and surgical treatment were analysed. Potential predictors of scar contracture-associated re-hospitalisation among burn inpatients were determined by univariate regression analyses. Of the 220,642 burn inpatients, 2146 (0.97%) were re-hospitalised for scar contracture. The re-hospitalised inpatients were predominantly men and blue-collar workers, showing younger median age at the time of burns, larger burn sizes, and higher percentage of surgical treatment compared other burn inpatients. Significant univariate predictors of scar contracture-associated re-hospitalisation included male sex, age < 50 years, blue-collar work, ≥ 40% total body superficial area burned, inhalation injured, and surgical treatment. Scar contracture is an intractable complication and a significant factor to increase re-hospitalisation rate among Chinese burn inpatients.

A Cationic Metal-Organic Framework to Scavenge Cell-Free DNA for Severe Sepsis Management.

Circulating cell-free DNA (cfDNA) released by damaged cells causes inflammation and has been associated with the progression of sepsis. One proposed strategy to treat sepsis is to scavenge this inflammatory circulating cfDNA. Here, we develop a cfDNA-scavenging nanoparticle (NP) that consists of cationic polyethylenimine (PEI) of different molecular weight grafted to zeolitic imidazolate framework-8 (PEI-g-ZIF) in a simple one-pot process. PEI-g-ZIF NPs fabricated using PEI 1800 and PEI 25k but not PEI 600 suppressed cfDNA-induced TLR activation and subsequent nuclear factor kappa B pathway activity. PEI 1800-g-ZIF NPs showed greater inhibition of cfDNA-associated inflammation and multiple organ injury than naked PEI 1800 (lacking ZIF), and had greater therapeutic efficacy in treating sepsis. These results indicate that PEI-g-ZIF NPs acts as a "nanotrap" that improves upon naked PEI in scavenging circulating cfDNA, reducing inflammation, and reversing the progression of sepsis, thus providing a novel strategy for sepsis treatment.

Soluble cluster of differentiation 74 regulates lung inflammation through the nuclear factor-κB signaling pathway.

The soluble form of the migration inhibitory factor receptor cluster of differentiation 74 (sCD74) has previously been shown to be elevated during the development of acute lung injury (ALI) in mice. However, the biological role of increased sCD74 in ALI remans poorly understood. Synthesized recombinant sCD74 protein was administered to mice intratracheally. Pro-inflammatory genes in lung tissue and the inflammatory factors in bronchoalveolar lavage fluid (BALF) were analyzed using RT-PCR and ELISA, respectively. Additionally, RAW264.7, A549, and human umbilical vein endothelial cells (HUVEC) were treated with sCD74, and the resulting pro-inflammatory factor protein and gene expression levels were analyzed in the supernatants and cell lysates. Meanwhile, the level of nuclear factor (NF)-κB components in cell lysates after stimulating macrophages with sCD74 was also assessed. After administration of 0.5 mg/kg body weight sCD74 to mice, the expression of Tnfa, Mip2, and Il6 increased in lung tissues after 2 h by 2.1-, 3.4-, and 2.8-fold, respectively. Moreover, the BALF concentrations of TNF-α and MIP-2 reached maximal levels of 560 and 107 pg/mL at 8 h compared to those in the saline group, respectively. Similarly, TNFA, MIP2, and IL6 expression increased by 4.0-, 11.8-, and 2.6-fold, respectively, 2 h after stimulating macrophages with 1000 ng/mL sCD74. The levels of phospho-IκB and phospho-p65 were also significantly increased in the cytoplasm and nucleus of macrophages following sCD74 stimulation. Taken together, these results suggest that sCD74 is a critical cellular factor involved in the lung acute inflammatory response through nuclear factor-κB signaling.

ABT-263 Reduces Hypertrophic Scars by Targeting Apoptosis of Myofibroblasts.

Background: Inhibiting proliferation and inducing apoptosis of myofibroblasts is becoming one of the promising and effective ways to treat hypertrophic scar. ABT-263, as an orally bioavailable BCL-2 family inhibitor, has showed great antitumor characteristics by targeting tumor cell apoptosis. The objective of this study was to explore whether ABT-263 could target apoptosis of overactivated myofibroblasts in hypertrophic scar. Methods: In vivo, we used ABT-263 to treat scars in a rabbit ear scar model. Photographs and ultrasound examination were taken weekly, and scars were harvested on day 42 for further Masson trichrome staining. In vitro, the expression levels of BCL-2 family members, including prosurvival proteins, activators, and effectors, were detected systematically in hypertrophic scar tissues and adjacent normal skin tissues, as well as in human hypertrophic scar fibroblasts (HSFs) and human normal dermal fibroblasts (HFBs). The roles of ABT-263 in apoptosis and proliferation of HSFs and HFBs were determined by annexin V/PI assay, CCK-8 kit, and cell cycle analysis. Mitochondrial membrane potential was evaluated by JC-1 staining and the expression of type I/III collagen and α-SMA was measured by PCR, western blotting, and immunofluorescence staining. Furthermore, immunoprecipitation was performed to explore the potential mechanism. Results: In vivo, ABT-263 could significantly improve the scar appearance and collagen arrangement, decrease scar elevation index (SEI), and induce cell apoptosis. In vitro, the expression levels of BCL-2, BCL-XL, and BIM were significantly higher in scar tissues and HSFs than those in normal skin tissues and HFBs. ABT-263 selectively induced HSFs apoptosis by releasing BIM from binding with prosurvival proteins. Moreover, ABT-263 inhibited HSFs proliferation and reduced the expression of α-SMA and type I/III collagen in a concentration- and time- dependent manner. Conclusion: HSFs showed increased mitochondrial priming with higher level of proapoptotic activator BIM and were primed to death. ABT-263 showed great therapeutic ability in the treatment of hypertrophic scar by targeting HSFs.

Cuprous oxide nanoparticles reduces hypertrophic scarring by inducing fibroblast apoptosis.

BACKGROUND: Less apoptosis and excessive growth of fibroblasts contribute to the progression of hypertrophic scar formation. Cuprous oxide nanoparticles (CONPs) could have not only inhibited tumor by inducing apoptosis and inhibiting proliferation of tumor cells, but also promoted wound healing. The objective of this study was to further explore the therapeutic effects of CONPs on hypertrophic scar formation in vivo and in vitro. METHODS: In vivo, a rabbit ear scar model was established on New Zealand albino rabbits. Six full-thickness and circular wounds (10 mm diameter) were made to each ear. Following complete re-epithelization observed on postoperative day 14, an intralesional injection of CONPs or 5% glucose solution was conducted to the wounds. The photo and ultrasonography of each wound were taken every week and scars were harvested on day 35 for further histomorphometric analysis. In vitro, the role of CONPs in human hypertrophic scar fibroblasts (HSFs) apoptosis and proliferation were evaluated by Tunnel assay, Annexin V/PI staining, cell cycle analysis, and EdU proliferation assay. The endocytosis of CONPs by fibroblasts were detected through transmission electron microscopy (TEM) and the mitochondrial membrane potential and ROS production were also detected. RESULTS: In vivo, intralesional injections of CONPs could significantly improve the scar appearance and collagen arrangement, and decreased scar elevation index (SEI). In vitro, CONPs could prominently inhibit proliferation and induce apoptosis in HSFs in a concentration-dependent manner. In addition, CONPs could be endocytosed into mitochondria，damage the mitochondrial membrane potential and increase ROS production. CONCLUSION: CONPs possessed the therapeutic potential in the treatment of hypertrophic scar by inhibiting HSFs proliferation and inducing HSFs apoptosis.

Amniotic Epithelial Cells Accelerate Diabetic Wound Healing by Modulating Inflammation and Promoting Neovascularization.

Human amniotic epithelial cells (hAECs) are nontumorigenic, highly abundant, and low immunogenic and possess multipotent differentiation ability, which make them become ideal alternative stem cell source for regenerative medicine. Previous studies have demonstrated the therapeutic potential of hAECs in many tissue repairs. However, the therapeutic effect of hAECs on diabetic wound healing is still unknown. In this study, we injected hAECs intradermally around the full-thickness excisional skin wounds of db/db mice and found that hAECs significantly accelerated diabetic wound healing and granulation tissue formation. To explore the underlying mechanisms, we measured inflammation and neovascularization in diabetic wounds. hAECs could modulate macrophage phenotype toward M2 macrophage, promote switch from proinflammatory status to prohealing status of wounds, and increase capillary density in diabetic wounds. Furthermore, we found that the hAEC-conditioned medium promoted macrophage polarization toward M2 phenotype and facilitated migration, proliferation, and tube formation of endothelial cells through in vitro experiments. Taken together, we first reported that hAECs could promote diabetic wound healing, at least partially, through paracrine effects to regulate inflammation and promote neovascularization.