Pattern of expression of CCN family members Cyr61, CTGF and NOV in human acute and chronic wounds

The CCN family is a group of extremely cysteine-rich proteins that are found within the extracellular matrix and are comprised of cysteine-rich 61 (Cyr61/CCN1), connective tissue growth factor (CTGF/CCN 2) and nephroblastoma overexpressed (NOV/CCN3). Collectively, these proteins stimulate mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration, and regulate angiogenesis, tumour growth, placentation, implantation, embryogenesis and endochondral ossification. Despite such diverse activity, CCN protein function has not been explored in human wounds and healing. In the present study, we investigated the expression of these proteins in samples of normal, acute and chronic wounds using immunohistochemical staining and real-time quantitative RT-PCR. Statistical analysis was performed using the Fisher's exact test. Our results showed that, although all CCN proteins were present in normal, acute and chronic wounds, their expression levels differed, particularly in the case of connective tissue growth factor (CTGF), for which significantly reduced levels were found in chronic wounds compared to acute wounds (p<0.002). Thus, the lack of CTGF in wound tissues may contribute to the abnormal healing of clinical wounds. This suggests that CCN proteins may play an important role in human tissue wound healing. This further suggests that human wound healing may be promoted by manipulating the levels of this protein

CCN family proteins in wound healing - a pivotal role? [Abstract]

Introduction: CCN family proteins comprised of cysteine-rich 61(Cyr61/ CCN1), connective tissue growth factor (CTGF/CCN2) and nephroblastoma - overexpressed (NOV/CCN3) found in the extracellular matrix. They stimulate mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration and regulate angiogenesis. Clinically they have been shown to have a role in embryogenesis, osteochondral ossification and tumour growth, however their function has not been explored in human wound healing. Methods: Samples of normal, acute and chronic wounds were collected. Immunohistochemical staining and real time quanitative RT-PCR was performed. GAPDH was used as the house keeping control. Statistical analysis was performed using the Fisher’s exact test. Results: Immunohistochemical staining Tissue Cyr61 CTGF Nov Normal skin present-strong present-weak present-weak Acute wound unchanged decreased unchanged Chronic wound increased decreased unchanged Real time quanitative RT-PCR &Cyr61 increased in chronic wounds as compared to acute (ns). &NOV decreased in chronic wounds as compared to acute wounds (ns). & CTGF decreased in chronic wounds: CTGF/GAPDH ratio 0.017(0.0004- 0.0457); median(IQR) as compared to acute wounds 0.16 (0.00–5.42) (statistically significant; po0.002). Conclusion: CCN family members have a differential pattern of expression in normal skin and in wound tissues and therefore manipulation of these proteins may play a pivotal role in wound healing

Biofunctional Hyaluronic Acid/&kappa;-Carrageenan Injectable Hydrogels for Improved Drug Delivery and Wound Healing

The in situ injectable hydrogel system offers a widespread range of biomedical applications in prompt chronic wound treatment and management, as it provides self-healing, maintains a moist wound microenvironment, and offers good antibacterial properties. This study aimed to develop and evaluate biopolymer-based thermoreversible injectable hydrogels for effective wound-healing applications and the controlled drug delivery of meropenem. The injectable hydrogel was developed using the solvent casting method and evaluated for structural changes using proton nuclear magnetic resonance, Fourier transforms infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy. The results indicated the self-assembly of hyaluronic acid and kappa-carrageenan and the thermal stability of the fabricated injectable hydrogel with tunable gelation properties. The viscosity assessment indicated the in-situ gelling ability and injectability of the hydrogels at various temperatures. The fabricated hydrogel was loaded with meropenem, and the drug release from the hydrogel in phosphate buffer saline (PBS) with a pH of 7.4 was 96.12%, and the simulated wound fluid with a pH of 6.8 was observed to be at 94.73% at 24 h, which corresponds to the sustained delivery of meropenem. Antibacterial studies on P. aeruginosa, S. aureus, and E. coli with meropenem-laden hydrogel showed higher zones of inhibition. The in vivo studies in Sprague Dawley (SD) rats presented accelerated healing with the drug-loaded injectable hydrogel, while 90% wound closure with the unloaded injectable hydrogel, 70% in the positive control group (SC drug), and 60% in the negative control group was observed (normal saline) after fourteen days. In vivo wound closure analysis confirmed that the developed polymeric hydrogel has synergistic wound-healing potential

Sex-Based Differences in Clinical Outcomes of Acute Coronary Syndrome Among Patients With Mediastinal Radiation Exposure: Insights From The National Inpatient Sample (2009-2020)

There is a paucity of data about the sex differences in acute coronary syndrome (ACS) outcomes in patients with prior mediastinal radiation. The National Inpatient Sample database from years 2009 to 2020 were queried for ACS hospitalizations of patients with prior mediastinal radiation. The primary outcome was MACCE (major cardiovascular events), and secondary outcomes included other clinical outcomes. A total of 23,385 hospitalizations for ACS with prior mediastinal radiation exposure ([15,904 (68.01%) females, and 7481 (31.99%) males]) were included in analysis. Males were slightly younger than females (median, age (70 [62-78] vs 72 [64-80]). Female patients with ACS had a higher burden of hypertension (80.82% vs 73.55%), diabetes mellitus (33% vs 28.35%), hyperlipidemia (66.09% vs 62.2%), obesity (17.02% vs 8.6%) however, males had a higher burden of peripheral vascular disease (18.29% vs 12.51%), congestive heart failure (41.8% vs 39.35%) and smoking (70.33% vs 46.92%). After propensity matching, primary outcome MACCE was higher in males (20.85% vs 13.29%, aOR: 1.80 95% CI (1.65-1.96), P \u3c 0.0001) along with cardiogenic shock (8.74% vs 2.42%, aOR: 1.77 95% CI (1.55-2.02), P \u3c 0.0001) and mechanical circulatory support use (aOR: 1.48 95% CI [1.29 -1.71], P \u3c 0.0001). We observed no differences in the length of hospital stay, however total hospitalization cost was higher in males. This nationwide analysis showed significant disparities in outcomes among male and female ACS patients with prior mediastinal radiation history, with increasing trend in hospitalization for ACS among males and females but decreasing mortality among females

Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study

Background: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. Methods: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. Findings: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. Interpretation: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. Funding: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center