Mesenchymal Tissue Research Articles

A 5-year-old Girl with Asymmetric Giant Toes: A Case of Mixed Pattern Macrodystrophia Lipomatosa

Macrodystrophia lipomatosa (MDL) is a rare congenital nonhereditary anomaly, in which progressive overgrowth of mesenchymal tissue leads to disproportionate enlargement of the digits of the hands and feet. We discuss the case of a 5-year-old girl who presented with progressive disproportionate enlargement of the third and fourth toes of the right foot since birth. A diagnosis of MDL was made on the basis of clinical and radiological findings.

Low NT5DC2 expression predicts favorable prognosis and suppresses soft tissue sarcoma progression via ECM-receptor interaction pathway

BackgroundSoft tissue sarcoma, a malignant tumor arising from mesenchymal tissues with poor prognosis. 5′-Nucleotidase Domain Containing 2 (NT5DC2) is a novel oncogene, and the precise involvement of NT5DC2 in soft tissue sarcoma were still undefined. Hence, our study aims to investigate NT5DC2 functions in soft tissue sarcoma progression. MethodsThe tumor immune single-cell hub 2 (TISCH2) website, The Cancer Genome Atlas (TCGA) pan-cancer or sarcoma and Gene Expression Omnibus (GEO, GSE21122) databases were applied to visualize the NT5DC2 status in the sarcoma databases. The NT5DC2 protein expression in sarcoma tissues in our hospital was detected by using immunohistochemistry (IHC) and analyzed the associations between NT5DC2 expression and clinicopathological parameters. Real-time quantitative polymerase chain reaction (RT-qPCR), colony formation, 5-ethynyl-2′-deoxyuridine (EdU) assay, wound healing, transwell, flow cytometry and xenograft model were used to elucidate the effects of NT5DC2 downregulated by lentivirus in sarcoma cell. ResultsThe TISCH2 website detection found that NT5DC2 expression is enriched in malignant cells in sarcoma single-cell database. Furthermore, the TCGA-sarcoma database indicated that NT5DC2 expression correlates with metastasis, positive margin status, prognosis, and diagnostic value. Additionally, IHC staining showed that 40 % of soft tissue sarcoma patients present high expression of NT5DC2, and NT5DC2 upregulation is closely associated with poor prognosis. Functional verification analysis further revealed that downregulating NT5DC2 expression can suppress sarcoma progression through the ECM-receptor interaction pathway. ConclusionLow expression of NT5DC2 predicts a favorable prognosis in soft tissue sarcoma, and downregulated NT5DC2 expression can suppress sarcoma cell progression through the ECM-receptor interaction pathway.

Development of a Mouse Experimental System for the In Vivo Characterization of Bioengineered Adipose-Derived Stromal Cells.

Human adipose-derived stromal cells (ADSCs) are an important resource for cell-based therapies. However, the dynamics of ADSCs after transplantation and their mechanisms of action in recipients remain unclear. Herein, we generated genetically engineered mouse ADSCs to clarify their biodistribution and post-transplantation status and to analyze their role in recipient mesenchymal tissue modeling. Immortalized ADSCs (iADSCs) retained ADSC characteristics such as stromal marker gene expression and differentiation potential. iADSCs expressing a fluorescent reporter gene were seeded into biocompatible nonwoven fabric sheets and transplanted into the dorsal subcutaneous region of neonatal mice. Transplanted donor ADSCs were distributed as CD90-positive stromal cells on the sheets and survived 1 month after transplantation. Although accumulation of T lymphocytes or macrophages inside the sheet was not observed with or without donor cells, earlier migration and accumulation of recipient blood vascular endothelial cells (ECs) inside the sheet was observed in the presence of donor cells. Thus, our mouse model can help in studying the interplay between donor ADSCs and recipient cells over a 1-month period. This system may be of value for assessing and screening bioengineered ADSCs in vivo for optimal cell-based therapies.

A primary cutaneous carcinosarcoma of the retro auricular region, how to treat and literature review.

Carcinosarcomas are malignant biphasic tumours of epithelial and mesenchymal tissue. They are most often found in visceral organs, but also appear on the skin. Older age, male sex and chronic sun exposure are risk factors for its development. In this article we report a case and provide a review of literature regarding primary cutaneous carcinosarcoma (CCS) with special regard to its management. A manual electronic search of the PubMed Medline and Web of Science Core Collection databases was performed encompassing all included reports until 30th November 2022 to identify studies that reported primary CCS. CCS is a rare and aggressive tumour. Diagnosis requires histological examination and immunoreactivity of epithelial and mesenchymal components to specific markers. On its diagnosis, possibility of metastasis of a visceral carcinosarcoma should always be excluded. Surgical excision with clear margins, including the use of Mohs micrographic surgery (MMS), is the primary treatment for CCS. Reconstruction the excision defect should be performed. Regular follow-up for 5 to 10 years after initial treatment is advised. Awareness for CCS is necessary in the diagnostic evaluation of skin tumours. Further research is needed to better understand the underlying mechanisms of CCS and to establish optimal management strategies for this challenging malignancy. We recommend complete surgical excision using MMS as the treatment modality for this type of skin cancer. Dermatological follow-up for at least 5 years should be conducted to monitor for recurrence.

Abstract 1880: Ecubectedin and PM54 demonstrate antitumor activity in patient-derived xenograft models of soft tissue sarcoma

Abstract Objective: Soft tissue sarcoma (STS) is a heterogenous group of rare, malignant tumors arising from mesenchymal tissue. Doxorubicin (DOX)-based chemotherapy is the standard for advanced or metastatic STS, despite low response rates and poor disease control. We explored the antitumor activity of two novel compounds, ecubectedin (ECU; PM14) and PM54 (PharmaMar), in two patient-derived xenograft (PDX) models of STS, leiomyosarcoma (LMS) and CIC-rearranged sarcoma (CRS). Mode of action of ECU and PM54 is similar to lurbinectedin (LUR), inhibiting oncogenic transcription by eviction of oncogenic transcription factors from gene promotors’ recognition sequences, while inducing the generation of double strand breaks through DNA adduct formation. Methods: Female NMRI nu/nu mice (n=104) were transplanted bilaterally with STS PDX: UZLX-STS134 (CRS) and UZLX-STS22_2 (LMS). Xenografted mice were randomized to six treatment groups: 1) vehicle (VEH) (5% dextrose) 5 mL/kg once weekly (QW) intravenously (IV); 2) DOX 5 mg/kg QW IV; 3) trabectedin (TRA) 0.15 mg/kg QW IV; 4) LUR 0.18 mg/kg QW IV; 5) ECU 1.2 mg/kg QW IV; 6) PM54 1.2 mg/kg QW IV. Treatment lasted 16 days and antitumor activity was assessed by tumor volume (TV) analysis, histopathology and western blot. The Mann-Whitney U test was used to compare groups, the Wilcoxon test to compare to baseline. Results: ECU and PM54 caused TV shrinkage in UZLX-STS134, while TV in other groups grew significantly on day 16 (Table 1). VEH treatment led to the largest TV increase on day 16, compared to any treatment. PM54 treatment showed TV stabilization in UZLX-STS22_2, and significantly smaller tumors than VEH and TRA treated tumors (p<0.05 and p<0.01, respectively). Histopathological evaluation corroborate the results from the relative TV analysis. Conclusion: Novel drugs exhibit promising results in the PDX models tested, supporting ongoing exploration in additional PDX models of synovial sarcoma and dedifferentiated liposarcoma. Table 1: TV change on day 16 versus baseline, and comparison of proliferative and apoptotic activity Tumor volume change Proliferative activity (pHH3) Apoptotic activity (cPARP) Subtypes UZLX-STS134 UZLX-STS22_2 UZLX-STS134 UZLX-STS22_2 UZLX-STS134 UZLX-STS22_2 VEH(5 ML/kg) 387%*** 349%** n/a n/a n/a n/a DOX (5 mg/kg/QW IV) 177%*** 243%** ↓*** ↓ ↑** ↑ TRA(0.15 mg/kg/QW IV) 230%** 254%*** ↓** ↓** ↑** ↑*** LUR(0.18 mg/kg/QW IV) 202%** 232%** ↓*** ↓*** ↑*** ↑** ECU(1.2 mg/kg/QW IV) 41%*** 181%** ↓*** ↓*** ↑*** ↑*** PM54 (1.2 mg/kg/QW IV) 76%*** 162% ↓*** ↓*** ↑*** ↑ Citation Format: Daniël Gorgels, Agnieszka Wozniak, Chao-Chi Wang, Pablo M. Avilés, Maria J. Guillen, Carmen Cuevas, Patrick Schöffski. Ecubectedin and PM54 demonstrate antitumor activity in patient-derived xenograft models of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1880.

Abstract 3009: ATRX loss blocks the differentiation of mesenchymal stem cells and promotes undifferentiated sarcoma development

Abstract Soft tissue sarcomas (STSs) are a collection of rare tumor types originated from the mesenchymal tissues. Among the over 70 histological subtypes of STS, undifferentiated sarcoma (US), which lacks any discernible morphological features of differentiated tissues, accounts for over 20% of all STSs and is correlated with high tumor grade and poor prognosis. Recent genomic profiling in US has identified p53 and ATRX among the most frequently mutated or deleted genes. ATRX is a SWI/SNF2 type of chromatin remodeling factor which functions in a histone variant H3.3-specific chaperone complex to orchestrates replication-independent nucleosome assembly at repetitive heterochromatic DNA regions including telomeres. Loss-of-function mutations occur frequently in many tumor types and is associated with the development of alternative lengthening of telomere (ALT). However, how loss of ATRX function may contribute to tumorigenesis is largely unknown. Here, we demonstrated that ATRX is required for the terminal differentiation of mouse mesenchymal stem cells (MSCs) into multiple lineages, such as adipocytes and osteocytes. Targeted deletion of Atrx in mouse MSCs, but not terminally differentiated mesenchymal lineage cells, accelerated sarcoma initiation induced by loss of p53 and significantly shortened the overall survival. Atrx-deficient tumors express high level of MSC markers such as CD44 and CD29 and exhibit pathological features highly reminiscent of human high-grade US. Transcriptomic analysis indicates that Atrx deficiency is associated with enhanced proliferation. Together, our data indicates that ATRX deficiency contributes to undifferentiated sarcoma development by inhibiting mesenchymal stem cell differentiation. Citation Format: Yiming Cai, Jun Yao, Dean N. Pan, Yanqiang Jin, James M. You, Wantong Yao, Haoqiang Ying. ATRX loss blocks the differentiation of mesenchymal stem cells and promotes undifferentiated sarcoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3009.

Abstract 73: Spatial profiling of pediatric rhabdomyosarcoma to elucidate their immunosuppressive tumor microenvironment

Abstract Background: Pediatric rhabdomyosarcoma (RMS) is a mesenchymal soft tissue malignancy. Despite intensive chemotherapy regimens, there is currently a gap in improving treatment outcomes for RMS. Chemotherapy can modulate the tumor microenvironment (TME) by altering the immune cell composition or their functions. However, the impact of chemotherapy in pediatric RMS TME is unclear. RMS tumors are also considered as “cold” tumors due to low immune infiltration, which could be a determinant of why immunotherapy is unlikely to work. Additional investigations are required to determine the reasons of why RMS is “cold” and whether a combined immunotherapy and chemotherapy approach should be administered for this hard-to-cure cancer. Methods We conducted for the first time spatial GeoMx whole transcriptome atlas and 51-plex Akoya CODEX profiling for a tissue microarray (TMA) from a cohort of pediatric RMS patients (n = 12) with pre-chemotherapy (n = 5) and post-chemotherapy (n = 5) samples. Regions of interest (ROIs) were selected based on tumor areas with immune cell infiltration, with the lymphocytes, tumor cells, and nuclei visualized using fluorescent morphological markers CD45, Desmin, and DAPI. ROIs were segmented into tumor stroma compartments and immune cell compartments. Computational analyses were conducted on the transcriptomics data using R package standR including quality control, normalization, differential expression analysis, gene set enrichment analysis, and cell type deconvolution. For CODEX data, we preformed cell segmentation, followed by further quality control, cell phenotyping, cellular neighborhood and cellular interaction analysis. Results: From differential expression analysis of the immune compartment, we have identified type I interferon-related genes (DTX3L, ADAP2, RNF135) and reactive oxygen species (ROS)-induced gene (NCF1) are upregulated, and an antioxidant enzyme gene (PRDX2) is downregulated in post-chemotherapy samples compared to pre-chemotherapy samples. Gene set enrichment analysis of the immune compartment revealed an enriched antigen presentation pathway in post-chemotherapy samples. In the tumor stroma compartment, we identified increased TGF-β binding pathway in post-chemotherapy samples. Cellular deconvolution revealed a higher proportion of endothelial cells in post-chemotherapy samples, which is validated via CODEX imaging analysis. Cellular neighborhoods and cell-cell interaction analysis for CODEX data also reveal how chemotherapy affect functional units and cellular interactions in RMS TME with spatial context preserved. Conclusion: By applying spatial transcriptomic and multiplexed imaging to RMS samples, we have revealed key genes, pathways and cell types involved in chemotherapy-induced alterations in the TME. This will provide a new perspective for developing novel chemoimmunotherapy for RMS patients. Citation Format: Cui Tu, Chin Wee Tan, Ning Liu, Arutha Kulasinghe, Fernando Souza-Fonseca-Guimaraes. Spatial profiling of pediatric rhabdomyosarcoma to elucidate their immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 73.

Abstract 6456: The utility of clinical sequencing in the diagnosis and treatment of soft tissue sarcomas; Real world data based on nation-wide database

Abstract Purpose: Soft tissue sarcomas (STS) are rare and heterogeneous tumors arising from mesenchymal connective tissue, accounting for approximately 1%-2% of all malignancies. Due to their rarity and heterogeneity, it is challenging for accurate diagnosis, prognosis, and treatment of sarcoma. Recently, next-generation sequencing (NGS)-based comprehensive cancer genome profiling (CGP) has increasingly become a routine practice for patients with solid cancers worldwide. To collect genomic information and clinical characteristics of patients who underwent CGP, the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) has also been established since 2018 in Japan. Almost all the clinical and genomic data of patients who received CGP tests the had been collected in C-CAT. Here, we examined the utility of CGP test in the diagnosis and treatment of STS using this nation-wide database. Patients and Methods: We retrospectively evaluated the records of patients with STS who received F1CDx between 2019 and 2022 and registered in C-CAT. This assay carries 324 genes and determines nucleotide substitutions, insertions/deletions, and copy number (CN) alterations of 309 genes, fusions of 36 genes, tumor mutation burden (TMB) and microsatellite instability (MSI). High TMB (TMB-H) was defined as a TMB value >10 muts/Mb. Ranges of the MSI score were assigned MSI-High (MSI-H) or microsatellite stable (MSS). Results: From 2019 to 2022, 1387 patients with STS were registered in C-CAT. The histological types included leiomyosarcoma in 357 patients, dedifferentiated liposarcoma in 178 patients, and undifferentiated pleomorphic sarcoma in 82 patients, and the others. The most commonly altered genes included TP53, CDKN2A, Rb1, and CDKN2B. Among the 1387 cases, we observed 110 fusion events in 108 cases (7.7%), and 2 cases showed 2 types of fusion transcripts. Fifteen (2.8%) patients were re-classified based on the detection of highly histology-specific translocations. Among them, an initial diagnosis of sarcoma NOS was classified as Ewing Sarcoma (EWSR1-FLI1 in 2 patients), NTRK-rearranged spindle cell neoplasm (NTRK fusion in 3 patients), CIC-rearranged sarcoma (CIC-DUX4 in 3 patients), and sarcoma with BCOR genetic alterations (BCOR-ZC3H7B in 1 patient) as these gene fusions were identified. Druggable gene alterations was detected in 347 patients (25%) and 55 patients (4%) who received genotype-matched therapy. In 38 patients for whom the effect of treatment could be evaluated, complete response and partial response were achieved in 2 (5%) and 10 (26%) patients, respectively. Discussion: In conclusion, the comprehensive genomic profiling test appears to be an important tool in the diagnosis and treatment of sarcomas. Citation Format: Eiji Nakada, Tomohiro Fujiwara, Toshi Kunisada, Shota Takihira, Daisuke Ennishi, Hideki Yamamoto, Kiichiro Ninomiya, Shuta Tomida, Mashu Futagawa, Akira Hirasawa, Shinichi Toyooka, Toshifumi Ozaki. The utility of clinical sequencing in the diagnosis and treatment of soft tissue sarcomas; Real world data based on nation-wide database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6456.

Construction of an oxidative phosphorylation-related gene signature for predicting prognosis and identifying immune infiltration in osteosarcoma.

Osteosarcoma is a prevalent malignant tumor that originates from mesenchymal tissue. It typically affects children and adolescents. Although it is known that the growth of osteosarcoma relies on oxidative phosphorylation for energy production, limited attention has been paid to exploring the potential of oxidative phosphorylation-related genes in predicting the prognosis of individuals suffering from osteosarcoma. All the data were retrieved from the UCSC Xena and GEO (GENE EXPRESSION OMNIBUS). Identification of the oxidative phosphorylation genes linked to the prognosis of individuals with osteosarcoma was done by means of univariate COX and LASSO regression analyses. Following that, patients were categorized into a high-risk group and a low-risk group as per the risk score determined by the identified oxidative phosphorylation genes. Furthermore, a comparison was made in terms of the survival and immune infiltration between both groups, and the prognostic model was established. Five oxidative phosphorylation genes (ATP6V0D1, LHPP, COX6A2, MTHFD2, NDUFB9) associated with the prognosis of individuals with osteosarcoma were identified and the risk prognostic models were constructed. In the current research, the analysis of the ROC curves indicated a superior predictive accuracy exhibited by the risk model. The prognosis was adversely affected by immune infiltration in the high-risk group in comparison with the low-risk group. The function of the oxidative phosphorylation-related prognostic gene set was verified by GO and KEGG analysis. Furthermore, the link between oxidative phosphorylation-related genes and osteosarcoma immune infiltration was examined by GSEA analysis. In this study, a prognostic model that demonstrated good predictive performance was constructed. Additionally, this study highlighted a correlation between oxidative phosphorylation-related genes and immune infiltration.

Singular Value Decomposition-Driven Non-negative Matrix Factorization with Application to Identify the Association Patterns of Sarcoma Recurrence.

Sarcomas are malignant tumors from mesenchymal tissue and are characterized by their complexity and diversity. The high recurrence rate making it important to understand the mechanisms behind their recurrence and to develop personalized treatments and drugs. However, previous studies on the association patterns of multi-modal data on sarcoma recurrence have overlooked the fact that genes do not act independently, but rather function within signaling pathways. Therefore, this study collected 290 whole solid images, 869 gene and 1387 pathway data of over 260 sarcoma samples from UCSC and TCGA to identify the association patterns of gene-pathway-cell related to sarcoma recurrences. Meanwhile, considering that most multi-modal data fusion methods based on the joint non-negative matrix factorization (NMF) model led to poor experimental repeatability due to random initialization of factorization parameters, the study proposed the singular value decomposition (SVD)-driven joint NMF model by applying the SVD method to calculate initialized weight and coefficient matrices to achieve the reproducibility of the results. The results of the experimental comparison indicated that the SVD algorithm enhances the performance of the joint NMF algorithm. Furthermore, the representative module indicated a significant relationship between genes in pathways and image features. Multi-level analysis provided valuable insights into the connections between biological processes, cellular features, and sarcoma recurrence. In addition, potential biomarkers were uncovered, while various mechanisms of sarcoma recurrence were identified from an imaging genetic perspective. Overall, the SVD-NMF model affords a novel perspective on combining multi-omics data to explore the association related to sarcoma recurrence.

Obliteration of the Processus Vaginalis After Testicular Descent

The testis develops in the abdominal cavity and descends into the scrotum. Although numerous theories have been proposed, the mechanism of descent and the reason for its inhibition remain unknown. Furthermore, none of the explanations account for the other occurrences related to the descent, such as failed obliteration of the processus vaginalis, or the reasons for the decrease in fertility and increase in the risk of malignancy associated with an undescended testis. The gubernaculum is a primitive mesenchymal tissue that was first described in 1786. However, the role of the gubernaculum in the descent process remains obscure. The testis descends through the processus vaginalis. Although the processus vaginalis (PV) is usually defined as a simple peritoneal protrusion, it actively develops into the gubernaculum. The gubernaculum gives rise to the smooth muscles that surround the processus vaginalis. The striated cremaster muscle (CM) is also derived from the gubernaculum. Because the testis descends through the processus vaginalis, the muscles develop to propel the testis. After propelling the testis, the smooth muscle (SM) undergoes programmed cell death. The initiation of programmed cell death through the intrinsic pathway requires activation of phospholipase C. A transient shift in the autonomic balance via a decrease in the sympathetic tonus and an increase in the parasympathetic tonus is essential for initiating this programmed cell death. Programmed cell death in the SM is the physiological pathway for the obliteration of the processus vaginalis. Differences in the timing, intensity, or duration of this physiological pathway result in pathological conditions. A shift before testicular descent diminishes the SM content that is required to propel the testis, and thus inhibits descent. The early shift persists throughout childhood and results in the decrease in fertility and increase in the risk of malignancy because of the differences in signal transduction. Despite a successful descent, persistence of the shift alters the contractility of the CM by increasing the cytosolic calcium levels. Contracted CMs retracts or even ascends the testis. Inadequate intensity or duration of the shift of autonomic tonus causes failure of the programmed cell death. Persistence of the SM hinders the obliteration of PV and gives rise to hydroceles or inguinal hernias depending on the amount of residual smooth muscles. Similar findings from different countries support these explanations. Thus, our proposed mechanism satisfactorily explains the process of descent while considering all the factors related to the process of testicular descent.

The spatio-temporal expression analysis of parathyroid hormone like hormone gene provides a new insight for bone growth of the antler tip tissue in sika deer.

Parathyroid hormone like hormone (PTHLH), as an essential factor for bone growth, is involved in a variety of physiological processes. The aim of this study was to explore the role of PTHLH gene in the growth of antlers. The coding sequence (CDS) of PTHLH gene cDNA was obtained by cloning in sika deer (Cervus nippon), and the bioinformatics was analyzed. The quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the differences expression of PTHLH mRNA in different tissues of the antler tip at different growth periods (early period, EP; middle period, MP; late period, LP). The CDS of PTHLH gene was 534 bp in length and encoded 177 amino acids. Predictive analysis results revealed that the PTHLH protein was a hydrophilic protein without transmembrane structure, with its secondary structure consisting mainly of random coil. The PTHLH protein of sika deer had the identity of 98.31%, 96.82%, 96.05%, and 94.92% with Cervus canadensis, Bos mutus, Oryx dammah and Budorcas taxicolor, which were highly conserved among the artiodactyls. The qRT-PCR results showed that PTHLH mRNA had a unique spatio-temporal expression pattern in antlers. In the dermis, precartilage, and cartilage tissues, the expression of PTHLH mRNA was extremely significantly higher in MP than in EP, LP (p<0.01). In the mesenchyme tissue, the expression of PTHLH mRNA in MP was significantly higher than that of EP (p<0.05), but extremely significantly lower than that of LP (p<0.01). The expression of PTHLH mRNA in antler tip tissues at all growth periods had approximately the same trend, that is, from distal to basal, it was first downregulated from the dermis to the mesenchyme and then continuously up-regulated to the cartilage tissue. PTHLH gene may promote the rapid growth of antler mainly through its extensive regulatory effect on the antler tip tissue.

Growth capacity of a Wharton's Jelly derived mesenchymal stromal cells tissue engineered vascular graft used for main pulmonary artery reconstruction in piglets.

Background: Surgical treatment of congenital heart defects affecting the right ventricular outflow tract (RVOT) often requires complex reconstruction and multiple reoperations due to structural degeneration and lack of growth of currently available materials. Hence, alternative approaches for RVOT reconstruction, which meet the requirements of biocompatibility and long-term durability of an ideal scaffold, are needed. Through this full scale pre-clinical study, we demonstrated the growth capacity of a Wharton's Jelly derived mesenchymal stromal cells (WJ-MSC) tissue engineered vascular graft used in reconstructing the main pulmonary artery in piglets, providing proof of biocompatibility and efficacy. Methods: Sixteen four-week-old Landrace pigs were randomized to undergo supravalvar Main Pulmonary Artery (MPA) replacement with either unseeded or WJ-MSCs-seeded Small Intestinal Submucosa-derived grafts. Animals were followed up for 6months by clinical examinations and cardiac imaging. At termination, sections of MPAs were assessed by macroscopic inspection, histology and fluorescent immunohistochemistry. Results: Data collected at 6months follow up showed no sign of graft thrombosis or calcification. The explanted main pulmonary arteries demonstrated a significantly higher degree of cellular organization and elastin content in the WJ-MSCs seeded grafts compared to the acellular counterparts. Transthoracic echocardiography and cardiovascular magnetic resonance confirmed the superior growth and remodelling of the WJ-MSCs seeded conduit compared to the unseeded. Conclusion: Our findings indicate that the addition of WJ-MSCs to the acellular scaffold can upgrade the material, converting it into a biologically active tissue, with the potential to grow, repair and remodel the RVOT.

Unraveling the challenges in the diagnosis and management of desmoplastic fibroma of the mandible–a case report

Desmoplastic fibroma (DF) is an uncommon bone tumor that originates from the mesenchymal tissue and despite being benign, exhibits aggressive behavior locally. The following report describes the case of a 7-year-old boy with a rapidly enlarging swelling on the right side of the mandible. After a thorough clinical examination, radiographic imaging, and histopathological analysis, the diagnosis of DF was confirmed. Treatment planning was formulated considering both the tumor’s tendency for local recurrence and the patient’s well-being. Due to the patient’s young age, segmental resection was not deemed appropriate, and an aggressive curettage and enucleation of the lesion followed by the bone graft was performed instead. The patient was kept under close follow-up for the first month of post-surgery and later reviewed after 3, 6, 9, and 12 months, respectively. Good bone healing was observed on radiographs. The patient did not show any signs of recurrence based on clinical or radiographic assessments and did not exhibit any neurosensory deficits as well.

Garcinol prevents oxidative stress-induced bone loss and dysfunction of BMSCs through NRF2-antioxidant signaling

There are multiple published data showing that excessive oxidative stress contributes to bone loss and even bone tissue damage, and it is also correlated with the pathophysiology of bone degenerative diseases, including osteoporosis (OP). Garcinol, a polyisoprenylated benzophenone derivative, has been recently established as an anti-oxidant agent. However, it remains elusive whether Garcinol protects bone marrow mesenchymal stem cells (BMSCs) and bone tissue from oxidative stress-induced damage. Here, we explored the potential effects of Garcinol supplementation in ameliorating oxidative stimulation-induced dysfunction of BMSCs and bone loss in osteoporotic mice. In this study, we verified that Garcinol exerted potent protective functions in the hydrogen peroxide (H2O2)-induced excessive oxidative stress and dysfunction of BMSCs. Besides, Garcinol was also identified to improve the reduced bone mass and abnormal lineage commitment of BMSCs in the condition of OP by suppressing the oxidative stimulation. Subsequent analysis revealed that nuclear factor erythroid 2-related factor 2 (NRF2) might be a key regulator in the sheltering effects of Garcinol on the H2O2-regulated oxidative stress, and the protective functions of Garcinol was mediated by NRF2-antioxidant signaling. Collectively, Garcinol prevented oxidative stress-related BMSC damage and bone loss through the NRF2-antioxidant signaling, which suggested the promising therapeutic values of Garcinol in the treatment of oxidative stress-related bone loss. Therefore, Garcinol might contribute to treating OP.

A154 PRIMARY APPENDICEAL GASTROINTESTINAL STROMAL TUMOR (GIST) IN A PATIENT WITH DELAYED APPENDICITIS: CASE PRESENTATION AND LITERATURE REVIEW

Abstract Background Gastrointestinal stromal tumors (GISTs) are uncommon neoplasias, arising from mesenchymal tissue in the gastrointestinal tract. However, primary appendiceal GISTs (PA-GISTs) are rare, with less than 27 cases reported to date. Although treatable with neoadjuvant chemotherapy and subsequent resection, GISTs of the appendix can initially present with appendicitis-like symptoms, and are often treated as acute appendicitis (AA) due to initial misdiagnosis. A 75-year-old man presented to the emergency department of Brightshores Health System (BSHS) with right upper abdominal pain progressing to the right lower quadrant. He was referred to our surgical service, and his condition was treated as delayed appendicitis. Aims 1. To raise awareness of GIST as a distinct diagnostic possibility in patients presenting with acute appendicitis (AA)-like symptoms. 2. To assess whether delayed appendectomy has an impact in the overall disease outcome for PA-GIST. Methods A rare case of PA-GIST was found after a retrospective review of all appendectomies performed at BSHS for appendicitis with or without neoplasia in the last 11 years. To our surprise, we uncovered a rare case PA-GIST. Comprehensive chart review was performed. Results A 75-year-old man presenting with a 5-day history of right upper and lower abdominal pain was clinically diagnosed with AA. CT abdomen and ultrasound showed probable appendicitis with phlegmon, distal tip inflammation, no abcess and mild left hydronephrosis. After initial antibiotics and colonoscopy, the patient underwent interval appendectomy. Pathology revealed no AA, a low-grade GIST with focal interstitial cell of Cajal hyperplasia of the distal appendix and positive margin. Six weeks later, cecectomy showed no clinicopathologic evidence of residual PA-GIST. Literature review revealed 27 other PA-GIST tumors to date. Twenty three were found incidentally through imaging, colonoscopy, or surgery. Four cases involved patients presenting with AA symptoms. Our patient was among those presenting with AA symptoms, but with no histological evidence of appendicitis in the delayed appendectomy specimen. Consistent with 25/27 cases, our patient’s GIST displayed spindle morphology, ampersand:003C5cm in size, and without atypia, mitosis, or necrosis. Conclusions PA-GISTs tumors are rare, with only 28 cases reported to date, including ours. Some PA-GIST tumors are found incidentally in patients that present with symptoms of AA. Although there is no concensus opinion for optimal treatment of PA-GIST, delayed appendectomy followed by cecectomy have proven to be an acceptable treatment for our patient with no evidence of recurrent or metastatic disease after 6.5 years on follow up by clinical and endoscopic surveilance. Funding Agencies None

Intracranial solitary fibrous tumor in a 15-year-old girl: illustrative case.

Solitary fibrous tumor (SFT) is an infrequent spindle cell tumor derived from mesenchymal tissue, which can manifest in diverse anatomical locations, primarily in the pleural cavity and infrequently in the central nervous system. SFT is predominantly observed in individuals aged between 40 and 50 years old, with a slightly higher occurrence in males than in females. This case report describes a female, age 15, who had migraines for 2 months prior to the diagnosis of an intracranial tumor. Computed tomography and magnetic resonance imaging showed a mass located in the right parietooccipital region with surrounding edema and a compressed right lateral ventricle. Neurosurgery was utilized to successfully remove the mass, and single intracranial fibrous tumor (grade I) was identified by postoperative pathological analysis. During an 8-month follow-up period, the patient did not experience any recurrences. SFT is often misdiagnosed as meningioma because of their similar imaging characteristics. However, identifying the distinctive features of SFT on magnetic resonance imaging can distinguish it from meningioma and help to select appropriate treatment. The complete preoperative imaging data for this case indicated a highly vascularized tumor. Preoperative vascular embolization treatment reduced any difficulties during the subsequent tumor resection and minimized intraoperative bleeding.

The Role of Neutrophil Extracellular Traps in the Outcome of Malignant Epitheliomas: Significance of CA215 Involvement

Neutrophil extracellular traps (NETs) were originally discovered as a part of the innate immune response of the host to bacteria. They form a web-like structure that can immobilize microorganisms or exhibit direct antimicrobial properties, such as releasing reactive oxygen species (ROS). NETs are established when neutrophils undergo a sort of cellular death following exposure to ROS, chemokines, cytokines, or other soluble factors. This process results in the release of the neutrophil’s DNA in a web-like form, which is decorated with citrullinated histones (H3/H4-cit), neutrophil elastase (NE), and myeloperoxidase (MPO). Emerging studies have put into perspective that NETs play an important role in oncology as they were shown to influence tumor growth, malignant initiation, and proliferation, mediate the transition from endothelial to mesenchymal tissue, stimulate angiogenesis or metastasis, and can even help cancer cells evade the immune response. The role of NETs in cancer therapy resides in their ability to form and act as a mechanical barrier that will provide the primary tumor with a reduced response to irradiation or pharmaceutical penetration. Subsequently, cancer cells are shown to internalize NETs and use them as a strong antioxidant when pharmaceutical treatment is administered. In this review, we explored the role of NETs as part of the tumor microenvironment (TME), in the context of malignant epitheliomas, which are capable of an autonomous production of CA215, a subvariant of IgG, and part of the carcinoembryonic antigen (CEA) superfamily. Studies have shown that CA215 has a functional Fc subdivision able to activate the Fc-gamma-RS receptor on the surface of neutrophils. This activation may afterward stimulate the production of NETs, thus indicating CA215 as a potential factor in cancer therapy surveillance.

Peran igf-1 dan let-7 dalam morfogenesis gigi ditinjau dari sel punca mesenkimal pulpa gigi

Tooth development is a complex process involving the interaction between dental epithelium and mesenchymal tissues. IGF-1 plays a crucial role in regulating cell proliferation, differentiation, apoptosis, and migration. Its significance is particularly notable during the proliferation and differentiation stages of root development, as well as in the stem cells derived from the apical papilla responsible for root pulp and dentin formation. IGF-1 exhibits osteoconductive potential in bone healing by modulating osteoclasts in bone resorption and osteoblasts in bone formation. Stem cells from dental pulp or apical papilla represent a mesenchymal stem cell or progenitor population that forms calcium nodules in osteo/odontogenic media. This study aims to elucidate the roles of IGF-1 and Let-7 in tooth morphogenesis, utilizing the PRISMA guidelines for data collection. A total of 12 literature sources were identified, with 3 articles published in the last 5 years. Only 5 articles were selected for inclusion in this study. Further exploration of IGF-1/IGF-1R/hsa-let-7c modulation in odonto/osteogenic differentiation holds promise for future tooth regeneration. IGF-1 enhances the size of tooth bud cultures, suggesting potential applications in genetic engineering for tooth morphogenesis. IGF-1 plays a crucial role in odontogenic proliferation and differentiation.

Emerging Roles of Macrophage Polarization in Osteoarthritis: Mechanisms and Therapeutic Strategies.

Osteoarthritis (OA) is the most common chronic degenerative joint disease in middle-aged and elderly people, characterized by joint pain and dysfunction. Macrophages are key players in OA pathology, and their activation state has been studied extensively. Various studies have suggested that macrophages might respond to stimuli in their microenvironment by changing their phenotypes to pro-inflammatory or anti-inflammatory phenotypes, which is called macrophage polarization. Macrophages accumulate and become polarized (M1 or M2) in many tissues, such as synovium, adipose tissue, bone marrow, and bone mesenchymal tissues in joints, while resident macrophages as well as other stromal cells, including fibroblasts, chondrocytes, and osteoblasts, form the joint and function as an integrated unit. In this study, we focus exclusively on synovial macrophages, adipose tissue macrophages, and osteoclasts, to investigate their roles in the development of OA. We review recent key findings related to macrophage polarization and OA, including pathogenesis, molecular pathways, and therapeutics. We summarize several signaling pathways in macrophage reprogramming related to OA, including NF-κB, MAPK, TGF-β, JAK/STAT, PI3K/Akt/mTOR, and NLRP3. Of note, despite the increasing availability of treatments for osteoarthritis, like intra-articular injections, surgery, and cellular therapy, the demand for more effective clinical therapies has remained steady. Therefore, we also describe the current prospective therapeutic methods that deem macrophage polarization to be a therapeutic target, including physical stimulus, chemical compounds, and biological molecules, to enhance cartilage repair and alleviate the progression of OA.