The early treatment and rapid closure of acute or chronic wounds is essential for normal healing and prevention of hypertrophic scarring. The use of split thickness autografts is often limited by the ...availability of a suitable area of healthy donor skin to harvest. Cellular and non-cellular biological skin-equivalents are commonly used as an alternative treatment option for these patients, however these treatments usually involve multiple surgical procedures and associated with high costs of production and repeated wound treatment. Here we describe a novel design and a proof-of-concept validation of a mobile skin bioprinting system that provides rapid on-site management of extensive wounds. Integrated imaging technology facilitated the precise delivery of either autologous or allogeneic dermal fibroblasts and epidermal keratinocytes directly into an injured area, replicating the layered skin structure. Excisional wounds bioprinted with layered autologous dermal fibroblasts and epidermal keratinocytes in a hydrogel carrier showed rapid wound closure, reduced contraction and accelerated re-epithelialization. These regenerated tissues had a dermal structure and composition similar to healthy skin, with extensive collagen deposition arranged in large, organized fibers, extensive mature vascular formation and proliferating keratinocytes.
Background: Mechanism of brain metastasis of breast cancer is poorly understood.
Results: Inflammatory factors secreted from cancer cells degrade tight junction of BBB and stimulate the ...tumor-microenvironment cross-talk.
Conclusion: COX2-prostaglandins-MMP1 pathway promotes brain metastasis by tampering with BBB and up-regulating CCL7 in astrocytes for the growth of tumor initiating cells.
Significance: The COX2-prostaglandins-MMP1 pathway may serve as a novel therapeutic target for brain metastasis.
Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of the critical rate-limiting steps of brain metastasis is the breaching of blood-brain barrier, which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only matrix metalloproteinase 1 (MMP1) is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1, which are key components of blood-brain barrier. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, whereas ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2-induced prostaglandins were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release chemokine (C-C motif) ligand 7 (CCL7), which in turn promoted self-renewal of tumor-initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis.
Ovarian cancer (OvCa) exhibits a specific predilection for metastasis to the omentum. Our earlier studies highlighted the tumour-suppressor effect of secreted protein acidic and rich in cysteine ...(SPARC) in OvCa through multi-faceted roles inhibiting cancer cell interactions within the peritoneal milieu. The goal of this study is to investigate the role of SPARC in OvCa interactions with omental adipocytes and its role in OvCa colonization in the omentum. We employed multi-pronged approach using primary omental adipocytes from Sparc knockout mice, genetically engineered human omental adipocytes in 3D co-cultures with OvCa cells, as well as treatment with recombinant SPARC protein. We show that SPARC suppresses multistep cascade in OvCa omental metastasis. SPARC inhibited in vivo and adipocyte-induced homing, proliferation, and invasion of OvCa cells. SPARC suppressed metabolic programming of both adipocytes and OvCa cells and exerted an inhibitory effect of adipocyte differentiation and their phenotypic switch to cancer-associated phenotype. Mechanistic studies revealed that this effect is mediated through inhibition of cEBPβ-NFkB-AP-1 transcription machinery. These findings define a novel and functionally important role of SPARC in OvCa and not only bridge the knowledge gap but highlight the need to consider SPARC protein expression in therapeutic development.
The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of ...human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials.
Human papillomavirus (HPV)-positive oropharyngeal carcinoma is a distinct type of head and neck carcinoma with improved prognosis. p16 immunostaining is often used as a surrogate marker for HPV ...infection in this particular setting. The aim of this study is to estimate the prevalence of p16 staining and HPV infection in head and neck sarcomatoid carcinomas as well as head and neck sarcomas. 21 sarcomatoid carcinomas and 28 head and neck sarcomas were tested for p16 positivity using immunohistochemical staining, and for high-risk HPV infection using In situ hybridization (ISH). 24 % of sarcomatoid carcinomas and 21 % of sarcomas were positive for p16 staining. All 49 cases were negative for HPV ISH. The results confirm that p16 staining is not specific and may not be associated with HPV infection in non-oropharyngeal head and neck sites. They also indicate that non-oropharyngeal head and neck sarcomatoid carcinomas are not likely to be HPV related.
•Strong p16 expression can be seen in head and neck mesenchymal tumors.•HPV infection is not common in head and neck mesenchymal tumors.•p16 stain should not be used as a confirmatory tool for HPV infection in head and neck mesenchymal tumors.•HPV infection is not common in non-oropharyngeal spindle cell carcinomas.
Background Appendiceal cancer (AC) patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) often demonstrate an unpredictable variability in their ...survival outcomes. Biomarkers predictive of CRS/HIPEC efficacy could better guide treatment decisions. We hypothesized that variation in the transcriptional programming of AC tumors might distinguish molecular subtypes with differential outcomes after CRS/HIPEC. Study Design Gene expression profiles of 2 AC cohorts were analyzed using Affymetrix whole-genome expression microarrays. Hierarchical clustering methods, Kaplan-Meier analysis, and Cox regression models were used to discover and validate prognostic molecular subtypes of AC. Gene set enrichment analysis was used to infer pathologic attributes of the molecular subtypes. Results Unsupervised hierarchical clustering analysis of tumor expression profiles revealed a 139-gene cassette that distinguished 2 molecular subtypes (based on low vs high expression of the gene cassette) with statistically significant survival differences (disease-specific survival, p = 0.0075; progression-free survival, p = 0.0072). In a second AC cohort, the 139-gene cassette reproducibly partitioned tumors into subtypes with significant survival differences. Tumors showing high relative expression of the genes comprising the cassette associated with poor survival outcomes (disease-specific survival, p = 0.047; progression-free survival, p = 0.0079), and exhibited gene expression patterns enriched for oncogenic processes and pathways. The prognostic value of the molecular subtypes was specific for low-grade appendiceal tumors (disease-specific survival, p = 0.028; progression-free survival, p = 0.0016), and remained significant in the presence of conventional prognostic markers, including grade, surgical resection score, Eastern Cooperative Oncology Group status, and age. Conclusions The 139-gene cassette can have actionable clinical utility for identifying low-grade appendiceal tumor molecular subtypes predictive of therapeutic efficacy of CRS/HIPEC.
Xantho-granulomatous mastitis (XGM) is a rare entity, only recently described in 2005. These lesions are often biopsied due to their clinical and radiological resemblance to breast cancer. With ...limited clinical experience, the etiopathogenesis and natural history of XGM remains unknown. We present two cases of pathologically proven XGM that were imaged at two time-points, with the findings alluding to the possibility of a precursor stage of cyst formation. In addition, we present a thorough review of all cases published to date and discuss the differential considerations and management implications of XGM.
•Xanthogranulomatous Mastitis (XGM) is a condition that can mimic breast cancer with 24 cases published to date.•A malignant predilection is evident in the current literature that requires further pooled studies.•Current hypothesis of granulomatous reaction to ruptured ectatic ducts could explain our findings of cystic precursor stage.•Young parous female with an incidentally detected solid mass within the peripheral breast is a typical clinical scenario.•Significant clinico-radiological overlap exists between XGM and other granulomatous mastitis, only clarified at pathology.
Cartilage-forming tumors Qasem, Shadi A., MD; DeYoung, Barry R., MD
Seminars in diagnostic pathology,
2014, January 2014, 2014-Jan, 2014-01-00, 20140101, Volume:
31, Issue:
1
Journal Article
Peer reviewed
Abstract Cartilage-forming tumors as a group are the most common primary bone tumors; this is largely due to the common occurrence of asymptomatic benign lesions such as osteochondroma and ...enchondroma. The common feature of these tumors is the presence of chondrocytic cells and the formation of cartilaginous tumor matrix. Some of these tumors are true neoplasms while others are hamartomas or developmental abnormalities. The morphologic heterogeneity of these tumors may be explained by a common multipotent mesenchymal cell differentiating along the lines of fetal–adult cartilage maturation. Recently mutations in IDH1 and IDH2 have been detected in a variety of benign and malignant cartilaginous tumors.1–4
Soft tissue tumors (STTs) pose diagnostic and therapeutic challenges due to their rarity, complexity, and morphological overlap. Accurate differentiation between benign and malignant STTs is ...important to set treatment directions, however, this task can be difficult. The integration of machine learning and artificial intelligence (AI) models can potentially be helpful in classifying these tumors. The aim of this study was to investigate AI and machine learning tools in the classification of STT into benign and malignant categories. This study consisted of three components: (1) Evaluation of whole-slide images (WSIs) to classify STT into benign and malignant entities. Five specialized soft tissue pathologists from different medical centers independently reviewed 100 WSIs, representing 100 different cases, with limited clinical information and no additional workup. The results showed an overall concordance rate of 70.4% compared to the reference diagnosis. (2) Identification of cell-specific parameters that can distinguish benign and malignant STT. Using an image analysis software (QuPath) and a cohort of 95 cases, several cell-specific parameters were found to be statistically significant, most notably cell count, nucleus/cell area ratio, nucleus hematoxylin density mean, and cell max caliper. (3) Evaluation of machine learning library (Scikit-learn) in differentiating benign and malignant STTs. A total of 195 STT cases (156 cases in the training group and 39 cases in the validation group) achieved approximately 70% sensitivity and specificity, and an AUC of 0.68. Our limited study suggests that the use of WSI and AI in soft tissue pathology has the potential to enhance diagnostic accuracy and identify parameters that can differentiate between benign and malignant STTs. We envision the integration of AI as a supportive tool to augment the pathologists' diagnostic capabilities.
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