MiRs are important players in cancer and primarily genetic/transcriptional means of regulating their gene expression are known. However, epigenetic changes modify gene expression significantly. Here, we evaluated genome-wide methylation changes focusing on miR genes from primary CRC and corresponding normal tissues. Differentially methylated CpGs spanning CpG islands, open seas, and north and south shore regions were evaluated, with the largest number of changes observed within open seas and islands. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed several of these miRs to act in important cancer-related pathways, including phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. We found 18 miR genes to be significantly differentially methylated, with MIR124-2, MIR124-3, MIR129-2, MIR137, MIR34B, MIR34C, MIR548G, MIR762, and MIR9-3 hypermethylated and MIR1204, MIR17, MIR17HG, MIR18A, MIR19A, MIR19B1, MIR20A, MIR548F5, and MIR548I4 hypomethylated in CRC tumor compared with normal tissue, most of these miRs having been shown to regulate steps of metastasis. Generally, methylation changes were distributed evenly across all chromosomes with predominance for chromosomes 1/2 and protein-coding genes. Interestingly, chromosomes abundantly affected by methylation changes globally were rarely affected by methylation changes within miR genes. Our findings support additional mechanisms of methylation changes affecting (miR) genes that orchestrate CRC progression and metastasis.
Patellar fractures can lead to extensor mechanism dysfunction if not repaired properly, impacting knee function and mobility, and this complication can be challenging to manage, especially in cases where previous surgical interventions have failed. The aim of this study was to evaluate the functional outcome of the salvaged extensor mechanism in patella fracture non-union using Krakow sutures in a 61-year-old female patient who presented with knee pain, reduced flexion, and a 40-degree extension lag after two previous patellar fracture surgeries using tension band wiring resulted in non-union. Despite rehabilitation attempts, her knee function remained compromised. Krakow suturing was performed to reinforce the patellar and quadriceps tendons, ensuring a secure extensor mechanism. This procedure provided a strong and reliable repair, even in compromised tissue. Post-surgery, successful salvage of the extensor mechanism was achieved, with improved knee function and mobility, significant improvement in Lysholm scores and Tegner activity levels, and 80% restoration of quadriceps strength compared to the contralateral side. This case demonstrates that Krakow suturing can be an effective salvage procedure for extensor mechanism dysfunction in patellar non-union, even in previously operated cases, restoring knee function and mobility.
Epithelial to mesenchymal transition (EMT) is a central regulatory program that is similar in many aspects to several steps of embryonic morphogenesis. In addition to its physiological role in tissue repair and wound healing, EMT contributes to chemo resistance, metastatic dissemination and fibrosis, amongst others. Classically, the morphological change from epithelial to mesenchymal phenotype is characterized by the appearance or loss of a group of proteins which have come to be recognized as markers of the EMT process. As with all proteins, these molecules are controlled at the transcriptional and translational level by transcription factors and microRNAs, respectively. A group of developmental transcription factors form the backbone of the EMT cascade and a large body of evidence shows that microRNAs are heavily involved in the successful coordination of mesenchymal transformation and vice versa, either by suppressing the expression of different groups of transcription factors, or otherwise acting as their functional mediators in orchestrating EMT. This article dissects the contribution of microRNAs to EMT and analyzes the molecular basis for their roles in this cellular process. Here, we emphasize their interaction with core transcription factors like the zinc finger enhancer (E)-box binding homeobox (ZEB), Snail and Twist families as well as some pluripotency transcription factors.
Lipoma Arborescens is a rare, chronic, gradually progressive intra-articular lesion of benign nature. It is seen in most commonly in the knee but can also be seen in shoulder, elbow and wrist joints. It is characterized by villous proliferation of Synovium and replacement of Sub synovial tissue by mature adipocytes. We report a 20 years old male patient. We elaborate clinical features, role of investigations, differential diagnosis and treatment options available. Case report: We present you a 20 years old male patient diagnosed with lipoma arborescens of knee joint. The MRI report of right knee showed synovium which appeared markedly thickened and showed post-contrast enhancement with fat containing non-enhancing frond-like synovial masses outlined by concurrent joint effusion. These frond like masses were found predominantly in suprapatellar pouch. This patient underwent open synovectomy which showed multiple grey yellow papillary like excrescences seen arising from underlying flat piece of synovium. Approximately 80 cc of lobulated globules were removed and was sent to histopathological examination which confirmed synovial lipomatosis (Hoffa’s disease) associated with chronic lymphoplasmocytic synovitis. On 3 months follow up the patient had complete symptomatic relief.
Metastasis still poses the highest challenge for personalized therapy in cancer, partly due to a still incomplete understanding of its molecular evolution. We recently presented the most comprehensive whole-genome study of colorectal metastasis vs. matched primary tumors and suggested novel components of disease progression and metastasis evolution, some of them potentially relevant for targeted therapy. In this review, we try to put these findings into perspective with latest discoveries of colleagues and recent literature, and propose a systematic international team effort to collectively define the "metastasome", a term we introduce to summarize all genomic, epigenomic, transcriptomic, further -omic, molecular and functional characteristics rendering metastases different from primary tumors. Based on recent discoveries, we propose a revised metastasis model for colorectal cancer which is based on a common ancestor clone, early dissemination but flexible early or late stage clonal separation paralleling stromal interactions. Furthermore, we discuss hypotheses on site-specific metastasis, colorectal cancer progression, metastasis-targeted diagnosis and therapy, and metastasis prevention based on latest metastasome data.
Abstract Cancer is a complex disease and multi step process evolving from malfunctions of molecules and their complex networks which regulate this process. The blockage of the cancer signalling network is crucial in the cancer treatment. In some cases, single drug therapy might not be comprehensive enough to inhibit the activity of secondary signals, feedback regulations and resistance to particular molecules, due to their abundant expression or activity. An understanding of these complex phenomena in cancer therapy for the benefit of patients is essential, especially since it bears the chance to establish novel concepts of combination drug therapy. In the present study, we have tried to find a compound combination to overcome resistance towards Cetuximab, which blocks ligand binding to the epidermal growth factor receptor (EGFR), in non-small cell lung cancer (NSCLC). The anti-malarial drug Artesunate (ART) has been shown to have a profound cytotoxic action against cancer cell lines, and we recently showed its anti-metastatic action in NSCLC. Initial screening experiments in NSCLC cell lines showed that Cetuximab sensitivity is positively correlated with the E-cadherin expression, whereas ART sensitivity was negatively associated with EGFR expression. A549 (high E-cadherin and EGFR, sensitive to Cetuximab alone and not sensitive to ART alone) and H1299 (no E-cadherin and medium EGFR, resistant to Cetuximab alone and sensitive to ART alone) were chosen as model cell lines for this study. Cell proliferation and colony formation assays were performed either with Cetuximab/ART alone or with the combination of both. Interestingly, Cetuximab alone was not able to reduce cell proliferation and colony formation significantly in comparison to ART. In contrast to that combination of both of the drugs able to reduce these phenomena significantly even more than ART alone (p≤0.05). Combination isobologram analysis for ART and Cetuximab showed a significantly reduced proliferation rate in both the tested cell lines. In vivo, chorioallantoic membrane (CAM) metastasis assays revealed that combinatorial treatment of the cells with both drugs significantly reduced primary tumor growth of A549 (p=0.01) and H1299 (p=0.02) cells, in contrast to the treatment by Cetuximab alone. Our findings suggest that ART is resensitizing Cetuximab resistant NSCLC cells for treatment with this antibody. Currently, our study will be completed by experiments to identified major molecules and signalling cascades mediating compound interaction and re-sensitization. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-243. doi:1538-7445.AM2012-LB-243
Liposarcomas are the most common soft tissue sarcomas, and although histology is the backbone for the diagnosis of all subtypes, differential diagnosis, clinical prognosis, and differential treatment remain a big clinical challenge. Recently, FUS-CHOP was identified as causal to the disease, but in view of the several transcripts and structural rearrangements, its identification remains a challenge. More important however, is that while this fusion protein has been found to be instrumental for specific oncogenic processes in liposarcoma, its ability to induce metastasis and the underlying mechanisms by which this can be achieved remain unknown.
Oblique crown-root fracture in the cervical third of the root is a common event following trauma to the anterior region of the mouth. As a result, sound tooth structure coronal to the attachment apparatus may not be available for restorative needs. Invasion of biological width by fracture line presents a clinical challenge in restorative planning. Placing a restoration margin on sound tooth structure within the dentogingival biological width might result in violation of biological width and should be considered a restorative failure. Maintaining a healthy periodontal attachment apparatus is crucial for long term prognosis and esthetics of the restored tooth. Surgical crown lengthening, surgical extrusion or orthodontic extrusions are the few alternative modalities to expose the fracture line. This case presentation demonstrates a predictable solution in overcoming an oblique crown-root fracture caused by trauma during a road accident. Orthodontic extrusion was used to elevate the fractured tooth from within the alveolar socket to allow the placement of crown margins on sound tooth structure without harming the biologic width. Combining fiberotomy with the extrusion procedure in this case eliminated the need for the surgical procedure. This allowed proper fabrication of post and core and the placement of the crown on sound tooth structure, fulfilling the biological and mechanical principles including obligatory ferrule effect.
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