The authors present their experience with a posterior approach for fixation of posterior Cruciate ligament avulsion from the tibia. Avulsion usually occurs at the tibial insertion. The approach is easy, safe and demands no great technical prowess or instruments. Some minor modifications and technical tips for a safer exposure and a better fixation are highlighted. This is a reproducible method for achieving good stability in these avulsion fractures, where early intervention prevents significant late disability. A single 4-mm screw gives sufficient initial stabilization to allow supervised mobilization. A high index of suspicion should be maintained in all dashboard injuries presenting with femoral shaft fractures, especially when the patella is also fractured. The patients were objectively (posterior drawer test) and subjectively (Lysholm scale) reevaluated after a minimum follow up period of 12 post operative months.
Femoral and tibial fractures are common long-bone injuries in children. Above five years of age all such fractures, when treated conservatively could lead to loss of reduction, malunion, intolerance and complications associated with plaster. The goals are to stabilize the fracture, to control length and alignment. Flexible Elastic Nailing has become the choice of stabilization in paediatric long bone fractures. The aim of our study was to see the outcome of Flexible elastic nailing system in diaphyseal fractures of children of 5-14 years age. The study included total of 50 children treated with flexible elastic nailing system and they were followed up at 3, 6, 12 and 24 weeks. The average duration of callus formation was 3.8weeks (4.2weeks in Tibia & 3.4 weeks in femur). Radiological union was seen in a mean time of 9.65 weeks. Full weight bearing was possible in a mean time of 10 weeks. According to flynn’s scoring criteria, excellent and satisfactory results were in 90% and 10% respectively. There were 2 cases of post-operative superficial infection which resolved with regular dressing and no cases of physeal injury and implant failure. Flexible elastic nail is a safe and satisfactory mode of treatment and is relatively easy to perform in disphyseal fracture of femur and tibia in children. It avoids the chances of physeal injury, infection and offers early mobilisation and rapid healing.
Abstract Growth factor receptor signalling plays a central and critical role in colorectal cancer. Most importantly, the EGFR signalling cascade involving PI3K/AKT/mTOR and Raf/MEK/ERK pathways are particularly relevant, since they are commonly activated in several cancer entities, including colorectal cancer. In this study, we show that miRs-134 and -370 are both capable of regulating these pathways by targeting EGFR and PIK3CA. In three different colorectal cancer cell lines (DLD1, HCT-116 and RKO), suppression of EGFR and PIK3CA through the enhanced expression of miR-134 or -370 led to a suppression of the key molecules of the PI3K/AKT/mTOR pathway. Furthermore, overexpression of miR-134 or -370 resulted in a significant reduction of cell proliferation, colony formation, migration, invasion and in-vivo tumor growth and metastasis. Concurrent experiments with small interfering RNAs targeting the prime targets show that our selected miRNAs exert a greater functional influence and affect more downstream molecules than is seen with silencing of the individual proteins. Taken together, these data indicate that miRs-134 and -370 are potential tumour suppressor miRNAs and could play a fundamental role in suppressing colorectal cancer tumorigenesis through their ability to co-ordinately regulate EGFR signalling cascade by independently targeting EGFR and PIK3CA.
Talus with its unique anatomy and function predisposes it to un4common but serious injuries, usually due to high energy trauma. obtaining satisfactory clinical results, while avoiding complications, presents a unique challenge in the treatment of talar fractures, especially of talar neck as it also remains controversial the requirement of emergency treatment in these fractures. Despite of all excellent management, nonunion rate in type 3 and type 4 Hawkins fracture was found to be 5% and AVN of body of talus was found to be 25% types 2,3,4 were associated with talar body dislocation which caused excessive pressure on soft tissues causing significant soft tissue complications. We retrospectively reviewed 25 patients with talar ractures treated operatively with an average follow up period of 1 year. Displaced talar fractures was a therapeutic challenge which had early and late complication
Abstract Alterations in miRNA expression have been implicated in the pathogenesis of colorectal cancer (CRC). Importantly, the p53 tumor suppressor is not only one of the most commonly altered genes in CRC, but it also regulates the expression of several protein and non-protein coding genes. In this study, we investigated a potential function of p53 in regulating miRNAs that mediate human CRC progression. MiRNA microarrays were performed on human isogenic CRC cell line pairs (p53 wt and ko, a generous gift by Bert Vogelstein) to identify deregulated miRNAs attributable to p53 loss. The analysis revealed members of the miR-30 family, miR-30e particularly, as the most significantly downregulated group in the p53 knock-out cells compared to the wild type. To elucidate the impact of p53 loss on the expression of miR-30e, we also performed p53 overexpression and silencing in CRC cells harboring wt p53. Indeed, p53 silencing resulted in a reduction of miR-30e expression, whereas an increase of mature miR-30e was observed in CRC cells treated with Nutlin-3a, a specific MDM2 antagonist which is known to increase p53 expression or activity. Next, we determined the miR-30e gene promoter region and found putative TP53 transcription factor binding motifs approximately 1 kb upstream the miR-30e genomic sequence by using in silico tools. The regions containing the predicted TF binding sites were cloned (pGL3-30e) and luciferase reporter gene assays were performed to determine if p53 indeed regulates the miR-30e promoter. Interestingly, promoter reporter activity of pGL3-30e was significantly transactivated in cell lines carrying a wt p53, and this response was further enhanced in the presence of Nutlin 3a. However, the activity of pGL3-30e was not affected in p53 ko cells. Our observations indicate that the tumor suppressor p53 is able to induce the expression of miR-30e in colorectal cancer cell lines. In addition, we identified two promising candidate targets of miR-30e within the integrin family. We demonstrated that miR-30e directly interacts with the 3’ UTRs of the mRNAs of these two candidates and downregulates their expression at both the mRNA and protein level. Functionally, we found that the forced expression of miR-30e led to an integrin-mediated reduction of cell motility, invasion, cell proliferation, and adhesion to the extracellular matrix (ECM). These results were corroborated by an inverse correlation of miR-30e and the identified integrins in a panel of resected CRC tissues. Taken together, our findings indicate that miR-30e is a p53 induced miRNA whose loss/downregulation in CRC orchestrates an integrin driven enhancement of in vitro tumor migration, invasion, proliferation and adhesion to the ECM. Ongoing experiments seek to recapitulate the above findings in vivo and also explore the impact of the p53/miR-30e/ITGs axis on metastasis. Citation Format: Sara Laudato, Nitin Patil, Jörg H. Leupold, Mohammed Abba, Heike Allgayer. P53-induced microRNA-30e suppresses colorectal cancer cell migration and invasiveness by regulating integrins. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1897.
Meeting abstractThe systemic and resistant nature of neuroblastoma metastasized to distant organs makes it largely incurable with current multimodal treatment. Clinical progression stems mainly from an increasing burden of metastatic colonization. Novel therapeutic perspectives may be won by blocking as yet poorly understood pathways triggering the migration-invasion-metastasis cascade in neuroblastoma. The CD9 cell surface glycoprotein was decoded as a major downstream player and direct target of the recently described GRHL1 tumor suppressor in in-depth transcriptome analyses and ChIP-qRT-PCR. CD9 is known to facilitate carcinoma cell motility and metastasis. High-level CD9 expression in primary neuroblastomas correlated with patient survival and established markers for favorable disease. Low-level CD9 expression was an independent risk factor for adverse outcome and predicted poor treatment response in patients with the worst outcome. MYCN and HDAC5 co-localized to the CD9 promoter and repressed transcription. CD9 expression was strongly reduced during progressive development of murine tumors in the TH-MYCN transgenic mouse model of neuroblastoma compared to expression in ganglia from wildtype mice, further supporting MYCN involvement in CD9 transcriptional repression in neuroblastoma cells. We detected differential CD9 methylation in 450K methylation array analyses of primary neuroblastomas, and CD9 hypermethylation was associated with reduced CD9 expression, supporting epigenetic regulation. Inducing CD9 expression in a SH-EP cell model inhibited migration and invasion in Boyden chamber assays. Enforced CD9 expression in neuroblastoma cells transplanted onto chicken chorioallantoic membranes strongly reduced metastasis to chicken embryo bone marrow. Combined treatment of neuroblastoma cells with inhibitors for HDACs and DNA methyltransferase induced CD9 expression. Our results show CD9 is a critical and indirectly druggable mediator of neuroblastoma cell invasion and metastasis.
Abstract Distant metastasis is the major determinant of patient outcome in colorectal cancer. By systematically analysing the miR expression profiles of resected metastasis-, corresponding primary tumor and normal tissues of colorectal cancer patients, we were able to delineate a miR-signature indicative of the metastatically critical microRNA landscape. This “hot list” of miRNAs, including established metastasis-related miRs like the miR-34- and let -7 families, as well as rather novel miR-candidates like miR-552, -218, -135, -210 and -654, together with their putative common targets were bioinformatically predicted to regulate the most significant metastasis-associated signaling pathways currently known. We were able to show for the first time that miR-135b, miR-210 and the loss of miR-218 constitute a novel network that regulates both E- and N-cadherin expression, which is achieved, in part, via several novel common targets such as the recently described tumor suppressors SIAH1 and SETD2, and, most importantly, FOXN3 transcription factor. This is paralleled by a significant impact on migration, invasion, in vivo intravasation and metastasis in chicken embryo and mouse models. We conclude that miR-218 as a novel metastasis suppressor, and pro-metastatic miR-135b and miR-210, constitute one important novel network critical for metastasis, resulting from the first study to systematically suggest the microRNA-driven master pathways of metatasis from solid cancer tissues. Citation Format: Giridhar Mudduluru, Mohammed Abba, Jasmin Batliner, Nitin Patil, Taral R. Lunavat, Maike Scharp, Jörg Leupold, Olga Oleksiuk, Ivo Buchhalter, Wilko Thiele, Melanie Rothley, Axel Benner, Jonathan Sleeman, Heike Allgayer. A systematic approach to the metastatically relevant microRNA landscape. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1443. doi:10.1158/1538-7445.AM2014-1443
MicroRNAs are integral molecules in the regulation of numerous physiological cellular processes including cellular differentiation, proliferation, metabolism and apoptosis. Their function transcends normal physiology and extends into several pathological entities including cancer. The matrix metalloproteinases play pivotal roles, not only in tissue remodeling, but also in several physiological and pathological processes, including those supporting cancer progression. Additionally, the contribution of active MMPs in metastatic spread and the establishment of secondary metastasis, via the targeting of several substrates, are also well established. This review focuses on the important miRNAs that have been found to impact cancer progression and metastasis through direct and indirect interactions with the matrix metalloproteinases.
Abstract Recently, we have characterized the metastatically relevant microRNA landscape by comparing microRNA (miR) expression between human colorectal metastasis and matched primary tumors and normal tissues (Mudduluru et. al. Cancer Res. 2015; PMID: 26069251). One of these, miR-494-5p, was deregulated already in primary tumors. In vitro invasion and migration (Boyden chamber and Matrigel) assays of cultured colorectal cancer cells were significantly reduced after miR-494-5p overexpression (mimic). Conversely, this was abolished by anti-miR-494-5p as an inhibitor. Overexpression of miR-494-5p in cell lines showed a significant reduction in cellular proliferation, which was reversed upon inhibitor co-transfection in a time dependent manner. In silico analysis suggested an interaction of miR-494-5p with the 3´UTR of JAK1. Accordingly, an overexpression of miR-494-5p in cultured colon cancer significantly reduced luciferase activity of a reporter plasmid containing the wild type JAK1-3'UTR, which was abolished when the miR-494-5p seed sequence was mutated to prevent miR-494-5p binding, suggesting a physical interaction and translational repression of JAK1 by miR-494-5p. Furthermore, overexpression of miR-494-5p led to a significant reduction of JAK1 expression in colorectal cancer cell lines in a time dependent manner, which was abolished by co-transfecting a specific anti-miR-494-5p as an inhibitor. Taken together, our preliminary data suggests that miR-494-5p inhibits the expression of JAK1 as a direct molecular target via specific interaction at the JAK1-3'UTR. Additionally, miR-494-5p is capable of reducing proliferation, migration, and invasion, suggesting miR-494-5p as an early tumor suppressor molecule in colorectal cancer. Citation Format: Heike Allgayer, Nitin Patil, Omar Abdelrahim, Joerg H. Leupold. MicroRNA 494-5p acts as tumor suppressor in colorectal cancer by targeting JAK1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2359.
'%3e%3ccircle r='20' fill='%23008'/%3e%3ccircle r='17.5' fill='%23fff'/%3e%3ccircle r='3.5' fill='%23008'/%3e%3cg id='d'%3e%3cg id='c'%3e%3cg id='b'%3e%3cg id='a' fill='%23008'%3e%3ccircle r='.875' transform='rotate(7.5 -8.75 133.5)'/%3e%3cpath d='M0 17.5.6 7 0 2l-.6 5L0 17.5z'/%3e%3c/g%3e%3cuse xlink:href='%23a' transform='rotate(15)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(30)'/%3e%3c/g%3e%3cuse xlink:href='%23c' transform='rotate(60)'/%3e%3c/g%3e%3cuse xlink:href='%23d' transform='rotate(120)'/%3e%3cuse xlink:href='%23d' transform='rotate(-120)'/%3e%3c/g%3e%3c/svg%3e)