ABSTRACT
With the understanding of microRNA (miRNA or miR) functions in tumor initiation, progression, and metastasis, efforts are underway to develop new miRNA-based therapies. Very recently, we demonstrated effectiveness of a novel humanized bioengineered miR-124-3p prodrug in controlling spontaneous lung metastasis in mouse models. This study was to investigate the molecular and cellular mechanisms by which miR-124-3p controls tumor metastasis. Proteomics study identified a set of proteins selectively and significantly downregulated by bioengineered miR-124-3p in A549 cells, which were assembled into multiple cellular components critical for metastatic potential. Among them, plectin (PLEC) was verified as a new direct target for miR-124-3p that links cytoskeleton components and junctions. In miR-124-3p-treated lung cancer and osteosarcoma cells, protein levels of vimentin, talin 1 (TLN1), integrin beta-1 (ITGB1), IQ motif containing GTPase activating protein 1 (IQGAP1), cadherin 2 or N-cadherin (CDH2), and junctional adhesion molecule A (F11R or JAMA or JAM1) decreased, causing remodeling of cytoskeletons and disruption of cell-cell junctions. Furthermore, miR-124-3p sharply suppressed the formation of focal adhesion plaques, leading to reduced cell adhesion capacity. Additionally, efficacy and safety of biologic miR-124-3p therapy was established in an aggressive experimental metastasis mouse model
ABSTRACT
MicroRNAs (miRNAs or miRs) are small noncoding RNAs derived from genome to control target gene expression. Recently we have developed a novel platform permitting high-yield production of bioengineered miRNA agents (BERA). This study is to produce and utilize novel fully-humanized BERA/miR-328-3p molecule (hBERA/miR-328) to delineate the role of miR-328-3p in controlling nutrient uptake essential for cell metabolism. We first demonstrated successful high-level expression of hBERA/miR-328 in bacteria and purification to high degree of homogeneity (>98%). Biologic miR-328-3p prodrug was selectively processed to miR-328-3p to suppress the growth of highly-proliferative human osteosarcoma (OS) cells. Besides glucose transporter protein type 1, gene symbol solute carrier family 2 member 1 (GLUT1/), we identified and verified large neutral amino acid transporter 1, gene symbol solute carrier family 7 member 5 (LAT1/) as a direct target for miR-328-3p. While reduction of LAT1 protein levels by miR-328-3p did not alter homeostasis of amino acids within OS cells, suppression of GLUT1 led to a significantly lower glucose uptake and decline in intracellular levels of glucose and glycolytic metabolite lactate. Moreover, combination treatment with hBERA/miR-328 and cisplatin or doxorubicin exerted a strong synergism in the inhibition of OS cell proliferation. These findings support the utility of novel bioengineered RNA molecules and establish an important role of miR-328-3p in the control of nutrient transport and homeostasis behind cancer metabolism.
ABSTRACT
Objective To investigate the efficacy of Ilizarov technique in treatment of Gustilo type Ⅲ B and C of large tibia bone defect combined with soft tissue defect. Methods Thirty cases with large tibia bone defect combined with soft tissue defect in our hospital from January 2016 to December 2018 were selected including 25 cases with type Ⅲ B and 5 cases with type Ⅲ C,who were all open tibia fractures and treated with Ilizarov technique. Results All patients were followed up for 10 to 18 months with an average of 15 months. The bone defects were reconstructed, the difference between the length of the affected limb and the healthy side was less than 2 cm. The fracture was healed and the wound was closed. One case was with paralysis of common peroneal nerve and recoveried after 3 months. Twenty-two cases recovered without extra surgery, five cases restored with skin graft and three cases covered the wound by rotating skin flap. Conclusion Ilizarov technique is one of effective ways to treat Gustilo Ⅲ type B and type C of large defect combined with soft tissue defect.
ABSTRACT
<p><b>OBJECTIVE</b>To investigate the anatomical study and clinical applications of sural neuron-myocutaneous flap transposition for repairing the special patients with soft tissue defect in foot and ankle.</p><p><b>METHODS</b>The branches, distributions and anastomoses of the vessels and nerves lie in superficial layer of the posterior crural region were observed on 30 sides of adult cadaver lower limb specimens perfused with red latex. Since February 2004, distally based sural neuron-myocutaneous flap was applied for repairing 7 cases of soft tissue defect in foot and ankle.</p><p><b>RESULTS</b>The nutrient vessels of sural nerve, small saphenous vein and posterior femoral cutaneous nerve anastomosed permanently with the musculocutaneous perforators of medial and lateral head of gastrocnemius. There were 2 - 3 anastomoses found respectively. The musculocutaneous perforators pierced the two heads of gastrocnemius muscle (1.8 +/- 0.5) cm medially and (3.7 +/- 0.9) cm laterally away from the groove of the muscle. The medial anastomoses more closed to the middle groove and their diameters were found larger than the lateral ones. In operation, we routinely observed the compound flap for 15 to 20 minutes and found actively errhysis on the muscle, so the fine blood circulation in the flap was demonstrated. All flap survived after operation and the cases were followed up 2 to 6 months with cured osteomyelitis and satisfied flap outline.</p><p><b>CONCLUSIONS</b>Distally based sural neuro-myocutaneous flap can live. The operative method is simple. The flap offers an excellent donor site for repairing the soft tissue defect in foot and ankle in special cases.</p>