PDK1 inhibition is a novel therapeutic target in multiple myeloma

Background:

Cancer cells utilise the glycolytic pathway even when adequate oxygen is present, a phenomenon known as the Warburg effect. We examined whether this system is operative in multiple myeloma (MM) cells and whether glycolysis inhibition is a potential therapeutic modality.

Methods:

The MM cells were purified from 59 patients using CD138-immunomagnetic beads. The expression levels of genes associated with glycolysis, c-MYC, GLUT1, LDHA, HIF1A and pyruvate dehydrogenase kinase-1 (PDK1) were determined by real-time PCR. Glucose consumption and lactate production by MM cell lines were analysed. Oxamate, an LDH inhibitor, and dichloroacetate (DCA), a PDK1 inhibitor, were employed. Inhibition of PDK1 expression was achieved using a siRNA.

Results:

High LDHA expression was found to be an indicator of poor prognosis. It was also positively correlated with the expression of PDK1, c-MYC and GLUT1. Greater glucose consumption and lactate production in MM cells was associated with higher LDHA expression. All the glycolysis inhibitors (oxamate, DCA and PDK1 siRNA) induced apoptosis in MM cells. DCA combined with bortezomib showed additive cytotoxic effects.

Conclusion:

The present data suggest that the Warburg effect is operative in MM cells. As PDK1 is not overexpressed in normal tissues, PDK1 inhibition could serve as a novel therapeutic approach.     

Giant Hepatic Cyst: A Possible Cause of Inferior Vena Cava Syndrome

An 80-year-old man was transferred to our institution with lower limb edema and worsening dyspnea following the administration of diuretic medication. Transthoracic echocardiography and computed tomography revealed a giant hepatic cyst (176×190 mm) compressing his right atrium and inferior vena cava (IVC). Laparoscopic cyst deroofing combined with omental packing and subsequent tube drainage immediately alleviated all his symptoms. The procedure was uneventful, and he was discharged without any complications on postoperative day 9; he had no recurrent symptoms or hepatic cysts at the postoperative 2-month follow-up. Therefore, a giant hepatic cyst can cause IVC syndrome, and laparoscopic deroofing is a beneficial approach for the treatment of accessible cysts.     

Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models

RET gene fusions are recurrent oncogenes identified in thyroid and lung carcinomas. Lenvatinib is a multi-tyrosine kinase inhibitor currently under evaluation in several clinical trials. Here we evaluated lenvatinib in RET gene fusion-driven preclinical models. In cellular assays, lenvatinib inhibited auto-phosphorylation of KIF5B-RET, CCDC6-RET, and NcoA4-RET. Lenvatinib suppressed the growth of CCDC6-RET human thyroid and lung cancer cell lines, and as well, suppressed anchorage-independent growth and tumorigenicity of RET gene fusion-transformed NIH3T3 cells. These results demonstrate that lenvatinib can exert antitumor activity against RET gene fusion-driven tumor models by inhibiting oncogenic RET gene fusion signaling.     

Immunohistochemical co-localization of lymphatics and blood vessels in oral squamous cell carcinomas

BACKGROUND: Differentiating lymphatic vessels from blood vessels is difficult, partly due to the lack of a specific method for identifying lymphatics. A new lymphatic vessel-reactive antibody, D2-40 has recently become commercially available. We examined the selectivity of D2-40 for lymphatics in oral neoplastic lesions for discrimination from blood vessels. METHODS: Formalin-fixed, paraffin-embedded sections of oral lymphangiomas (n = 3), oral hemangiomas (n = 7), and oral squamous cell carcinomas (OSCC, n = 46) were double immunostained with D2-40 and anti-CD34 monoclonal antibodies (MoAb) using ENVISION-polymer technique with 5-bromo-4-chloro-3-indoxyl-phosphate (BCIP)/nitroblue tetrazolium chloride (NBT) and 3,3'-diaminobenzidine (DAB) as color reagents, respectively. Results: In the oral lymphangiomas and hemangiomas D2-40 was detected in all lymphatics, while all blood vessels were positive for CD34. In OSCC, number of vessels for lymphatics (P < 0.01) and for blood vessels in the perineoplastic areas were significantly greater than those in intratumoral areas. CONCLUSIONS: These results indicate that lymphatic proliferation might be much more extensive in the peritumoral area than intratumoral.     

A comparison of mesial molar root canal preparations using two engine-driven instruments and the balanced-force technique

The purpose of this study was to compare the effects of two engine-driven, nickel-titanium instrument systems with hand files in the final shape of slight and moderately curved canals. A total of 72 mesial roots of extracted human mandibular molars were divided into three groups: ProFile .04 taper, Pow-R rotary systems, and Flex-R hand-filing technique. The roots were mounted and cross-sectioned at two different horizontal levels using a modified Bramante technique. Pre- and postinstrumented cross-sectional roots were imaged, recorded, and computer analyzed. Results showed that, at the middle third, in almost all groups, there was a tendency of cutting more toward the mesial side with only one exception: Pow-R cut more to the distal side (danger zone) (p < 0.02). At the apical third, Flex-R (p < 0.03) and ProFile (0.001) transported to the mesial side (danger zone) when the curvature increased. When the three techniques were compared analyzing each side and considering the two groups of curvature, at the middle third in the moderately curved-canal group, Flex-R cut statistically more than Pow-R toward the lingual side. The other comparisons showed no statistically significant difference. When the techniques were compared in relation with the degree of curvature, in the apical third, ProFile .04 cut statistically more toward the mesial side in the moderately curved canal group than in the slightly curved canal group. The other comparisons showed no statistically significant difference. Canal preparation time was shorter with hand instrumentation (p < .05) in a few instances.     

Effects of basic fibroblast growth factor on cultured rat and human submandibular salivary gland cells

Basic fibroblast growth factor (bFGF) is a strong mitogen for most mesoderm- and ectoderm-derived cells. Although bFGF exists in rat and human salivary glands, its physiological role in those glands is unknown. In this study, the effects of bFGF were investigated in monolayer culture of normal rat and human submandibular gland cells. Epithelial cells from rat and human submandibular glands were cultivated with the aid of 3T3 cells as a feeder layer. The effects of different concentrations of bFGF on the second passage of these cultured cells were examined. In both the rat and human cells, the percentage of bromodeoxyuridine (BrdU)-positive cells gradually increased up to 50 ng/ml, and then increased sharply at 100 ng/ml. However, at concentrations higher than 100 ng/ml, the percentages of BrdU-positive cells reached a plateau. In both rat and human cells, total cell numbers at 100 ng/ml bFGF were significantly higher than those of the control group from culture day 4. On the other hand, the morphology of the cultured cells showed no difference either with or without bFGF. These results indicate that a major effect of bFGF on salivary gland epithelial cells is to act as a mitogenic stimulus.     

Autotransplantation using endosseous implants as stabilizers

The surgical transfer of a tooth from one site to another in the same individual is known as autotransplantation. Usually the tooth transferred is an unerupted or partially erupted third molar which is placed into a first molar position with some external fixation. In this case report, the first molar was already missing and the second molar was hopeless. An erupted third molar was autotransplanted into the second molar site and endosseous implants were used to stabilize the tooth. A fixed bridge was placed 6 months later and the progress followed for 4 yr.     

Effects of basic fibroblast growth factor administration on vascular changes in wound healing of rat palates.

OBJECTIVE: The purpose of this study was to investigate the vascular changes induced by mucoperiosteal denudation of rat palate and to elucidate the effects of basic fibroblast growth factor (bFGF) administration on the palatal vascular network in wound healing. METHODS: A total of 117 male Wistar rats were used for the study on their 20th postnatal day. The animals were divided into three groups: a scar formation group, a basic fibroblast growth factor group, and a control group. The scar formation and basic fibroblast growth factor groups had lateral mucoperiosteum excised from the palate. In the basic fibroblast growth factor group, a solution of basic fibroblast growth factor was injected into the operated area 1 week after excision. At 6, 8, and 10 weeks postoperatively, palatal vascular changes were investigated by immunohistochemical staining and corrosion cast techniques. RESULTS: Throughout the experimental period, there were significantly fewer vessels in the scar formation group than in the control and basic fibroblast growth factor groups. In the basic fibroblast growth factor group, the elongation of new vessels and capillary proliferation proceeded, and after 10 weeks a highly organized vascular network was established. The scar formation group showed few Volkmann's canals that were shrunken or closed, whereas the basic fibroblast growth factor group evidenced Volkmann's canals with arterioles or venules, as seen in the control. CONCLUSIONS: The results suggested that injection of basic fibroblast growth factor into palatal wounds improves the vascular supply to the operated mucosa and underlying bone during and after palatal wound healing, which may contribute to tissue remodeling of the palate during growth.     

SAR Exploration Guided by LE and Fsp3: Discovery of a Selective and Orally Efficacious RORγ Inhibitor

相似文献