Tuberculosis-diabetes co-morbidity is characterized by heightened systemic levels of circulating angiogenic factors.

BACKGROUND: Tuberculosis-diabetes co-morbidity (TB-DM) is characterized by increased inflammation with elevated circulating levels of inflammatory cytokines and other factors. Circulating angiogenic factors are intricately involved in the angiogenesis-inflammation nexus. METHODS: To study the association of angiogenic factors with TB-DM, we examined the systemic levels of VEGF-A, VEGF-C, VEGF-D, VEGF-R1, VEGF-R2, VEGF-R3 in individuals with either TB-DM (n = 44) or TB alone (n = 44). RESULTS: Circulating levels of VEGF-A, C, D, R1, R2 and R3 were significantly higher in TB-DM compared to TB individuals. Moreover, the levels of VEGF-A, C, R2 and/or R3 were significantly higher in TB-DM with bilateral or cavitary disease or with hemoptysis, suggesting an association with both disease severity and adverse clinical presentation. The levels of these factors also exhibited a significant positive relationship with bacterial burdens and HbA1c levels. In addition, VEGF-A, C and R2 levels were significantly higher (at 2 months of treatment) in culture positive compared to culture negative TB-DM individuals. Finally, the circulating levels of VEGF-A, C, D, R1, R2 and R3 were significantly reduced following successful chemotherapy at 6 months. CONCLUSION: Our data demonstrate that TB-DM is associated with heightened levels of circulating angiogenic factors, possibly reflecting both dysregulated angiogenesis and exaggerated inflammation.

Overcoming inefficient secretion of recombinant VEGF-C in baculovirus expression vector system by simple purification of the protein from cell lysate.

The first reports about successfully expressed recombinant proteins with the use of a baculovirus vector were published over 30years ago. Despite the long time of refining this expression system, early problems with the production of baculovirus-derived secretory proteins are still not satisfactorily solved. The high expression level driven by baculoviral promoters often does not result in the desired yield of secreted recombinant proteins, which frequently accumulate inside insect cells and are only partially processed. During our attempts to produce vascular endothelial growth factor C (VEGF-C) with the use of a baculovirus vector we also faced an inefficient secretion of the recombinant protein to culture medium. We were not able to improve the outcome and obtain an acceptable concentration of VEGF-C in the medium by changing the culture conditions or utilizing different signal peptides. However, as a significant amount of native VEGF-C was detected inside the baculovirus-infected cells, we developed a simple method to purify recombinant, glycosylated VEGF-C from a lysate of the cells. The presented results indicate that the lack of a secretory protein in the insect cell culture medium after baculovirus infection does not necessarily signify failure in the production of the protein. As demonstrated by us and contrary to generally accepted views, the lysate of baculovirus-infected cells may constitute a valuable source of the biologically active, secretory protein.

Exogenous VEGF-C augments the efficacy of therapeutic lymphangiogenesis induced by allogenic bone marrow stromal cells in a rabbit model of limb secondary lymphedema.

OBJECTIVE: To determine the effect of bone marrow stromal cells transplantation and vascular endothelial growth factor C administration as a treatment for secondary lymphedema. METHODS: Bone marrow stromal cells and/or vascular endothelial growth factor C protein were injected into a rabbit model of limb lymphedema. Water displacement volumetry was performed to measure limb volume changes. Immunohistochemistry was performed to detect VEGFR-3 and to count lymph vessel. Western blot analysis was performed to detect vascular endothelial growth factor C. RESULTS: Before treatment, rabbits had an average volume of edema in the limb of 61.25 ± 5.28, 62.37 ± 4.97, 60.58 ± 7.18 and 61.79 ± 4.33 ml (P = 0.753), respectively, in the BMSC + VEGF-C, bone marrow stromal cell, vascular endothelial growth factor C and control groups. With therapy, this was reduced to an average volume of 7.60 ± 3.02, 12.78 ± 3.41, 31.55 ± 3.51 and 62.33 ± 6.59 ml, respectively, in the four groups 6 months after treatment. Quantitative analysis showed that the vessel numbers were significantly increased in the BMSC + VEGF-C, bone marrow stromal cell and vascular endothelial growth factor C groups compared with the control group at 28 days after the operation (P< 0.05). Western blot analysis demonstrated that expression of vascular endothelial growth factor C was higher in the BMSC + VEGF-C and BMSC groups. CONCLUSIONS: The combined treatment with bone marrow stromal cell transplantation and vascular endothelial growth factor C administration is superior to bone marrow stromal cell transplantation alone in the treatment of limb lymphedema. Bone marrow stromal cell transplantation and vascular endothelial growth factor C administration could enhance the therapeutic effect of each other.

Estadios precoces de cancer oral: pronóstico en relación con gradación histológica, linfagiogénesis intratumoral y expresión de factor de crecimiento endotelial vascular Tipo-C (VEGF-C) / Early stage oral cancer: prognosis with regard to histological grading, intratumoral lymphangiogenesis, and the expression of vascular endothelial growth factor-C (VEGF-C)

Los sistemas de gradación histológica se han usadoclásicamente como factor pronóstico y marcadores de comportamiento clínico en el carcinoma epidermoide intra-oral (CEI). Sin embargo, su utilidad pronóstica permanece controvertida. Nuestro objetivo ha sido evaluarla presencia de linfangiogénesis intratumoral (LI), un nuevo hallazgo morfológico, en un análisis retrospectivo de muestras de tejido en parafina dentro de un grupo de estadios precoces de CEI, relacionándolo con clásicos sistemas de gradación histológica y teniendo en cuenta su importancia pronóstica. Asimismo, pretendemos determinar si la expresión del factor de crecimiento endotelial vascular –C (VEGF-C) se correlaciona conla evolución de la enfermedad.Diseño. Realizamos un estudio retrospectivo basado en 96 casos de CEI. Todos los pacientes presentaban tumores intraorales T1-T2 y fueron tratados primariamente mediante resección local asociada con disección cervicalelectiva, la cual mostró ausencia de afectación ganglionar regional. En el grupo de 96 muestras analizamos la LI utilizando el marcador específicodel endotelio linfático PA2.26. Adicionalmente, estudiamos la expresión del VEGF-C. Todos los casos fueron clasificados de acuerdo con los sisintratutemasde gradación histológica descritos por Broders, Anneroth y Bryne. El estudio estadístico se fundamentó en el análisis univariante de supervivenciacausa-específica y supervivencia libre de recidiva según el método de Kaplan-Meier.Resultados. El grupo de pacientes con ausencia de LI mostró mejor pronóstico en cuanto a supervivencia y periodo libre de enfermedad, aunque la diferenciano mostró valores estadísticamente significativos. El estudio no mostró una relación entre la expresión de VEGF-C y la presencia de LI. Sin embargo, no observamos recidivas entre el grupo con ausencia de expresión deVEGF-C. El análisis comparativo de los sistemas de gradación histológica mostró una relación estadísticamente significativa entre los sistemas de Broders y Anneroth (p<0,01) y entre los sistemas de Broders y Bryne (p<0,001). Nuestro estudio demostró una relación inversa entre los valores de los sistemasde gradación Anneroth (p<0,01) – Bryne (p<0,001) y la presencia de LI.Conclusión. El valor clínico de los sistemas de gradación histológica puede incrementarse si se incluyen nuevos parámetros que consideren el comportamientobiológico del tumor. La expresión de VEGF-C y la presencia de linfáticos intratumorales pueden ser marcadores marcadores pronósticos de utilidad en el CEI

Objectives. Histological grading systems have been classically used as a prognostic factor and clinical behavior markers in oral squamous cell carcinoma (OSCC). However, their prognostic usefulness remains controversial. Our aim was to evaluate the presence of intratumoral lymphangiogenesis (IL), a new morphologicalfinding, in a retrospective analysis of paraffin embedded tissue samples that corresponded to a group of early stage oral squamous cell carcinoma cases, and to relate this with histological grading systems while keeping in mind their prognostic significance.We also wanted to determine if the expression of vascular endothelial growth factor-C (VEGF-C) is correlated with the evolution of the disease.Design. We performed a retrospective analysis of 96 patients with OSCC. All cases were T1-T2 neoplasms and were treated primarily by local resection and elective neck dissection that showed no neck involvement. In the group of 96 specimens, we analyzed IL using the specific marker PA2.26 for lymphatic endothelium. Also,we studied the expression of (VEGF-C). All cases were classified according to the histological grading systems described by Broders, Anneroth and Bryne. The statistical analysis was based on the univariateanalysis of cause-specific survival and disease recurrence free-survival according to the Kaplan-Meier method.Results. The group of patients without intratumoral lymphangiogenesis showed a better prognosis with regard to survival and disease-free period, but the difference was not statistically significant. The study showed no relationship between VEGF-C expression and the presence of intratumoral lymphangiogenesis. However, no recurrences were observed in the group without VEGF-C expression. The comparative analysis of the histological grading system showed a statistical relationship between the Broders and Anneroth systems (p<0.01) and between the Broders and Bryne systems (p<0.001). Our study demonstrated an inverse relationship between the valuesof the Anneroth system (p<0.01) - Bryne system (p<0.001) and the presence of intratumoral lymphangiogenesis.Conclusion. The clinical value of the histological grading systems can increase by including new parameters that take into account the biological behavior of the tumor. Expression of VEGF-C and intratumoral lymphatics may thus be useful prognostic markers for oralsquamous cell carcinoma

Estadios precoces de cancer oral: pronóstico en relación con gradación histológica, linfagiogénesis intratumoral y expresión de factor de crecimiento endotelial vascular Tipo-C (VEGF-C) / Early stage oral cancer: prognosis with regard to histological grading, intratumoral lymphangiogenesis, and the expression of vascular endothelial growth factor-C (VEGF-C)

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