Longitudinal alterations in mRNA expression of the BDNF neurotrophin signaling cascade in blood correlate with changes in depression scores in patients undergoing electroconvulsive therapy

Electroconvulsive therapy (ECT) appears to be the most effective treatment for severe depression. However, its mechanisms of action are incompletely understood. Evidence suggests ECT enhances neuroplasticity and neurogenesis. While studies on ECT-induced neuroplasticity focused on brain-derived neurotrophic factor (BDNF), other factors of the BDNF/TrkB signaling cascade remain underinvestigated. We assessed longitudinal changes in depression scores, serum BDNF protein levels, and mRNA expression of BDNF/TrkB related genes (BDNF, AKT1, ERK1, CREB), NR3C1 and IGF1 in peripheral blood in 19 treatment-resistant depressed patients undergoing ECT. We also analysed DNA methylation patterns at various timepoints to explore possible epigenetic regulation of mRNA expression. Using multilevel regression, we found a negative association between depression scores and blood-based mRNA expression of BDNF/TrkB related genes and NR3C1. Expression of BDNF, ERK1 and NR3C1 increased significantly over time (BDNF: β = 0.0295, p = 0.003; ERK1: β = 0.0170, p = 0.034; NR3C1: β = 0.0035, p = 0.050). For these three genes changes in mRNA expression were highly correlated (R = 0.59 - 0.88) with changes in DNA methylation for multiple CpG sites in the respective genes. Also, serum BDNF protein levels increased across the study period (β = 0.11, p = 0.001). Our findings show that the antidepressant effects of ECT are associated with changes in expression of BDNF and its signaling molecules and that these molecular markers can be detected in peripheral blood. Alterations in DNA methylation could be a key mechanism whereby ECT influences gene expression

Solid stress and elastic energy as measures of tumour mechanopathology.

Solid stress and tissue stiffness affect tumour growth, invasion, metastasis and treatment. Unlike stiffness, which can be precisely mapped in tumours, the measurement of solid stresses is challenging. Here, we show that two-dimensional spatial mappings of solid stress and the resulting elastic energy in excised or in situ tumours with arbitrary shapes and wide size ranges can be obtained via three distinct and quantitative techniques that rely on the measurement of tissue displacement after disruption of the confining structures. Application of these methods in models of primary tumours and metastasis revealed that: (i) solid stress depends on both cancer cells and their microenvironment; (ii) solid stress increases with tumour size; and (iii) mechanical confinement by the surrounding tissue significantly contributes to intratumoural solid stress. Further study of the genesis and consequences of solid stress, facilitated by the engineering principles presented here, may lead to significant discoveries and new therapies

A phase II study of preoperative (preop) bevacizumab (bev) followed by dose-dense (dd) doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in combination with bev in HER2-negative operable breast cancer (BC).

1026 Background: Two recent preop studies evaluating bev showed conflicting results, particularly in hormone receptor (HR)+ BC. Identification of predictive markers and their relationship to the pharmacodynamic effects of bev would facilitate the identification of BCs most likely to benefit from bev. To accomplish these goals, we conducted a unique preop trial with a run-in of single agent bev followed by ddACT with bev in two cohorts, one with HR+HER2– BC, and a smaller triple negative (TN) cohort. Methods: Pts with HR+, HER2– or TN BC were eligible if their tumor (T) was ≥1.5 cm and high grade, or had axillary LN involvement; or if T≥2.5cm and was low/intermediate grade. Treatment consisted of a single dose of bev 10 mg/kg, followed two wks later by A 60 mg/m2 and C 600 mg/m2 with bev 10 mg/kg q2 wks x 4, followed by T 175 mg/m2 with bev 10 mg/kg q2 wks x 3, followed by T 175 mg/m2 x1. Research core biopsies and interstitial fluid pressure (IFP) were assessed pre- and post- bev alone. Pathologic response was confirmed centrally and Miller-Payne (MP) was assessed. Results: 84 pts with HR+ and 20 pts with TN breast cancer were enrolled. Amongst HR+ pts, 74 had surgical tissue centrally reviewed, and 6 (8%) had a pCR. Amongst TN pts, 18 pts had tissue centrally reviewed and 8 (44%) had a pCR. Grade was found to predict MP response in both HR+ and TN pts (p=0.001). Several biomarkers were evaluated as predictors of response to bev. Baseline sVEGFR1 correlated with MP response to treatment among TN pts (p=0.015). Single-agent bev reduced the mean vascular density by 18.5% (p=0.049) in HR+ patients and the mean IFP in the overall cohort and HR+ patients by 20 (p=0.020) and 24.5% (p=0.001), respectively. The reductions in IFP correlated with higher levels of sVEGFR2 (p=0.003). The IFP decreased &gt; 50% in 24/65 pts and did not change in others. Gene expression profiling by PAM50 is underway. Conclusions: The addition of bev to preop chemotherapy is well tolerated. Tumor grade appears to predict MP response in HR+ and TN tumors, and sVEGFR1 may be a predictor of MP response to bev in TN tumors. Further work for biomarker predictors of response to bev is ongoing. </jats:p

Ly6C[superscript lo] monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

Current anti-VEGF therapies for colorectal cancer (CRC) provide limited survival benefit, as tumors rapidly develop resistance to these agents. Here, we have uncovered an immunosuppressive role for nonclassical Ly6C lo monocytes that mediates resistance to anti-VEGFR2 treatment. We found that the chemokine CX3CL1 was upregulated in both human and murine tumors following VEGF signaling blockade, resulting in recruitment of CX3CR1+Ly6C lo monocytes into the tumor. We also found that treatment with VEGFA reduced expression of CX3CL1 in endothelial cells in vitro. Intravital microscopy revealed that CX3CR1 is critical for Ly6C lo monocyte transmigration across the endothelium in murine CRC tumors. Moreover, Ly6C lo monocytes recruit Ly6G + neutrophils via CXCL5 and produce IL-10, which inhibits adaptive immunity. Preventing Ly6C lo monocyte or Ly6G + neutrophil infiltration into tumors enhanced inhibition of tumor growth with anti-VEGFR2 therapy. Furthermore, a gene therapy using a nanoparticle formulated with an siRNA against CX3CL1 reduced Ly6C lo monocyte recruitment and improved outcome of anti-VEGFR2 therapy in mouse CRCs. Our study unveils an immunosuppressive function of Ly6C lo monocytes that, to our knowledge, has yet to be reported in any context. We also reveal molecular mechanisms underlying antiangiogenic treatment resistance, suggesting potential immunomodulatory strategies to enhance the long-term clinical outcome of anti-VEGF therapies

Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases

Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.Version of Recor

La Abeja montañesa : Periódico de intereses locales: Año IX Número 1961 - 1865 marzo 30

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 201