We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process.
The extent of surgical resection (EOR) has been recorded as conditioning outcome in glioblastoma multiforme (GBM) patients but no significant improvements were recorded in survival. The study aimed to evaluate the impact of EOR on survival, investigating the role of fluid-attenuated inversion recovery (FLAIR) abnormalities removal. 282 newly diagnosed GBM patients were treated with surgery followed by concurrent and adjuvant chemo-radiotherapy. The EOR was defined as: SUPr, in case of resection amounting to 100% of enhanced and FLAIR areas; gross total (GTR) in case of resection between 90 and 100% of enhanced areas with variable amount of FLAIR abnormalities; sub-total (STR), between 10 and 89%; biopsy (B) <10%. FLAIR-RTV was dichotomized in percentage values to identify the best separation threshold for progression free survival (PFS) and overall survival (OS). SUPr was obtained in 21 patients (7.4%), GTR in 60 (21.3%), STR in 143 (50.7%) and biopsy only in 58 (20.6%). The median, 1, 2-year PFS were 10.4 ± 0.4 months, 39.0 ± 3.0, and 17.0 ± 2.0%; the median, 1, 2-year OS were 14.5 ± 0.5 months, 63.3 ± 3.0, and 23.1 ± 3.1%. EOR was significantly influencing survival (p < 0.001). The median, 1, 2-year OS were 28.6 ± 5.2 months, 90.0 ± 6.0, 71.0 ± 10.0% for patients underwent SUPr vs. 16.2 ± 1.2 months, 81.0 ± 5.0, 24.0 ± 6.0% for GTR. The FLAIR removal threshold conditioning survival was 45%. Minor complications were recorded in 14 (5%) patients and major in 8 (2.8%). surgical resection beyond contrast-enhancing boundaries could represent a promising strategy to improve outcome in GBM patients. The identification of a FLAIR-RTV threshold can be useful in clinical practice and it was recorded as factor influencing survival.
The service was the first of its kind in the UK. This evaluation provides evidence to inform the potential roll-out of further online strategies to enhance community HIV testing.
Background-Thrombocytopenia is a possible complication of treatment with glycoprotein (GP) IIb/IIIa antagonists during percutaneous coronary interventions, but it is not clear whether different GP IIb/IIIa inhibitors carry a different risk of thrombocytopenia, and its relation to clinical outcome is unknown. Methods and Results-We analyzed data from the Do Tirofiban and Reopro Give Similar Efficacy Outcomes (TARGET) study, which compared the safety and efficacy of abciximab and tirofiban in patients undergoing coronary stenting. Platelets were measured at baseline and 6 and 24 hours after the beginning of treatment. Thrombocytopenia (nadir platelet count Ͻ100ϫ10 9 cells/L) developed in 2.4% of patients treated with abciximab and 0.5% of those treated with tirofiban (PϽ0.001). The variables independently associated with thrombocytopenia were treatment with abciximab within the previous 6 months (OR, 4.4; 95% CI, 1.7 to 11.2), baseline creatinine levels of Ն0.8 mg/dL (OR, 3.8; 95% CI, 1.7 to 8.8), previous transient ischemic attack (OR, 3.2; 95% CI, 1.4 to 7.6), female gender (OR, 1.9; 95% CI, 1.2 to 3.1), and history of peripheral vascular disease (OR, 1.78; 95% CI, 1.0 to 3.1). Severe bleeding occurred more frequently in patients with thrombocytopenia (5.1% versus 0.7%, Pϭ0.001), who also more frequently received blood transfusions (6.1% versus 1.4%, Pϭ0.001). At the 30-day follow-up, 2.0% of patients with thrombocytopenia and 0.4% of those without (Pϭ0.022) had died; myocardial infarction occurred in 9.13% versus 6.11% (PϭNS); and target vessel revascularization occurred in 6.07% versus 0.60% (PϽ0.001). Conclusions-During coronary stenting, abciximab and other risk factors are independently associated with thrombocytopenia. Regardless of the cause, thrombocytopenia is associated with more ischemic events, bleedings, and transfusions.
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