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Trabanelli S.,University of Bologna | Trabanelli S.,University of Lausanne | La Manna F.,University of Bologna | La Manna F.,Osteoncology and Rare Tumors Center | And 7 more authors.
Journal of Immunology Research | Year: 2015

In vitro differentiation of mesenchymal stromal cells (MSC) into osteocytes (human differentiated osteogenic cells, hDOC) before implantation has been proposed to optimize bone regeneration. However, a deep characterization of the immunological properties of DOC, including their effect on dendritic cell (DC) function, is not available. DOC can be used either as cellular suspension (detached, Det-DOC) or as adherent cells implanted on scaffolds (adherent, Adh-DOC). By mimicking in vitro these two different routes of administration, we show that both Det-DOC and Adh-DOC can modulate DC functions. Specifically, the weak downregulation of CD80 and CD86 caused by Det-DOC on DC surface results in a weak modulation of DC functions, which indeed retain a high capacity to induce T-cell proliferation and to generate CD4+CD25+Foxp3+ T cells. Moreover, Det-DOC enhance the DC capacity to differentiate CD4+CD161+CD196+ Th17-cells by upregulating IL-6 secretion. Conversely, Adh-DOC strongly suppress DC functions by a profound downregulation of CD80 and CD86 on DC as well as by the inhibition of TGF-β production. In conclusion, we demonstrate that different types of DOC cell preparation may have a different impact on the modulation of the host immune system. This finding may have relevant implications for the design of cell-based tissue-engineering strategies. © 2015 Sara Trabanelli et al. Source

Severi S.,Nuclear Medicine Unit | Sansovini M.,Nuclear Medicine Unit | Ianniello A.,Nuclear Medicine Unit | Bodei L.,Italian National Cancer Institute | And 7 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2015

Purpose: Peptide receptor radionuclide therapy (PRRT) is a valid therapy for grade 1/2 gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). Although a median progression-free survival (PFS) of more than 20 months is frequently observed, the majority of patients relapse after 2 – 3 years. In the present study, we investigated the use of low dosage re-treatment with 177Lu-DOTATATE (Lu-PRRT) in patients with GEP-NENs who relapsed after treatment with 90Y-DOTATOC (Y-PRRT). Methods: Upon tumour progression, 26 patients with a PFS of at least 12 months after Y-PRRT were consecutively enrolled in a phase II study of re-treatment with Lu-PRRT. All patients had preserved kidney and haematological parameters and received 14.8 – 18.5 GBq of Lu-PRRT in four or five cycles. The disease control rate (DCR), toxicity, PFS and prognostic factors were evaluated. Results: Median total activity of Lu-PRRT was 16.5 GBq in five cycles. The DCR was 84.6 %, median PFS was 22 months (95 % CI 16 months – not reached) compared to 28 months (95 % CI 20 – 36 months) after Y-PRRT. Tumour burden and number of liver metastases were important prognostic factors. Toxicity was mild after Lu-PRRT re-treatment in the majority of patients, with only two patients with grade 2 and one with grade 3 bone marrow toxicity; one patient had grade 2 and one grade 3 renal toxicity. Conclusion: Patients with GEP-NEN who have previously responded to Y-PRRT are suitable candidates for Lu-PRRT re-treatment on progression. Although our sample size was limited, low-dosage Lu-PRRT was safe, and led to DCR and PFS rates comparable with those observed when Y-PRRT was used as primary treatment. © 2015, Springer-Verlag Berlin Heidelberg. Source

Zhang Y.,Duke University | Yang P.,Duke University | Sun T.,Duke University | Li D.,Shanghai University | And 11 more authors.
Nature Cell Biology | Year: 2013

The tumour stroma is an active participant during cancer progression. Stromal cells promote tumour progression and metastasis through multiple mechanisms including enhancing tumour invasiveness and angiogenesis, and suppressing immune surveillance. We report here that miR-126/miR-126 *, a microRNA pair derived from a single precursor, independently suppress the sequential recruitment of mesenchymal stem cells and inflammatory monocytes into the tumour stroma to inhibit lung metastasis by breast tumour cells in a mouse xenograft model. miR-126/miR-126 * directly inhibit stromal cell-derived factor-1 alpha (SDF-1α) expression, and indirectly suppress the expression of chemokine (C-C motif) ligand 2 (Ccl2) by cancer cells in an SDF-1α-dependent manner. miR-126/miR-126 * expression is downregulated in cancer cells by promoter methylation of their host gene Egfl7. These findings determine how this microRNA pair alters the composition of the primary tumour microenvironment to favour breast cancer metastasis, and demonstrate a correlation between miR-126/126 * downregulation and poor metastasis-free survival of breast cancer patients. © 2013 Macmillan Publishers Limited. All rights reserved. Source

Ianniello A.,Nuclear Medicine and Radiometabolic Unit | Sansovini M.,Nuclear Medicine and Radiometabolic Unit | Severi S.,Nuclear Medicine and Radiometabolic Unit | Nicolini S.,Nuclear Medicine and Radiometabolic Unit | And 10 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2016

Purpose: Typical and atypical carcinoids (TC and AC) represent 20 – 25 % of all neuroendocrine tumours. No standard therapeutic approach is available for patients with advanced disease. The aim of this phase II study was to investigate the efficacy and safety of peptide receptor radionuclide therapy with 177Lu-DOTATATE (Lu-PRRT) and the role of thyroid transcription factor 1 (TTF-1) and 18F-FDG PET as prognostic factors in patients with advanced TC or AC. Methods: A total of 34 consecutive patients with radiologically documented progressive disease were treated with Lu-PRRT at a therapeutic cumulative activity of 18.5 or 27.8 GBq in four or five cycles according to the patient’s kidney function and bone marrow reserve. Information on TTF-1 was available in all patients. FDG PET studies prior to Lu-PRRT were available in 29 patients. Results: The median follow-up was 29 months (range 7 – 69 months). The disease control rate (DCR) in patients with TC was 80 %: 6 % complete response, 27 % partial response and 47 % stable disease. The median progression-free survival (mPFS) was 20.1 months (95 % CI 11.8 – 26.8 months). Stable disease was achieved in 47 % of patients with AC with a mPFS of 15.7 months (95 % CI 10.6 – 25.9 months). No major acute or delayed toxicity occurred in either group or with either cumulative activity. mPFS in patients with TTF-1-negative TC was 26.3 months (95 % CI 12.9 – 45.2 months), but in patients with TTF-1-positive TC mPFS was 7.2 months (4.2 – 14.0 months; p = 0.0009). FDG PET was negative in 13 patients (10 TC and 3 AC) and positive in 16 patients (4 TC and 12 AC). The mPFS in the FDG PET-negative group was 26.4 months (95 % CI 14.2 – 48.9 months) and 15.3 months (11.7 – 31.1 months) in the FDG PET-positive group. Conclusion: Lu-PRRT showed antitumour activity in terms of DCR and PFS and proved safe, even in patients with a higher risk of side effects. TTF-1 would appear to be a prognostic factor. FDG PET positivity in bronchial carcinoids is a hallmark of aggressive tumour and is more frequent in patients with AC than in those with TC. © 2015, Springer-Verlag Berlin Heidelberg. Source

Chakrabarti R.,Princeton University | Wei Y.,Princeton University | Hwang J.,Princeton University | Hang X.,Princeton University | And 14 more authors.
Nature Cell Biology | Year: 2014

Emerging evidence suggests that cancer is populated and maintained by tumour-initiating cells (TICs) with stem-like properties similar to those of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signalling. Importantly, Fzd7-dependent enhancement of Wnt signalling by ΔNp63 also governs tumour-initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms. © 2014 Macmillan Publishers Limited. All rights reserved. Source

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