A multifunctional gold (Au) nanorod (NR)-based nanocarrier capable of co-delivering small interfering RNA (siRNA) against achaete-scute complex-like 1 (ASCL1) and an anticancer drug (doxorubicin (DOX)) specifically to neuroendocrine (NE) cancer cells was developed and characterized for combined chemotherapy and siRNA-mediated gene silencing. The Au NR was conjugated with (1) DOX, an anticancer drug, via a pH-labile hydrazone linkage to enable pH-controlled drug release, (2) polyarginine, a cationic polymer for complexing siRNA, and (3) octreotide (OCT), a tumor-targeting ligand, to specifically target NE cancer cells with overexpressed somatostatin receptors. The Au NR-based nanocarriers exhibited a uniform size distribution as well as pH-sensitive drug release. The OCT-conjugated Au NR-based nanocarriers (Au-DOX-OCT, targeted) exhibited a much higher cellular uptake in a human carcinoid cell line (BON cells) than non-targeted Au NR-based nanocarriers (Au-DOX) as measured by both flow cytometry and confocal laser scanning microscopy (CLSM). Moreover, Au-DOX-OCT-ASCL1 siRNA (Au-DOX-OCT complexed with ASCL1 siRNA) resulted in significantly higher gene silencing in NE cancer cells than Au-DOX-ASCL1 siRNA (non-targeted Au-DOX complexed with ASCL1 siRNA) as measured by an immunoblot analysis. Additionally, Au-DOX-OCT-ASCL1 siRNA was the most efficient nanocarrier at altering the NE phenotype of NE cancer cells and showed the strongest anti-proliferative effect. Thus, combined chemotherapy and RNA silencing using NE tumor-targeting Au NR-based nanocarriers could potentially enhance the therapeutic outcomes in treating NE cancers.

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Notch1-3 are transmembrane receptors that appear to be absent in Medullary Thyroid Cancer (MTC). Previous research has shown that induction of Notch1 has a tumor suppressor effect in MTC cell lines, but little is known about the biological consequences of Notch3 activation for the progression of the disease. We elucidate the role of Notch3 in MTC by genetic (doxycycline inducible Notch3 intracellular domain) and pharmacological (AB3, novel HDAC inhibitor) approaches. We find that overexpression of Notch3 leads to the dose dependent reduction of neuroendocrine tumor markers. In addition, Notch3 activity is required to suppress MTC cell proliferation, and the extent of growth repression depends on the amount of Notch3 protein expressed. Moreover, activation of Notch3 induces apoptosis. The translational significance of this finding is highlighted by our observation that MTC tumors lack active Notch3 protein and reinstitution of this isoform could be a therapeutic strategy to treat patients with MTC. We demonstrate, for the first time, that overexpression of Notch3 in MTC cells can alter malignant neuroendocrine phenotype in both in vitro and in vivo models. In addition, our study provides a strong rationale for using Notch3 as a therapeutic target to provide novel pharmacological treatment options for MTC.

A case of disseminated malignant melanoma with generalized melanosis of the skin and other tissues, melanuria, melanoptysis, and a dark brown blood serum is reported. The reticuloendothelial system contained large amounts of melanin pigment. Lysis of degenerating pigment-loaded melanoma cells in peripheral blood vessels seemed to be of considerable importance in the pigmentation of tissues. Focal pigmentation of capillary endothelium and perivascular deposition of melanin pigment in macrophages and, occasionally contained large amounts of melanin pigment. Lysis of degenerating pigment-loaded melanoma cells in peripheral blood vessels seemed to be of considerable importance in the pigmentation of tissues. Focal pigmentation of capillary endothelium and perivascular deposition of melanin pigment in macrophages and, occasionally contained large amounts of melanin pigment. Lysis of degenerating pigment-loaded melanoma cells in peripheral blood vessels seemed to be of considerable importance in the pigmentation of tissues. Focal pigmentation of capillary endothelium and perivascular deposition of melanin pigment in macrophages and, occasionally, in other cells, was noted. Single cell metastases contributed to melanin pigmentation of most organs, but were not found in sections of the skin. Melanoptysis (black sputum) was due to diffuse melanoma cell infiltration of the lungs, with secondary pigment deposition in macrophages and in bronchial epithelial cells. In this case the 'glomerular melanoma cell emboli' recorded by previous authors consisted of melanin pigment and cell debris. Focal damage of glomeruli affected by pigment emboli is described allowing access of melanoma cell debris (including melanin pigment granules) into glomerular tubules.

The results suggest that probiotics primarily act superficially, with change of gross appearance of the mucosa at endoscopy, but without significant effect on histological picture, mucosal perfusion or faecal calprotectin, during a relatively short period of 4 weeks.