Booneporterfield2209

Silver nanoparticles (AgNPs) show promise for treatment of aggressive cancers including triple-negative breast cancer (TNBC) in preclinical cancer models. For clinical development of AgNP-based therapeutics, it will be necessary to clearly define the specific physicochemical features of the nanoparticles that will be used, and to tie these properties to biological outcomes. To fill this knowledge gap, we performed thorough structure/function, mechanistic, safety, and efficacy studies to assess the potential for AgNPs to treat TNBC. We establish that AgNPs, regardless of size, shape, or stabilizing agent, are highly cytotoxic to TNBC cells at doses that are not cytotoxic to non-malignant breast epithelial cells. In contrast, TNBC cells and non-malignant breast epithelial cells are similarly sensitive to exposure to silver cation (Ag+), indicating that the nanoparticle formulation is essential for the TNBC-specific cytotoxicity. Mechanistically, AgNPs are internalized by both TNBC and non-malignant breast cells, but are rapidly degraded only in TNBC cells. Exposure to AgNPs depletes cellular antioxidants and causes endoplasmic reticulum stress in TNBC cells without causing similar damage in non-malignant breast epithelial cells. AgNPs also cause extensive DNA damage in 3D TNBC tumor nodules in vitro, but do not disrupt the normal architecture of breast acini in 3D cell culture, nor cause DNA damage or induce apoptosis in these structures. Lastly, we show that systemically administered AgNPs are effective at non-toxic doses for reducing the growth of TNBC tumor xenografts in mice. This work provides a rationale for development of AgNPs as a safe and specific TNBC treatment. © 2019 The Authors.Suramin was introduced into the clinic a century ago and is still used to treat the first stage of acute human sleeping sickness. Due to its size and sixfold negative charge, uptake is mediated through endocytosis and the suramin receptor in trypanosomes is thought to be the invariant surface glycoprotein 75 (ISG75). Nevertheless, we recently identified a variant surface glycoprotein (VSGSur) that confers strong in vitro resistance to suramin in a Trypanosoma brucei rhodesiense line. In this study, we introduced VSGSur into the active bloodstream expression site of a T. b. brucei line. This caused suramin resistance and cross resistance to trypan blue. We quantified the endocytosis of different substrates by flow cytometry and showed that the expression of VSGSur strongly impairs the uptake of low-density lipoprotein (LDL) and transferrin, both imported by receptor-mediated endocytosis. However, bulk endocytosis and endocytosis of the trypanolytic factor were not affected, and the VSGSur -expressors did not exhibit a growth phenotype in the absence of suramin. Knockdown of ISG75 was synergistic with VSGSur expression, indicating that these two proteins are mediating distinct suramin resistance pathways. In conclusion, VSGSur causes suramin resistance in T. brucei bloodstream forms by decreasing specific, receptor-mediated endocytosis pathways. © 2019 The Authors.Background Subcutaneous implantable cardioverter-defibrillators (S-ICDs) are increasingly used in patients at risk of fatal cardiac arrhythmias. Twiddler's syndrome is a condition in which a device is manipulated by the patient after implantation leading to lead twisting and retraction. Device manipulation has been reported multiple times in transvenous pacing systems and occasionally leads to inappropriate discharges from implanted defibrillators. However, little has been reported about device manipulation in S-ICD devices. Case summary We present the case of a 16-year-old who underwent insertion of an S-ICD for idiopathic dilated cardiomyopathy. He represented for a pacing check following a discharge from the device. This showed a significant change in the sensed vectors. Chest radiographs confirmed lead retraction and suggested device manipulation. The device was turned off to prevent further inappropriate shocks. The patient underwent successful reimplantation of a S-ICD device. Discussion This case highlights that twiddler's syndrome can occur in those with an S-ICD and lead to an inappropriate device discharge. The patient in this case had a number of risk factors that have been previously associated with twiddler's syndrome. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.Background Cardiac metastasis of melanoma rarely causes heart failure symptoms and the recognition of cardiac involvement is in most cases first established post-mortem. Surgical removal might be considered in selected cases in patients with an inflow or outflow tract obstruction even though the survival remains poor. Frequently, the metastasis cannot be removed and therapeutic options include conventional chemotherapy or immunotherapy, which is currently recommended as first-line treatment. Since the introduction of immunotherapy survival in metastatic disease has significantly increased but data on patients treated for melanoma with cardiac involvement are scarce. Selleckchem tetrathiomolybdate Case summary A 65-year-old man presented with dyspnoea and fatigue. Computed tomography scan revealed tumour processes in the heart, which was confirmed on echocardiography. Biopsies taken from fluorodeoxyglucose positron emission tomography positive lymph nodes in the axilla and groin showed melanoma. Analyses did not reveal BRAF mutation and the PD-L1 expression in tumour cells was below 1%. Treatment with ipilimumab and nivolumab was initiated and cardiopulmonary symptoms subsided during the following months with significant reduction in cardiac metastasis on echocardiography. Unfortunately, the patient developed immune checkpoint inhibitor-induced colitis and could no longer continue on the therapy. Due to development of extra-cardiac and cerebral metastasis, he was referred to palliative care. Discussion This case demonstrates that timely treatment with immunotherapy could be a safe and effective option for melanoma with cardiac involvement. During treatment, the patient developed severe colitis, a known side effect to immunotherapy. Though this often can be managed with steroids it complicates further treatment. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.