Copper stimulates the proliferation and migration of endothelial cells and is required for the secretion of several angiogenic factors by tumour cells. Copper chelation decreases the secretion of ...many of these factors. Serum copper levels are upregulated in many human tumours and correlate with tumour burden and prognosis. Copper chelators reduce tumour growth and microvascular density in animal models. New orally active copper chelators have enabled clinical trials to be undertaken, and there are several studies ongoing. A unifying mechanism of action by which copper chelation inhibits endothelial cell proliferation and tumour secretion of angiogenic factors remains to be elucidated, but possible targets include copper-dependent enzymes, chaperones, and transporters.
Copper is required for the proliferation of endothelial cells and copper-lowering therapy reduces tumour growth in animal models. It has been reported that ATN-224, a novel copper chelator, potently ...inhibits the activity of the copper-dependent enzyme superoxide dismutase 1 (SOD1) in endothelial cells. We performed microarray analysis of gene expression in endothelial cells exposed to ATN-224 which revealed upregulation of stress response genes including heme-oxygenase 1 (HO-1) and differential regulation of several genes previously implicated in angiogenesis including CXCR4, ANGP2, PGES2, RHAMM, ITB4 and AQP1 (
p
<
0.01). These changes were confirmed on qPCR. Treatment of HUVEC with ATN-224 caused increased superoxide levels, phospho-ERK signalling, nuclear NRF1 expression, HO-1 expression and induction of the anti-apoptotic proteins P21, BCL2 and BCLXL. There was also nuclear translocation of SOD1. SOD1 RNA interference replicated the effects of ATN-224 on endothelial cell function but did not cause upregulation of HO-1 or PGES2, suggesting additional mechanisms of action of ATN-224. Downregulation of AQP1, which has been shown to have a role in angiogenesis, was seen with both ATN-224 and SOD1 siRNA. AQP1 expression could be rescued after ATN-224 by added copper. RNA interference to AQP1 inhibited endothelial proliferation and migration, confirming the role of AQP1 in endothelial cell function. Therefore regulation of AQP1 may represent an important action of copper chelation therapy.
Background
The adjuvanted recombinant zoster vaccine (RZV) has demonstrated >90% efficacy against herpes zoster in adults ≥50 years of age and 68% efficacy in autologous hematopoietic stem cell ...transplant recipients ≥18 years of age. We report the immunogenicity and safety of RZV administered to patients with solid tumors (STs) before or at the start of a chemotherapy cycle.
Method
In this phase 2/3 observer‐blind, multicenter study (NCT01798056), patients with STs who were ≥18 years of age were randomized (1:1) to receive 2 doses of RZV or placebo 1‐2 months apart and stratified (4:1) according to the timing of the first dose with respect to the start of a chemotherapy cycle (first vaccination 8‐30 days before the start or at the start ±1 day of a chemotherapy cycle). Anti‐glycoprotein E (gE) antibody concentrations, gE‐specific CD4+ T cell frequencies, and vaccine response rates (VRRs) were assessed 1 month after dose 1 and 1 and 12 months after dose 2. Reactogenicity and safety were assessed in the total vaccinated cohort through 12 months after dose 2.
Results
There were 232 participants in the total vaccinated cohort, 185 participants in the according‐to‐protocol cohort for humoral immunogenicity, and 58 participants in the according‐to‐protocol cohort for cell‐mediated immunogenicity. Postvaccination anti‐gE antibody concentrations, gE‐specific CD4+ T cell frequencies and VRRs were higher in RZV recipients than in placebo recipients. Solicited adverse events (AEs) were more frequent among RZV recipients than placebo recipients. Incidence of unsolicited AEs, serious AEs, fatalities, and potential immune‐mediated diseases were similar between RZV and placebo recipients.
Conclusion
RZV was immunogenic in patients with STs receiving immunosuppressive chemotherapies. Humoral and cell‐mediated immune responses persisted 1 year after vaccination. No safety concerns were identified.
In patients with solid tumors treated with immunosuppressive chemotherapies, the adjuvanted recombinant zoster vaccine (RZV) was immunogenic and immunogenicity persisted through 1 year after vaccination. RZV was well tolerated, and no safety concerns were identified.
Rituximab is a chimeric mouse/human anti-CD20 antibody licensed for the treatment of low-grade non-Hodgkin’s lymphoma and has recently also been shown to have a role in the treatment of diffuse large ...B-cell lymphoma. We report a case of Stevens–Johnson syndrome after treatment with rituximab, which occurred in a 36-year-old man with relapsed follicular lymphoma. The patient developed mucositis and fevers after the first two injections, followed by a florid maculopapular rash with severe orogenital ulceration after the third infusion. Over several weeks his symptoms progressed with severe cutaneous, orogenital and conjunctival ulceration, leading to visual problems and malnutrition. No improvement occurred with steroids and immunosuppressant therapy. A review of the literature reveals this to be the first reported case of Stevens–Johnson syndrome associated with rituximab therapy.
In this consideration of Thea Djordjadze's work, Sarah Lowndes looks at the processes of creation, ritual and translation in her obliquely referential sculptures and installations.
Despite adequate surgery, a diagnosis of stage III melanoma carries a high risk of relapse, and hence mortality. Interferon alfa is the only treatment that has currently been shown to alter the ...natural history of the disease, delaying relapse-free survival, particularly in patients with micrometastatic disease. There is also recent evidence of a prognostic advantage conferred by the development of autoimmune conditions in patients receiving adjuvant interferon therapy.
We present the case of a 27-year-old woman with stage IIIa melanoma who was entered into the European Organisation for the Research and Treatment of Cancer 18991 trial of 5-year adjuvant treatment with pegylated interferon (peginterferon) alfa-2b. The patient developed thyrotoxicosis 3 months after commencing treatment, which required treatment with propylthiouracil. The degree of thyrotoxicosis corresponded closely to the dose of peginterferon alfa-2b given. However, in this patient, the hyperthyroidism resolved spontaneously after 4 years when peginterferon treatment was still ongoing. Seven years following the initial diagnosis, the patient has not had disease relapse.
Hyperthyroidism is less common than hypothyroidism as a consequence of interferon therapy, and this case is atypical in that it resolved spontaneously during interferon therapy but is in accordance with the recent evidence of a positive association between interferon-associated autoimmunity and prognosis.
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