Investigating the effect of photodynamic therapy on nerves using tissue engineered culture models

Introduction: Photodynamic therapy (PDT) shows potential as an effective treatment for prostate cancer. Clinical observations indicate that this approach causes fewer nerve damage related side-effects than conventional treatments. The aim here is to investigate the effect of PDT on nerve tissue using engineered 3-dimensional cell culture models. Initial experiments focussed on establishing photosensitiser localisation in neurones and Schwann cells, then developing a model for simulating nerve PDT in culture

Endoplasmic reticulum stress in malignancy.

The combination of relative nutrient deprivation and dysregulation of protein synthesis make malignant cells especially prone to protein misfolding. Endoplasmic reticulum stress, which results from protein misfolding within the secretory pathway, has a profound effect on cancer cell proliferation and survival. In this review, we examine the evidence implicating endoplasmic reticulum dysfunction in the pathology of cancer and discuss how recent findings may help to identify novel therapeutic targets

p53 and translation attenuation regulate distinct cell cycle checkpoints during endoplasmic reticulum (ER) stress.

Cell cycle checkpoints ensure that proliferation occurs only under permissive conditions, but their role in linking nutrient availability to cell division is incompletely understood. Protein folding within the endoplasmic reticulum (ER) is exquisitely sensitive to energy supply and amino acid sources because deficiencies impair luminal protein folding and consequently trigger ER stress signaling. Following ER stress, many cell types arrest within the G(1) phase, although recent studies have identified a novel ER stress G(2) checkpoint. Here, we report that ER stress affects cell cycle progression via two classes of signal: an early inhibition of protein synthesis leading to G(2) delay involving CHK1 and a later induction of G(1) arrest associated both with the induction of p53 target genes and loss of cyclin D(1). We show that substitution of p53/47 for p53 impairs the ER stress G(1) checkpoint, attenuates the recovery of protein translation, and impairs induction of NOXA, a mediator of cell death. We propose that cell cycle regulation in response to ER stress comprises redundant pathways invoked sequentially first to impair G(2) progression prior to ultimate G(1) arrest

Reply to 'Comment on 'Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy''.

Background: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. Methods: We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. Results: Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. Conclusions: Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance

Evaluating the Effects of Membranes, Cell Designs, and Flow Configurations on the Performance of Cu-GDEs in Converting CO2to CO

In this study, we evaluate the effect of cell configuration parameters on electrochemical reduction of CO2 using Cu gas-diffusion electrodes (Cu-GDEs), including the use of proton- or anion-exchange membranes, the CO2 flow configuration, and the Nafion content used in the ink formulation to prepare the Cu-GDEs. Using a cell configuration (i) containing a Sustainion membrane, (ii) allowing a liquid flow of catholyte and anolyte, and (iii) providing convective supply of CO2 in a flow-through mode, outstanding faradaic efficiencies toward carbon monoxide (FECO = ∼85%, at -0.88 V vs RHE, and 50 mA·cm-2) were obtained. We attribute this performance to an efficient desorption and transport of CO to the exit of the reactor, in agreement with the remarkably low FE toward ethylene at the applied electrochemical potentials. Most importantly, in this configuration and optimizing the Nafion content in the ink formulation to 10 wt %, cell performance could be maintained for at least 10 h of continuous operation at the high FECO of ∼85%

Infliximab for the treatment of Ipilimumab (anti CTLA-4) and Nivolumab/Pembrolizumab (anti PD-1) associated colitis

Introduction: Immunotherapy with anti CTLA-4 (Ipilimumab) or anti PD-1 (Pembrolizumab, Nivolumab) antibodies are now the standard of care for metastatic melanoma and other malignancies. These drugs have been associated with various immune related adverse events, including autoimmune colitis with marked similarity to idiopathic inflammatory bowel disease. Current literature regarding immunotherapy related colitis (IRC) are scarce and very little treatment-related data exist. Aims: To describe the clinical spectrum of immunotherapy-related colitis (IRC) and treatment response to systemic steroids alone or a combination of systemic steroids and infliximab therapy. Methods: A retrospective review of case-notes of patients undergoing treatment with Ipilimumab and anti PD-1 therapy from 2009–2015 was conducted across two tertiary referral facilities,Westmead Hospital and the Melanoma Institute Australia. Multiple variables related to the development of colitis, doses of immunotherapy, time from therapy to colitis and treatment of colitis were documented. Patients received treatment with steroid alone or steroids plus infliximab. Symptom resolution was defined no episodes of diarrhea as per patient survey on follow up. Statistical analysis was with SPSS version 23 using t-test analysis. Results: 19 patients (11 male, 8 female) developed IRC. Mean age of onset was 62 years (41–83 yrs). Of these, 16 received treatment with Ipilimumab (15 melanoma, 1 renal cell carcinoma) while three received anti PD-1 therapy alone (2 melanoma, 1 lung cancer). 17 patients had documented endoscopic and histopathological evidence of colitis. All patients received high dose steroid either as intravenous, oral (1–2 mg/kg) or combination. 14/16 patients treated with Ipilimumab were documented to have mild-moderately active disease, with a mean Mayo Endoscopic Score of 1.78 (0–3) with presence of cryptitis, crypt abscesses and lymphocytic infiltration on histopathology. Colitis was predominantly limited to distal colon (proctitis n = 4, left colon n = 7, pancoltis n = 2, R. sided n = 1). Mean onset of colitis from first dose of Ipilimumab was 72 days (8–146 days). 10 patients received high dose steroid therapy only, while 9 patients, with persistent symptoms despite steroid therapy received further treatment with infliximab, as per physician discretion. The mean time to resolution for those treated with corticosteroids only was 61 days whereas those treated with corticosteroids then infliximab was 12 days from the initiation of rescue therapy (p = 0.0873). Of the 16 patient’s treated with Ipilimumab it was noted three patients developed colitis upon being changed rapidly from Ipilimumab to PD-1 therapy (2–26 days). These were though unlikely to be attributable to the addition of PD-1 therapy, given the timing of symptom onset. Three patient’s developed IRC while being treated with anti-PD-1 monotherapy. Anti PD-1 associated IRC, was limited to a L. sided colitis, and were recorded to have Mayo Endoscopy scores of 1,1 and 1 respectively consistent with mild disease. In this group two patients had symptom resolution with steroid therapy alone with one patient requiring rescue therapy with infliximab. The mean time to resolution of symptoms for treatment with steroids only was 36 days, while the mean time to resolution after initiation of rescue therapy was also noted to be 36 days. Conclusions / Discussion: Immunotherapy-related colitis is an important emerging clinical entity and has clinical and histologic similarities to idiopathic inflammatory bowel disease. Infliximab appears to induce earlier resolution of symptoms in patient’s refractory to steroid treatment, and this result trends towards significance. Future research implications include immune-pathogenic analysis of IRC to improve insight into the pathogenesis of idiopathic inflammatory bowel disease.1 page(s