Objectives: Lutetium-177 (¹⁷⁷Lu)-PSMA-617 (LuPSMA) is a radioligand with high affinity for prostate specific membrane antigen (PSMA) enabling targeted beta-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castrate-resistant prostate cancer (mCRPC). We now report their longer-term outcomes including a 20 patient extension cohort and outcomes of subsequent systemic treatments following completion of trial therapy. Methods: 50 patients with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. Endpoints included PSA response (PCWG2), toxicity (CTCAE v4.03), imaging response, patient-reported health-related quality of life (QoL), progression-free and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including LuPSMA. Results: 75 men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 months) and extensive prior treatment including prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline ≥ 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with ≥ 80% decrease. Of 27 patients with measurable soft tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to LuPSMA were self-limiting G1-2 dry mouth (66%), transient G1-2 nausea (48%), G3-4 thrombocytopenia (10%) and G3 anemia (10%). Brief pain inventory severity and interference scores decreased at all time points including at the 3 month follow-up with a decrease of -1.2 (95% CI -0.5 to -1.9, P = 0.001) and 1.0 (95% CI -0.2 to -0.18, P = 0.013), respectively. At a median follow-up of 31.4 months, median OS was 13.3 months (95% CI 10.5-18.7) with a significantly longer survival of 18.4 months (95% CI 13.8-23.8) in patients achieving a PSA decline ≥ 50%. At progression following prior response, further LuPSMA was administered to 15 (30%) patients (median 2 cycles commencing 359 days from enrolment) with PSA decline ≥ 50% in 11 patients (73%). 4 of 21 patients (19%) receiving other systemic therapies upon progression experienced PSA decline ≥ 50%. There were no unexpected adverse events with LuPSMA re-treatment. Conclusion: This expanded 50 patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity and improved QoL with LuPSMA radioligand therapy. Upon progression, re-challenge LuPSMA demonstrated higher response rates than other systemic therapies.

Purpose: To investigate differences between positron emission tomography/magnetic resonance imaging (PET/MRI) and PET/computed tomography (PET/CT) in lesion detection and classification in oncological whole-body examinations and to investigate radiation exposure differences between both modalities. Material and Methods: In this prospective, single-center, observational study 1003 oncological examinations (918 patients, mean age 57.8±14.4y) were included. Patients underwent PET/CT and subsequent PET/MRI (149.8±49.7min after tracer administration). Examinations were reviewed by radiologists and nuclear medicine physicians in consensus. Additional findings, characterization of indetermiante findings in PETCT, missed findings in PET/MRI including their clinical relevance and effective dose of both modalities were investigated. McNemar’s test was used to compare lesion detection between both hybrid imaging modalities (p<0.001 indicating statistical significance). Results: Additional information in PET/MRI was reported in 26.3% (264/1003) of examinations compared to PET/CT (p<0.001). Of these, additional malignant findings were detected in 5.3% (53/1003), leading to a change in TNM-staging in 2.9% (29/1003) due to PET/MRI. Definite lesion classification of indeterminate PET/CT findings was possible in 11.1% (111/1003) with PET/MRI. In 2.9% (29/1003), lesions detected in PET/CT were not visible in PET/MRI. Malignant lesions were missed in 1.2% (12/1003) by PET/MRI leading to a change in TNM-staging in 0.5% (5/1003). The estimated mean effective-dose for whole-body PET/CT amounted to 17.6±8.7mSv in comparison to 3.6±1.4mSv in PET/MRI, resulting in a potential dose reduction of 79.6% (p<0.001). Conclusion: PET/MRI improves lesion detection and potentially reduces additional examinations in tumor staging. Especially younger patients may benefit from the clinically relevant dose reduction of PET/MRI compared to PET/CT.

We performed post-hoc analyses on the utility of pre-therapeutic and early interim ⁶⁸Ga-DOTA-Tyr3-octreotide (⁶⁸Ga-DOTATOC) positron emission tomography (PET) tumor uptake and volumetric parameters and a recently proposed biomarker, the inflammation-based index (IBI), for peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumor (NET) patients treated with ⁹⁰Y-DOTATOC in the setting of a prospective phase II trial. Methods: Forty-three NET patients received up to four cycles of 1.85 GBq/m²/cycle ⁹⁰Y-DOTATOC with a maximal kidney biologic effective dose of 37 Gy. All patients underwent a ⁶⁸Ga-DOTATOC PET/computed tomography (CT) at baseline and seven weeks after the first PRRT cycle. ⁶⁸Ga-DOTATOC-avid tumor lesions were semi-automatically delineated using a customized standardized uptake value (SUV) threshold-based approach. PRRT response was assessed on CT using RECIST 1.1. Results: Median progression-free survival (PFS) and overall survival (OS) were 13.9 and 22.3 months, respectively. An SUVmean higher than 13.7 (75th percentile (P75)) was associated with better survival (hazard ratio (HR) 0.45; P = 0.024), whereas a ⁶⁸Ga-DOTATOC-avid tumor volume higher than 578 ml (P75) was associated with worse OS (HR 2.18; P = 0.037). Elevated baseline IBI was associated with worse OS (HR 3.90; P = 0.001). Multivariate analysis corroborated independent associations between OS and SUVmean (P = 0.016) and IBI (P = 0.015). No significant correlations with PFS were found. A composite score based on SUVmean and IBI allowed to further stratify patients in three categories with significantly different survival. On early interim PET, a decrease in SUVmean of more than 17% (P75) was associated with worse survival (HR 2.29; P = 0.024). Conclusion: Normal baseline IBI and high ⁶⁸Ga-DOTATOC tumor uptake predict better outcome in NET patients treated with ⁹⁰Y-DOTATOC. This can be used for treatment personalization. Interim ⁶⁸Ga-DOTATOC PET does not provide information for treatment personalization.

Triple negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer leading to the worst prognosis. Because current therapeutic approaches lack efficacy, there is a clinically unmet need for effective treatment alternatives. Herein, we demonstrate a promising strategy utilizing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with ¹⁷⁷Lu for targeted radionuclide therapy (TRT) of TNBC. In two murine syngeneic models of TNBC, we confirmed excellent tumor targeting and rapid normal tissue clearance of the PET imaging analog ⁸⁶Y-NM600. Based on longitudinal PET/CT data acquired with ⁸⁶Y-NM600, we estimated the dosimetry of therapeutic ¹⁷⁷Lu-NM600, which showed larger absorbed doses in the tumor compared to normal tissues. Administration of ¹⁷⁷Lu-NM600 resulted in significant tumor growth inhibition and prolonged overall survival in mice bearing syngeneic 4T07 and 4T1 tumors. Complete response was attained in 60% of 4T07 bearing mice, but animals carrying aggressive 4T1 tumor grafts succumbed to metastatic progression. The injected activities used for treatment (9.25 and 18.5 MBq) were well tolerated, and only mild transient cytopenia was noted. Overall, our results suggest that ¹⁷⁷Lu-NM600 TRT has potential for treatment of TNBC and merits further exploration in a clinical setting.

Rationale: The treatment of choice for insulinomas and focal lesions in congenital hyperinsulinism (CHI) is surgery. However, intra-operative detection can be challenging. This could be overcome with intra-operative fluorescence imaging, which provides real-time lesion detection with a high spatial resolution. Here, a novel method for targeted near-infrared (NIR) fluorescence imaging of glucagon-like peptide 1 receptor (GLP-1R) positive lesions, using the GLP-1 agonist exendin-4, labeled with IRDye800CW, was examined in vitro and in vivo. Methods: A competitive binding assay was performed using Chinese hamster lung (CHL) cells transfected with the GLP-1R. Tracer biodistribution was determined in BALB/c nude mice bearing subcutaneous CHL-GLP-1R xenografts. In vivo NIR fluorescence imaging of CHL-GLP-1R xenografts was performed. Localization of the tracer in the pancreatic islets of BALB/c nude mice was examined using fluorescence microscopy. Laparoscopic imaging was performed to detect the fluorescent signal of the tracer in the pancreas of mini pigs. Results: Exendin-4-IRDye800CW binds the GLP-1R with an IC50 value of 3.96 nM. The tracer accumulates in CHL-GLP-1R xenografts. Subcutaneous CHL-GLP-1R xenografts were visualized using in vivo NIR fluorescence imaging. The tracer accumulates specifically in the pancreatic islets of mice and a clear fluorescent signal was detected in the pancreas of mini pigs. Conclusion: These date provide the first in vivo evidence of the feasibility of targeted fluorescence imaging of GLP-1R positive lesions. Intra-operative lesion delineation using exendin-4-IRDye800CW could benefit open as well as laparoscopic surgical procedures for removal of insulinomas and focal lesions in CHI.

The purpose of this study was to establish the dose-response relationship of selective internal radiation therapy (SIRT) in patients with metastatic colorectal cancer (mCRC), when informed by radiobiological sensitivity parameters derived from mCRC cell lines exposed to yttrium-90 (⁹⁰Y). Methods: 23 mCRC patients with liver metastases refractory to chemotherapy were included. ⁹⁰Y bremsstrahlung SPECT images were transformed into dose maps assuming the local dose deposition method. Baseline and follow-up CT scans were segmented to derive liver and tumor volumes. Mean, median, and D₇₀ (minimum dose to 70% of tumor volume) values determined from dose maps were correlated with change in tumor volume and vRECIST response using linear and logistic regression, respectively. Radiosensitivity parameters determined by clonogenic assays of mCRC cell lines HT-29 and DLD-1 after exposure to ⁹⁰Y or external beam radiotherapy (EBRT; 6MV photons) were used in biological effective dose (BED) calculations. Results: Mean administered radioactivity was 1469±428 MBq (847-2185 MBq), achieving a mean radiation absorbed tumor dose of 35.5±9.4 Gy and mean normal liver dose of 26.4±6.8 Gy. A 1.0 Gy increase in mean, median, and D₇₀ absorbed dose was associated with reduction in tumor volume of 1.8%, 1.8%, and 1.5%, respectively, and increased probability of vRECIST response (odds ratio: 1.09, 1.09, and 1.10 respectively). Threshold mean, median and D₇₀ doses for response were 48.3, 48.8, and 41.8 Gy respectively. EBRT-equivalent BEDs for ⁹⁰Y are up to 50% smaller than those calculated by applying protraction-corrected radiobiological parameters derived from EBRT alone. Conclusion: Dosimetric studies have assumed equivalence between ⁹⁰Y SIRT and EBRT, leading to inflation of BED for SIRT and possible under-treatment. Radiobiological parameters for ⁹⁰Y were applied to a BED model, providing a calculation method that has the potential to improve assessment of tumor control.

In randomized clinical trials (RCTs), no survival benefit has been observed for selective internal radiotherapy (SIRT) over sorafenib in patients with advanced hepatocellular carcinoma (aHCC). This study aimed to assess by means of a meta-analysis whether overall survival (OS) with SIRT, as monotherapy or followed by sorafenib, is non-inferior to sorafenib, and compare safety profiles for patients with aHCC. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library up to February 2019 to identify RCTs comparing SIRT as monotherapy, or followed by sorafenib, to sorafenib monotherapy among patients with aHCC. The main outcomes were OS and frequency of treatment-related severe adverse events (AEs grade ≥3). The per-protocol population was the primary analysis population. A non-inferiority margin of 1.08 in terms of hazard ratio (HR) was pre-specified for the upper boundary of 95% confidence interval (CI) for OS. Pre-specified subgroup analyses were performed. Results: Three RCTs, involving 1,243 patients, comparing sorafenib with SIRT (SIRveNIB and SARAH) or SIRT followed by sorafenib (SORAMIC), were included. After randomization, 411/635 (64.7%) patients allocated to SIRT and 522/608 (85.8%) allocated to sorafenib completed the studies without major protocol deviations. Median OS with SIRT, whether or not followed by sorafenib, was non-inferior to sorafenib (10.2 and 9.2 months, [HR 0.91, 95% CI 0.78–1.05]). Treatment-related severe adverse events were reported in 149/515 patients (28.9%) who received SIRT and 249/575 (43.3%) who received sorafenib only (p<0.01). Conclusion: SIRT as initial therapy for aHCC is non-inferior to sorafenib in terms of OS, and offers a better safety profile.

Invitation Only Research Event

Event participants

Abebe Aemro Selassie, Director, African Department, International Monetary Fund
Chair: Elizabeth Donnelly, Deputy Head and Research Fellow, Africa Programme, Chatham House

10 October 2019

This briefing note is the result of a collaborative research process with the Zimbabwean private sector, government representatives, industry organizations and experts, drawing on best practice and senior-level insights to identify policy options for long-term economic revival and expansion in Zimbabwe, and pathways for inclusive development.

Invitation Only Research Event

Event participants

Hon Guillaume Soro, Chairman, Rassemblement Pour la Côte d’Ivoire (RACI)
Chair: Paul Melly, Consulting Fellow, Africa Programme, Chatham House

Research Event

Event participants

HE Alassane Ouattara, President, Republic of Côte d'Ivoire
Chair: Bob Dewar CMG, Associate Fellow, Africa Programme, Chatham House

Research Event

Event participants

Tutu Alicante, Executive Director, EG Justice
Chair: Dr Alex Vines OBE, Managing Director, Ethics, Risk & Resilience; Director, Africa Programme, Chatham House

Research Event

Event participants

Jon Temin, Director, Africa Programs, Freedom House
Chair: Rachael Jolley, Editor-in-chief, Index on Censorship 

Research Event

The increasing incidence of antimalarial drug resistance to the first-line artemisinin combination therapies underpins an urgent need for new antimalarial drugs, ideally with a novel mode of action. The recently developed 2-aminomethylphenol, JPC-3210, (MMV 892646) is an erythrocytic schizonticide with potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity, potent in vivo efficacy against murine malaria, and favorable preclinical pharmacokinetics including a lengthy plasma elimination half-life. To investigate the impact of JPC-3210 on biochemical pathways within P. falciparum-infected red blood cells, we have applied a "multi-omics" workflow based on high resolution orbitrap mass spectrometry combined with biochemical approaches. Metabolomics, peptidomics and hemoglobin fractionation analyses revealed a perturbation in hemoglobin metabolism following JPC-3210 exposure. The metabolomics data demonstrated a specific depletion of short hemoglobin-derived peptides, peptidomics analysis revealed a depletion of longer hemoglobin-derived peptides, and the hemoglobin fractionation assay demonstrated decreases in hemoglobin, heme and hemozoin levels. To further elucidate the mechanism responsible for inhibition of hemoglobin metabolism, we used in vitro β-hematin polymerization assays and showed JPC-3210 to be an intermediate inhibitor of β-hematin polymerization, about 10-fold less potent then the quinoline antimalarials, such as chloroquine and mefloquine. Further, quantitative proteomics analysis showed that JPC-3210 treatment results in a distinct proteomic signature compared with other known antimalarials. While JPC-3210 clustered closely with mefloquine in the metabolomics and proteomics analyses, a key differentiating signature for JPC-3210 was the significant enrichment of parasite proteins involved in regulation of translation. These studies revealed that the mode of action for JPC-3210 involves inhibition of the hemoglobin digestion pathway and elevation of regulators of protein translation. Importantly, JPC-3210 demonstrated rapid parasite killing kinetics compared with other quinolones, suggesting that JPC-3210 warrants further investigation as a potentially long acting partner drug for malaria treatment.

The use of protein biomarkers as surrogates for clinical endpoints requires extensive multilevel validation including development of robust and sensitive assays for precise measurement of protein concentration. Multiple reaction monitoring (MRM) is a well-established mass-spectrometric method that can be used for reproducible protein-concentration measurements in biological specimens collected via microsampling. The dried blood spot (DBS) microsampling technique can be performed non-invasively without the expertise of a phlebotomist, and can enhance analyte stability which facilitate the application of this technique in retrospective studies while providing lower storage and shipping costs, because cold-chain logistics can be eliminated. Thus, precise, sensitive, and multiplexed methods for measuring protein concentrations in DBSs can be used for de novo biomarker discovery and for biomarker quantification or verification experiments. To achieve this goal, MRM assays were developed for multiplexed concentration measurement of proteins in DBSs.

The lower limit of quantification (LLOQ) was found to have a median total coefficient of variation (CV) of 18% for 245 proteins, whereas the median LLOQ was 5 fmol of peptide injected on column, and the median inter-day CV over 4 days for measuring endogenous protein concentration was 8%. The majority (88%) of the assays displayed parallelism, whereas the peptide standards remained stable throughout the assay workflow and after exposure to multiple freeze-thaw cycles. For 190 proteins, the measured protein concentrations remained stable in DBS stored at ambient laboratory temperature for up to 2 months. Finally, the developed assays were used to measure the concentration ranges for 200 proteins in twenty same sex, same race and age matched individuals.

Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behcet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position ). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ~40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.

Coenzyme Q (Qn) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1–coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q6. The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q6 at an impaired rate. Thus, Coq10 is required for the function of Q6 in respiration and as an antioxidant and is believed to chaperone Q6 from its site of synthesis to the respiratory complexes. In several fungi, Coq10 is encoded as a fusion polypeptide with Coq11, a recently identified protein of unknown function required for efficient Q6 biosynthesis. Because “fused” proteins are often involved in similar biochemical pathways, here we examined the putative functional relationship between Coq10 and Coq11 in yeast. We used plate growth and Seahorse assays and LC-MS/MS analysis to show that COQ11 deletion rescues respiratory deficiency, sensitivity to lipid peroxidation, and decreased Q6 biosynthesis of the coq10Δ mutant. Additionally, immunoblotting indicated that yeast coq11Δ mutants accumulate increased amounts of certain Coq polypeptides and display a stabilized CoQ synthome. These effects suggest that Coq11 modulates Q6 biosynthesis and that its absence increases mitochondrial Q6 content in the coq10Δcoq11Δ double mutant. This augmented mitochondrial Q6 content counteracts the respiratory deficiency and lipid peroxidation sensitivity phenotypes of the coq10Δ mutant. This study further clarifies the intricate connection between Q6 biosynthesis, trafficking, and function in mitochondrial metabolism.

Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance.

Research Event

Event participants

Michael Gasiorek, Professor of Economics, University of Sussex; Director, Interanalysis; Fellow, UK Trade Policy Observatory, University of Sussex
Julia Magntorn Garrett, Research Officer, UK Trade Policy Observatory, University of Sussex
Prof Jim Rollo, Deputy Director, UK Trade Policy Observatory, University of Sussex; Associate Fellow, Global Economy and Finance Department, Chatham House
Nicolo Tamberi, Research Officer in the Economics of Brexit, University of Sussex
L. Alan Winters, Professor of Economics, Director, UK Trade Policy Observatory, University of Sussex

14 January 2020

Corporate Members Event

Event participants

Dr Yu Jie, Senior Research Fellow on China, Asia-Pacific Programme, Chatham House
David Lubin, Associate Fellow, Global Economy and Finance Programme, Chatham House; Managing Director and Head of Emerging Markets Economics, Citi
Jinny Yan, Managing Director and Chief China Economist, ICBC Standard
Chair: Creon Butler, Director, Global Economy and Finance Programme, Chatham House

24 March 2020

Members Event Webinar

Event participants

Pepijn Bergsen, Research Fellow, Europe Programme, Chatham House

Dr Sheri Berman, Professor of Political Science, Barnard College

Chair: Hans Kundnani, Senior Research Fellow, Europe Programme, Chatham House

Edward A Dennis
Apr 28, 2020; 0:jlr.T120000868v1-jlr.T120000868
Tribute

Ashley J. Snider
Apr 1, 2020; 61:466-467
Tribute

Souad Amiar
Apr 15, 2020; 0:jlr.ILR120000753v1-jlr.ILR120000753
Images in Lipid Research

Producer Chris dives in this week to discuss the HTC 10 release, and why it's difficult to get excited about good mobile phones. Then Techworld.com editor Charlotte Jee chats Facebook chatbots and other F8 news (12:30). Finally, editor at Digitalartsonline.co.uk Neil Bennett jumps in to discuss the new Amazon e-reader (31:00) Kindle Oasis and why everyone is kicking off about the price.  

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Editor Matt Egan sits down with staff writer at PC Advisor Lewis Painter to chat about Samsung's S8 rumours. Editor of Techworld.com Charlotte Jee discusses all the goings on from London Tech Week and if London is as much of a tech city as it says it is (12:00). Finally, regular guest David Price, editor at Macworld UK, comes on to discuss Mark Zuckerberg's webcam paranoia and cyber security (22:00).  

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This week host Matt Egan is joined by first time podder and editor of PC Advisor Jim Martin to chat Microsoft Windows 10 anniversary updates and the impact on Microsoft Surface devices. Producer Chris then comes on to chat about Sky's two big NOW TV announcements, and the future of television and broadband (16:00). Finally, UKTW podcast regular David Price chats about the impact technology is having on our holidays (26:30).  

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In Matt Egan's absence first time host Henry Burrell heroically steps in to chat about Pokemon Go with producer Chris. Then fellow staff writer Chris Minasians discusses iOS 10 beta and all of the rumoured features for the latest Apple operating system, including dark mode (10:30). Finally, Lewis Painter, staff writer at PC Advisor, talks about Playstation VR being released for the PS4, pricing and games (23:30).  

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Hosting duties fall to Henry Burrell this week as he discusses the deadline for the free Microsoft Windows 10 update with Chris Minasians, staff writer at PC Advisor. Scott Carey, online editor at Techworld.com jumps in to talk about why the Verizon deal for Yahoo is ridiculous and charts the missteps that got the company to this point (15:00). Finally, regular guest David Price discusses Apple's less than stellar financial results and if the iPhone is plateauing (26:00).  

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This week Ashleigh Allsopp is simultaneously fascinated and worried by the UK launch of Amazon's Dash buttons, and discusses the many wonderful and not-so-wonderful things they enable you to buy on a drunken whim. Then David Price takes his turn to shine a spotlight on Apple's mysterious tax affairs (12:20) and tries to explain why the Irish government doesn't want to be given 13 billion euros. Finally a surprisingly riled-up Neil Bennett explains why women wearing headphones are not fair game for dimwitted pick-up artists (25:00), and ponders the social conventions surrounding the place of technology in each of our lives.  

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Host Matt Egan is in a sombre mood this week as the tech industry comes to terms with a Donald Trump US presidency. Staff writer at Macworld UK dives into what this could mean for Silicon Valley, Apple products and wether social media is at fault. Then producer Chris comes on to discuss the latest addition to the VR headset market with Google's Daydream. Will it be held back by a lack of applications though? (14:45) Finally, online editor at Computerworld UK talks about the biggest data breach at a UK bank, as Tesco Bank suffers a £2.5 million cyber theft and what this means for the banking industry as a whole (25:00).  

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The first pod of 2017 explodes into view like your hangover on January 1st with host David Price probing the panel on its blurry eyed take on tech in the New Year. Ashleigh Macro, Engagement Editor of PC Advisor and Macworld UK returns to the pod to recap the expected and unexpected tech of 2016. Will Apple and Amazon reign supreme? Then Chris Martin, Consumer Tech Editor at PC Advisor, hot off the plane from CES in Las Vegas to discuss what was hot and what was really not at the largest tech show in the world. To top it off with some New Year optimism is pod debutant Tom MacAulay, Online Editor at Computerworld UK to let us know all the good (but mainly bad) things we can expect in warfare tech in the next decade.  

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Momentous scenes as the pod celebrates its Golden Jubilee. Matt Egan is joined by some very special guests to congratulate the gang on the milestone while indulging in some points based tech quizzing. Join Chris Martin, Charlotte Jee, Dom Preston and Henry Burrell to recap questions from pods gone by with a new twist, and have a long hard think about what tech will be 50 more episodes from now. The prize? A small bronze jug. Obviously. NB. May not actually be 50 minutes, sorry.  

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Techworld Editor Charlotte Jee conducts the tech orchestra this week, trying to get a tune out of this cold, creaking week. Online Editor at Computerworld UK Scott Carey lets us know all about Snapchat's upcoming IPO, billions of dollars, and the gang comes to the realisation they'll perhaps never understand what it's for. Then Senior Staff Writer at PC Advisor Henry Burrell recaps on Google and LG's launch of Android Wear 2.0 and ask - frankly - is it a big deal? Finally Acting Editor at Macworld UK David Price discusses Apple's rumoured plans to move manufacturing to India, which inevitably moves us on to Tech Trumps.  

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Matt Egan takes us where no other pod has dared gone before (September 2000) and asks Digital Arts Editor Neil Bennett if anyone cares that Nokia is rereleasing the famous 3310. Is it cool to rock one now? Then Techworld Audience Development Editor Christina Mercer lets us know that the future is already here with self driving drone taxis. Would you hitch a lift round Dubai on a massive quadcopter? Finally Deputy Editor at Macworld David Price ruminates on Apple's forecast foray into the world of snackable media content - will it challenge Netflix or try to buy it?  

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Back with a bumper edition after the Easter break, as Henry Burrell takes Scott Carey, David Price and Dom Preston on a chat odyssey to discuss Facebook's F8 conference. Will chat bots ever be good and who uses QR codes? The gang then discusses Apple's out of character decision to brief journos on the Mac Pro and even admit they got it wrong. Finally we talk about Nintendo stopping production of the NES Classic and whether there's more affordable retro goodness around the corner.  

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A classic edition of the pod as we hark back to the hallowed three topic format. Henry Burrell hosts David Price, Scott Carey and Chris Martin to ask just how Netflix got so popular. Will it sustain it though? Windows Phone is also pretty much actually dead but the funeral march is long. Other phone stuff includes the hallowed iPhone 8, the demise of Vertu and Nokia not really being Nokia. David then tells us why Google Glass is back, what it means for the enterprise, and why didn't they realise the first time round that it wasn't a consumer play?  

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Scott Carey necessarily tries to get his pronunciation game on fleek to deliver the latest Uber news - there's a new CEO in town, and it isn't a woman. Should it have been? He tells Henry Burrell what's next for the company. Then roles are reversed as Henry updates Scott on the Galaxy Note 8, LG V30 and September 12's very own iPhone 8 - will it be called that? Will anyone spend £1,000 on it?  

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