Interaction between the NS4B amphipathic helix, AH2, and charged lipid headgroups alters membrane morphology and AH2 oligomeric state — Implications for the Hepatitis C virus life cycle

AbstractThe non-structural protein 4B (NS4B) from Hepatitis C virus (HCV) plays a pivotal role in the remodelling of the host cell's membranes, required for the formation of the viral replication complex where genome synthesis occurs. NS4B is an integral membrane protein that possesses a number of domains vital for viral replication. Structural and biophysical studies have revealed that one of these, the second amphipathic N-terminal helix (AH2), plays a key role in these remodelling events. However, there is still limited understanding of the mechanism through which AH2 promotes these changes. Here we report on solid-state NMR and molecular dynamics studies that demonstrate that AH2 promotes the clustering of negatively charged lipids within the bilayer, a process that reduces the strain within the bilayer facilitating the remodelling of the lipid bilayer. Furthermore, the presence of negatively charged lipids within the bilayer appears to promote the disassociation of AH2 oligomers, highlighting a potential role for lipid recruitment in regulating NS protein interactions

Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma

Background: AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC). Methods: AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival. Results: During escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III–IV AEs. Six-month PFS was 85% (90% CI: 66%–94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024). Conclusion: Xelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791)

Performance of asphalt concrete mixes containing large size mineral aggregates

Peer reviewed: YesNRC publication: Ye

Components of the full blood count as risk factors for colorectal cancer detection: a systematic review protocol

Introduction: Colorectal cancer is the fourth most common type of cancer and second most common cause of cancer-related death in the UK. The full blood count (FBC) is a blood test that may play a role in early detection of the disease. Previous studies have aimed to identify how levels of individual components, such as haemoglobin, can be used to assist diagnosis. We aim to systematically review studies to identify whether components of the FBC are risk factors for diagnosis of colorectal cancer, critically appraise the methods used to assess the association, and assess performance of components. Methods and analysis: The MEDLINE (via OVID), EMBASE (via OVID), CINAHL (via EBSCOhost), and Web of Science databases will be searched to identify in-human studies reporting the association between levels of at least one FBC component and risk of a future diagnosis of colorectal cancer. Clincialtrials.gov and the World Health Organisation (WHO) registry will be searched to identify relevant on-going research. Search terms will include relevant Medical Subject Headings (MeSH) and Emtree headings and free-text terms relating to the FBC, colorectal cancer, and diagnosis. No date or language restrictions will be applied. Two reviewers will independently identify studies for inclusion and perform data extraction. Time intervals between the blood tests and diagnosis will form subgroups for analysis. Ethics and dissemination: There is no direct patient involvement and only published articles will be reviewed; no ethical approval is required. Results from this review will set a foundation for intended future work on developing a new risk score for early detection of colorectal cancer, derived using FBC data. This systematic review will also provide guidance on the analysis of time to diagnosis. The model will be freely available to UK primary care practices.</p

Components of the full blood count as risk factors for colorectal cancer detection: a systematic review protocol

Introduction: Colorectal cancer is the fourth most common type of cancer and second most common cause of cancer-related death in the UK. The full blood count (FBC) is a blood test that may play a role in early detection of the disease. Previous studies have aimed to identify how levels of individual components, such as haemoglobin, can be used to assist diagnosis. We aim to systematically review studies to identify whether components of the FBC are risk factors for diagnosis of colorectal cancer, critically appraise the methods used to assess the association, and assess performance of components. Methods and analysis: The MEDLINE (via OVID), EMBASE (via OVID), CINAHL (via EBSCOhost), and Web of Science databases will be searched to identify in-human studies reporting the association between levels of at least one FBC component and risk of a future diagnosis of colorectal cancer. Clincialtrials.gov and the World Health Organisation (WHO) registry will be searched to identify relevant on-going research. Search terms will include relevant Medical Subject Headings (MeSH) and Emtree headings and free-text terms relating to the FBC, colorectal cancer, and diagnosis. No date or language restrictions will be applied. Two reviewers will independently identify studies for inclusion and perform data extraction. Time intervals between the blood tests and diagnosis will form subgroups for analysis. Ethics and dissemination: There is no direct patient involvement and only published articles will be reviewed; no ethical approval is required. Results from this review will set a foundation for intended future work on developing a new risk score for early detection of colorectal cancer, derived using FBC data. This systematic review will also provide guidance on the analysis of time to diagnosis. The model will be freely available to UK primary care practices.</p

The full blood count blood test for colorectal cancer detection: a systematic review, meta-analysis, and critical appraisal

Introduction A full blood count (FBC) blood test includes 20 components. We systematically reviewed studies that assessed the association of the FBC and diagnosis of colorectal cancer to identify components as risk factors. We reviewed FBC-based prediction models for colorectal cancer risk. Methods: MEDLINE, EMBASE, CINAHL, and Web of Science were searched until 3 September 2019. We meta-analysed the mean difference in FBC components between those with and without a diagnosis and critically appraised the development and validation of FBC-based prediction models. Results We included 53 eligible articles. Three of four meta-analysed components showed an association with diagnosis. In the remaining 16 with insufficient data for meta-analysis, three were associated with colorectal cancer. Thirteen FBC-based models were developed. Model performance was commonly assessed using the c-statistic (range 0.72–0.91) and calibration plots. Some models appeared to work well for early detection but good performance may be driven by early events. Conclusion Red blood cells, haemoglobin, mean corpuscular volume, red blood cell distribution width, white blood cell count, and platelets are associated with diagnosis and could be used for referral. Existing FBC-based prediction models might not perform as well as expected and need further critical testing

Repair and Upgrading of Infrastructure Facilities

Aussi disponible en francais: La R\ue9paration et la r\ue9fection des infrastructuresPeer reviewed: NoNRC publication: Ye