Ultrastructural study of hepatic stellate cells ( Ito cells) after teratogenic drug treatment in pregnancy: Experimental study in Balb/c mice

Introduction-Aim of the study: Ito cells are the hepatic stellate cells in the space of Disse. They play a key role in the development and regeneration of liver. Retinoid analogues are used therapeutically, while hydroxyurea (HU) is an antiretroviral and chemotherapeutic agent. The aim of this study is to evaluate the effect of the above substances on Ito cells’ ultrastructural morphology by TEM observations.Materials-Methods: Six groups of pregnant Balb/C mice were used for the study. All animals were treated on gestational days 10th, 11th, 12th. The first group was treated with All-Trans Retinoic Acid (RA), the second group with Retinyl Palmitate (RP), the third group with a combination of 13-cis RA and RP and the fourth group with HU. The fifth and the sixth groups were the control animals. Animals were sacrificed on the 19th gestational day. Livers from all animals were removed and were properly prepared for TEM observation.Results: Observation of the liver of All-Trans RA treated pregnant animals revealed Ito cell activation. Microbodies similar to peroxisomes and lysosomes were present in their cytoplasm. Similar findings were found in RP treated animals. In the activated stellate cells, the presence of microfibrils around their nuclei appeared with chromatin condensation in the periphery. In the liver of animals treated with a combination of RP and 13-Cis RA, microfibrils in the cytoplasm, fibrosis and extracellular edema were observed around the sinusoids. In the liver of HU treated animals, peroxisomes with different density were observed in the hepatocyte cytoplasm, surrounded by lipid droplets. In the cytoplasm of activated Ito cells, low density peroxisomes were observed. Fibrosis and extracellular edema were observed surrounding the sinusoids among the stellate cells and in the space of Disse.Conclusions: This ultrastructural study indicates that the drugs induced Ito cell activation and caused possibly irreversible damage to liver parenchyma

Parvovirus 4 Infection and Clinical Outcome in High-Risk Populations

Parvovirus 4 (PARV4) is a DNA virus frequently associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, but its clinical significance is unknown. We studied the prevalence of PARV4 antibodies in 2 cohorts of HIV- and HCV-infected individuals (n=469) and the correlations with disease status. We found that PARV4 infection frequently occurred in individuals exposed to bloodborne viruses (95% in HCV-HIV coinfected intravenous drug users [IDUs]). There were no correlations between PARV4 serostatus and HCV outcomes. There was, however, a significant association with early HIV-related symptoms, although because this was tightly linked to both HCV status and clinical group (IDU), the specific role of PARV4 is not yet clea

Adopt to adapt: Efforts to Keep the RAMPART Trial of Adjuvant Immunotherapy in Renal Cancer on Track in the COVID-19 Era

Introduction: The RAMPART trial is an international, UCL-led, multi-arm multi-stage (MAMS) platform trial investigating the use of immune checkpoint inhibitors after nephrectomy in patients with renal cell carcinoma. It was initiated with a control (active monitoring) and two research arms (durvalumab monotherapy and durvalumab with tremelimumab) and has been open to recruitment since July 2018. Due to the COVID-19 pandemic, recruitment and treatment delivery was suspended for four months in the Spring/Summer of 2020 and accrual has only recovered in 2022. / Methods/Approach: The RAMPART team provided clear communication to sites on how to manage priorities during the temporary suspension and relaunch of the trial. The protocol was amended to ensure the safe treatment of patients and to offer flexibility to conduct consent and certain assessments remotely. Sites were asked to focus on the submission of high priority data to permit continued oversight of patient safety and allow primary outcome data to be collected. Data completeness has been carefully monitored and targeted data chases have been conducted to maximise data integrity. We have explored the extent to which the pandemic will prolong recruitment and follow-up, and the timelines for our primary analyses. To maximise options for patients and to aid accrual, we examined the impact of re-randomisation of control arm patients within the protocol, an approach that has been employed in other trials within the CTU in other disease areas. / Results Structure & Timelines: This section will contain an update on compliance, recruitment, sites open and timelines for analysis. In order to be able to present these adequately and robustly, we will use data up to September 2022. / Potential Relevance & Impact: The pandemic era has been challenging for clinical trials. Adaptations can be made to prioritise patient safety, to allow activity to continue where there is capacity and to ensure trial integrity is maintained

Parvovirus 4 Infection and Clinical Outcome in High-Risk Populations

Parvovirus 4 (PARV4) is a DNA virus frequently associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, but its clinical significance is unknown. We studied the prevalence of PARV4 antibodies in 2 cohorts of HIV- and HCV-infected individuals (n = 469) and the correlations with disease status. We found that PARV4 infection frequently occurred in individuals exposed to bloodborne viruses (95% in HCV-HIV coinfected intravenous drug users [IDUs]). There were no correlations between PARV4 serostatus and HCV outcomes. There was, however, a significant association with early HIV-related symptoms, although because this was tightly linked to both HCV status and clinical group (IDU), the specific role of PARV4 is not yet clear

Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial.

PURPOSE: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.CRU

Polarization and Effects on Hidden Node/Shadowing Margin for TVWS

Dual polarized measurements comparing the received power of a line of sight broadcast signal in the ultra-high frequency band with received power in suburban streets and indoors including high rise buildings are presented in this paper. Both the co-polarized and cross-polarized fades are therefore measured in the different locations. Their purpose is twofold: 1) to identify the importance of using polarization when considering hidden node margins in spectrum sensing of television white spaces and 2) to indicate how polarization can be beneficial in improving the shadowing margin to increase the path loss from the secondary to primary user and thus further protect digital terrestrial television receivers from harmful interference. The impact of polarization in open environments with low clutter or near windows inside high rise buildings is more significant than in densely cluttered spaces experiencing strong multipath

RAMPART : a model for a regulatory-ready academic-led phase III trial in the adjuvant renal cell carcinoma setting

AstraZeneca LP have provided an educational grant for the trial and free of charge durvalumab and tremelimumab. A small grant is also provided by Kidney Cancer UK. MRC CTU at UCL provides funding for staff working on the trial.The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations.Publisher PDFPeer reviewe

RAMPART : a phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse

AstraZeneca LP have provided an educational grant for the trial and free of charge durvalumab and tremelimumab. A small grant is also provided by Kidney Cancer UK. MRC CTU at UCL also provides funding for staff working on the trial. The TransRAMPART sample collection is being funded by a Prospective Sample Collection award from Cancer Research UK.Background 20–60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. Methods/design RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3–11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART).Publisher PDFPeer reviewe

Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease:Study protocol for a randomised controlled trial (ELAD study)

Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. Methods/design: ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale - Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study - Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. Discussion: Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. Trial registration: ClinicalTrials.gov, NCT01843075. Registration 30 April 2013

Association of cardiovascular risk factors with MRI indices of cerebrovascular structure and function and white matter hyperintensities in young adults

Importance: Risk of stroke and brain atrophy in later life relate to levels of cardiovascular risk in early adulthood. However, it is unknown whether cerebrovascular changes are already present in young adults. Objective: To examine relationships between modifiable cardiovascular risk factors and cerebrovascular structure, function and white matter integrity in young adults. Design, Setting, and Participants: A cross-sectional observational study completed between August 2014 and May 2016 at the University of Oxford, United Kingdom. Participants recruited through active and passive recruitment from the local community, including invitation from the Oxford University Hospitals Hypertension Service. Exposures: Clinic and ambulatory blood pressure (mmHg), body mass index (kg/m2), objective physical activity (hours/week), alcohol intake (drinks/week), smoking (pack years), peak oxygen uptake (ml/kg/min), peak exercise blood 65 pressure (mmHg), lipid profile (mg/dL), insulin resistance and use of anti-66 hypertension medication. 67 Main Outcomes and Measures: Cerebral vessel density (vessels/cm3), caliber (μm) and tortuosity, brain white matter hyperintensity lesion count (number), and in a subgroup (n=52) brain blood arrival time (seconds) and cerebral blood flow (ml/100g/min) assessed by brain magnetic resonance. Results: 125 participants (mean age 25±5 years, 49% female) were recruited. Cerebrovascular morphology and white matter hyperintensity count correlated with cardiovascular risk factors in univariable and multivariable models. In a risk score, for each healthier modifiable risk factor, characterised as: ambulatory blood pressure ; BMI < 25kg/m2; top tertile of cardiovascular fitness; non-smoker; <8 alcoholic drinks/week; normotensive exercise blood pressure response; cholesterol <200mg/dL; and fasting glucose <100mg/dL, vessel density increased by 0.3 vessels/cm3 (95%CI 0.1 to 0.5, p=0.003), vessel caliber by 8μm (95%CI 3 to 13, p=0.01) and white matter hyperintensity lesions reduced by 1.6 lesions (95%CI 0.6 to 2.8, p=0.006). In subgroup analysis, cerebral blood flow varied with vessel density and increased by 2.5ml/min/100g per risk score (95%CI 0.05 to 4.98, p=0.05). Conclusions and Relevance: In this preliminary study, involving young adults without clinical evidence of cerebrovascular disease, modifiable cardiovascular risk factors were associated with MR indices of cerebral vessel structure and function, and white matter hyperintensities. Further research is needed to determine the clinical importance of these findings for the primordial prevention of cerebrovascular disease