Plant-mediated effects on mosquito capacity to transmit human malaria

The ecological context in which mosquitoes and malaria parasites interact has received little attention, compared to the genetic and molecular aspects of malaria transmission. Plant nectar and fruits are important for the nutritional ecology of malaria vectors, but how the natural diversity of plant-derived sugar sources affects mosquito competence for malaria parasites is unclear. To test this, we infected Anopheles coluzzi, an important African malaria vector, with sympatric field isolates of Plasmodium falciparum, using direct membrane feeding assays. Through a series of experiments, we then examined the effects of sugar meals from Thevetia neriifolia and Barleria lupilina cuttings that included flowers, and fruit from Lannea microcarpa and Mangifera indica on parasite and mosquito traits that are key for determining the intensity of malaria transmission. We found that the source of plant sugar meal differentially affected infection prevalence and intensity, the development duration of the parasites, as well as the survival and fecundity of the vector. These effects are likely the result of complex interactions between toxic secondary metabolites and the nutritional quality of the plant sugar source, as well as of host resource availability and parasite growth. Using an epidemiological model, we show that plant sugar source can be a significant driver of malaria transmission dynamics, with some plant species exhibiting either transmission-reducing or -enhancing activities

Targeting the rheumatoid arthritis synovial fibroblast via cyclin dependent kinase inhibition: An early phase trial

Introduction: Targeted biologic therapies demonstrate similar efficacies in rheumatoid arthritis despite distinct mechanisms of action. They also exhibit a ceiling effect, with 10% to 20% of patients achieving remission in clinical trials. None of these therapies target synovial fibroblasts, which drive and maintain synovitis. Seliciclib (R-roscovitine) is an orally available cyclin-dependent kinase inhibitor that suppresses fibroblast proliferation, and is efficacious in preclinical arthritis models. We aim to determine the toxicity and preliminary efficacy of seliciclib in combination with biologic therapies, to inform its potential as an adjunctive therapy in rheumatoid arthritis. Methods and analysis: TRAFIC is a non-commercial, multi-center, rolling phase Ib/IIa trial investigating the safety, tolerability, and efficacy of seliciclib in patients with moderate to severe rheumatoid arthritis receiving biologic therapies. All participants receive seliciclib with no control arm. The primary objective of part 1 (phase Ib) is to determine the maximum tolerated dose and safety of seliciclib over 4 weeks of dosing. Part 1 uses a restricted 1-stage Bayesian continual reassessment method based on a target dose-limiting toxicity probability of 35%. Part 2 (phase IIa) assesses the potential efficacy of seliciclib, and is designed as a single arm, single stage early phase trial based on a Fleming-A’Hern design using the maximum tolerated dose recommended from part 1. The primary response outcome after 12 weeks of therapy is a composite of clinical, histological and magnetic resonance imaging scores. Secondary outcomes include adverse events, pharmacodynamic and pharmacokinetic parameters, autoantibodies, and fatigue. Ethics and dissemination: The study has been reviewed and approved by the North East - Tyne & Wear South Research Ethics Committee (reference 14/NE/1075) and the Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom. Results will be disseminated through publication in relevant peer-reviewed journals and presentation at national and international conferences. Trials Registration: ISRCTN, ISRCTN36667085. Registered on September 26, 2014; http://www.isrctn.com/ISRCTN36667085 Current protocol version: Protocol version 11.0 (March 21, 2019

Patient-reported outcomes as early warning signs of flare following drug cessation in rheumatoid arthritis

\ua9 2025 BMJ Publishing Group. All rights reserved. Objectives Drug withdrawal in rheumatoid arthritis (RA) in remission can reduce toxicity, but with the risk of flare which requires close monitoring. We explored the potential of patient-reported outcomes (PROs) for flare detection among RA patients in sustained remission after conventional synthetic disease-modifying antirheumatic drug (csDMARD) cessation. Methods Four PROs (Factors that Limit sustAined Remission in rhEumatoid arthritis (FLARE-RA), EuroQol-5 Dimensions (EQ5D), Routine Assessment of Patient Index Data-3 (RAPID-3) and RA Flare Questionnaire (RA-FQ)) were captured at baseline and at sequential visits until time-of-flare or end of 6-month follow-up as part of the BIO-FLARE prospective cohort study. Flare was defined as any of (i) Disease Activity Score 28 (DAS28)-C reactive protein (CRP) ≥3.2 at any visit, (ii) DAS28-CRP≥2.4 on two visits within 2 weeks or (iii) resuming DMARD and/or steroid therapy despite DAS28-CRP<2.4. Cox regression models with time-varying covariates were fitted to evaluate associations between PRO changes and likelihood of flare. Receiver-operating characteristic (ROC) curves enabled discriminatory changes in each PRO to be compared as a means of identifying flare. Results 58/121 (47.9%) participants (70.1% females, mean age 64.8 years) experienced a flare. A 1-point change in each PRO score was strongly associated with flare development in the multivariate Cox regression model (p<0.001 in each case). ROC curve analysis confirmed that monitoring adverse changes in PROs from baseline offered robust discriminatory utility for identifying flare occurrence. This was most evident for RA-FQ and FLARE-RA (both areas under the curves 0.90, 95% CI 0.84 to 0.96; p=0.001); for example, an RA-FQ increment of ≥5.5 from baseline identified objective flare with positive and negative predictive values of 80% and 91%, respectively. Conclusions Our data support the potential value of remote PRO monitoring of RA patients in drug-free remission to identify flare occurrence

Clinical predictors of flare and drug-free remission in rheumatoid arthritis: preliminary results from the prospective BIO-FLARE experimental medicine study

\ua9 Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.Objectives Huge advances in rheumatoid arthritis (RA) treatment mean an increasing number of patients now achieve disease remission. However, long-term treatments can carry side effects and associated financial costs. In addition, some patients still experience painful and debilitating disease flares, the mechanisms of which are poorly understood. High rates of flare and a lack of effective prediction tools can limit attempts at treatment withdrawal. The BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (BIO-FLARE) experimental medicine study was designed to study flare and remission immunobiology. Here, we present the clinical outcomes and predictors of drug-free remission and flare, and develop a prediction model to estimate flare risk. Design, setting and participants BIO-FLARE was a multicentre, prospective, single-arm, open-label experimental medicine study conducted across seven National Health Service Trusts in the UK. Participants had established RA in clinical remission (disease activity score in 28 joints with C reactive protein (DAS28-CRP)<2.4) and were receiving methotrexate, sulfasalazine or hydroxychloroquine (monotherapy or combination). Interventions The intervention was disease-modifying anti-rheumatic drug cessation, followed by observation for 24 weeks or until flare, with clinical and immune monitoring. Outcome measures The primary outcome measure was the proportion of participants experiencing a confirmed flare, defined as DAS28-CRP≥3.2 or DAS28-CRP≥2.4 twice within 2 weeks, and time to flare. Exploratory predictive modelling was also performed using multivariable Cox regression to understand risk factors for flare. Results 121 participants were recruited between September 2018 and December 2020. Flare rate by week 24 was 52.3% (95% CI 43.0 to 61.7), with a median (IQR) time to flare of 63 (41-96) days. Female sex, baseline methotrexate use, anti-citrullinated peptide antibody level and rheumatoid factor level were associated with flare. An exploratory prediction model incorporating these variables allowed estimation of flare risk, with acceptable classification (C index 0.709) and good calibration performance. Conclusion The rate of flare was approximately 50%. Several baseline clinical parameters were associated with flare. The BIO-FLARE study design provides a robust experimental medicine model for studying flare and remission immunobiology

Irreversible Pulmonary Hypertension Associated with the use of Interferon Alpha for Chronic Hepatitis C

The interferons are a complex group of virally induced proteins produced by activated macrophages and lymphocytes, which have become the mainstay of therapy for hepatitis C infection. Sustained viral response (SVR) rates in noncirrhotic patients vary from 40–80% with interferon-based therapy. This, along with transplantation, has drastically changed the course of hepatitis C virus (HCV) infection over the last two decades. Numerous side effects associated with interferon therapy have been reported. These range from transient flu-like symptoms to serious effects such as cardiac arrhythmias, cardiomyopathy, renal and liver failure, polyneuropathy, and myelosuppression. Pulmonary side effects including pneumonitis, pulmonary fibrosis, and reversible pulmonary hypertension have been reported. Herein, we present four cases in which irreversible pulmonary hypertension was diagnosed after prolonged treatment with interferon alpha. In each case, other causes of pulmonary hypertension were systematically eliminated. Pulmonary artery hypertension, which may be irreversible, should be considered in patients being treated with interferon alpha who present with exertional dyspnea and do not have a readily identifiable inflammatory or thromboembolic cause

Loss of heterozygosity (LOH), malignancy grade and clonality in microdissected prostate cancer

The aim of the present study was to find out whether increasing malignancy of prostate carcinoma correlates with an overall increase of loss of heterozygosity (LOH), and whether LOH typing of microdissected tumour areas can help to distinguish between multifocal or clonal tumour development. In 47 carcinomas analysed at 25 chromosomal loci, the overall LOH rate was found to be significantly lower in grade 1 areas (2.2%) compared with grade 2 (9.4%) and grade 3 areas (8.3%, P = 0.007). A similar tendency was found for the mean fractional allele loss (FAL, 0.043 for grade 1, 0.2 for grade 2 and 0.23 for grade 3, P = 0.0004). Of 20 tumours (65%) with LOH in several microdissected areas, 13 had identical losses at 1–4 loci within two or three areas, suggesting clonal development of these areas. Markers near RB, DCC, BBC1, TP53 and at D13S325 (13q21–22) showed higher loss rates in grades 2 and 3 (between 25% and 44.4%) compared with grade 1 (0–6.6%). Tumour-suppressor genes (TSGs) near these loci might, thus, be important for tumour progression. TP53 mutations were detected in 27%, but BBC1 mutations in only 7%, of samples with LOH. Evaluation of all 25 loci in every tumour made evident that each prostate cancer has its own pattern of allelic losses. © 1999 Cancer Research Campaig

Targeting synovial fibroblast proliferation in rheumatoid arthritis (TRAFIC): an open-label, dose-finding, phase 1b trial

Background Current rheumatoid arthritis therapies target immune inflammation and are subject to ceiling effects. Seliciclib is an orally available cyclin-dependent kinase inhibitor that suppresses proliferation of synovial fibroblasts—cells not yet targeted in rheumatoid arthritis. Part 1 of this phase 1b/2a trial aimed to establish the maximum tolerated dose of seliciclib in patients with active rheumatoid arthritis despite ongoing treatment with TNF inhibitors, and to evaluate safety and pharmacokinetics. Methods Phase 1b of the TRAFIC study was a non-randomised, open-label, dose-finding trial done in rheumatology departments in five UK National Health Service hospitals. Eligible patients (aged ≥18 years) fulfilled the 1987 American College of Rheumatology (ACR) or the 2010 ACR–European League Against Rheumatism classification criteria for rheumatoid arthritis and had moderate to severe disease activity (a Disease Activity Score for 28 joints [DAS28] of ≥3·2) despite stable treatment with anti-TNF therapy for at least 3 months before enrolment. Participants were recruited sequentially to a maximum of seven cohorts of three participants each, designated to receive seliciclib 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg administered in 200 mg oral capsules. Sequential cohorts received doses determined by a restricted, one-stage Bayesian continual reassessment model, which determined the maximum tolerated dose (the primary outcome) based on a target dose-limiting toxicity rate of 35%. Seliciclib maximum concentration (Cmax) and area under the plasma concentration time curve 0–6 h (AUC0–6) were measured. This study is registered with ISRCTN, ISRCTN36667085. Findings Between Oct 8, 2015, and Aug 15, 2017, 37 patients were screened and 15 were enrolled to five cohorts and received seliciclib, after which the trial steering committee and the data monitoring committee determined that the maximum tolerated dose could be defined. In addition to a TNF inhibitor, ten (67%) enrolled patients were taking conventional synthetic disease modifying antirheumatic drugs. The maximum tolerated dose of seliciclib was 400 mg, with an estimated dose-limiting toxicity probability of 0·35 (90% posterior probability interval 0·18–0·52). Two serious adverse events occurred (one acute kidney injury in a patient receiving the 600 mg dose and one drug-induced liver injury in a patient receiving the 400 mg dose), both considered to be related to seliciclib and consistent with its known safety profile. 65 non-serious adverse events occurred during the trial, 50 of which were considered to be treatment related. Most treatment-related adverse events were mild; 20 of the treatment-related non-serious adverse events contributed to dose-limiting toxicities. There were no deaths. Average Cmax and AUC0–6 were two-times higher in participants developing dose-limiting toxicities. Interpretation The maximum tolerated dose of seliciclib has been defined for rheumatoid arthritis refractory to TNF blockade. No unexpected safety concerns were identified to preclude ongoing clinical evaluation in a formal efficacy trial. Funding UK Medical Research Council, Cyclacel, Research into Inflammatory Arthritis Centre (Versus Arthritis), and the National Institute of Health Research Newcastle and Birmingham Biomedical Research Centres and Clinical Research Facilities

Fibronectin matrix-mediated cohesion suppresses invasion of prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Invasion is an important early step in the metastatic cascade and is the primary cause of death of prostate cancer patients. In order to invade, cells must detach from the primary tumor. Cell-cell and cell-ECM interactions are important regulators of cohesion - a property previously demonstrated to mediate cell detachment and invasion. The studies reported here propose a novel role for α5β1 integrin - the principle mediator of fibronectin matrix assembly (FNMA) - as an invasion suppressor of prostate cancer cells.</p> <p>Methods</p> <p>Using a combination of biophysical and cell biological methods, and well-characterized prostate cancer cell lines of varying invasiveness, we explore the relationship between cohesion, invasiveness, and FNMA.</p> <p>Results</p> <p>We show that cohesion is inversely proportional to invasive capacity. We also show that more invasive cells express lower levels of α5β1 integrin and lack the capacity for FNMA. Cells were generated to over-express either wild-type α5 integrin or an integrin in which the cytoplasmic domain of α5 was replaced with that of α2. The α2 construct does not promote FNMA. We show that only wild-type α5 integrin promotes aggregate compaction, increases cohesion, and reduces invasion of the more aggressive cells, and that these effects can be blocked by the 70-kDa fibronectin fragment.</p> <p>Conclusions</p> <p>We propose that restoring capacity for FNMA in deficient cells can increase tumor intercellular cohesion to a point that significantly reduces cell detachment and subsequent invasion. In prostate cancer, this could be of therapeutic benefit by blocking an early key step in the metastatic cascade.</p

Androgen regulation of the androgen receptor coregulators

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