Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC.

Advancing translational research for colorectal immuno-oncology.

Colorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast majority of CRC patients. Patients that are most likely to respond are those with DNA mismatch repair deficient (dMMR) and microsatellite instability (MSI) disease.

Engineered bacteria detect tumor DNA.

Synthetic biology has developed sophisticated cellular biosensors to detect and respond to human disease. However, biosensors have not yet been engineered to detect specific extracellular DNA sequences and mutations. Here, we engineered naturally competent to detect donor DNA from the genomes of colorectal cancer (CRC) cells, organoids, and tumors.

Colorectal cancer detection and treatment with engineered probiotics.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment strategies. Here, we demonstrate the phenomenon of selective, long-term colonization of colorectal adenomas after oral delivery of probiotic Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition. We show that, after oral administration, adenomas can be monitored over time by recovering EcN from stool.

Molecular Characterization of Testicular Mesothelioma and the Role of Asbestos as a Causative Factor.

Context.—: Mesothelioma of the tunica vaginalis testis (TVT) is an extremely rare form of mesothelioma.

Objective.

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis.

Background & Aims: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis.

Delayed HIV diagnosis in a cystic fibrosis patient: Not just another exacerbation.

Patients with cystic fibrosis (CF) are living longer due to advancements in treatment. We present a patient with CF in whom diagnoses of Human Immunodeficiency Virus (HIV) and severe pneumocystis pneumonia were delayed due to anchor bias. Our case highlights the importance of routine age-appropriate health screenings in patients with CF.

Treatment of Syphilis With Doxycycline in a Pregnant Woman Unable to Be Desensitized to Penicillin.

A pregnant woman with a non-IgE-mediated penicillin allergy was treated for syphilis with doxycycline with resolution of infection and no evidence of adverse outcome for mother or infant.

Portal Vein Injection of Colorectal Cancer Organoids to Study the Liver Metastasis Stroma.

Hepatic metastasis of colorectal cancer (CRC) is a leading cause of cancer-related death. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play a crucial role in metastatic CRC progression and predict poor patient prognosis. However, there is a lack of satisfactory mouse models to study the crosstalk between metastatic cancer cells and CAFs.

Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion.

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC of 1.

Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection.

Background: A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease.

Methods: In this phase 1-2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56.

TBC1D1 interacting proteins, VPS13A and VPS13C, regulate GLUT4 homeostasis in C2C12 myotubes.

Proteins involved in the spaciotemporal regulation of GLUT4 trafficking represent potential therapeutic targets for the treatment of insulin resistance and type 2 diabetes. A key regulator of insulin- and exercise-stimulated glucose uptake and GLUT4 trafficking is TBC1D1. This study aimed to identify proteins that regulate GLUT4 trafficking and homeostasis via TBC1D1.

A Randomized, Placebo-Controlled, Respiratory Syncytial Virus Human Challenge Study of the Antiviral Efficacy, Safety, and Pharmacokinetics of RV521, an Inhibitor of the RSV-F Protein.

Effective treatments for respiratory syncytial virus (RSV) infection are lacking. Here, we report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial, healthy adults were challenged with RSV-A Memphis-37b.

Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity.

AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energy homeostasis which achieves this through the phosphorylation of a myriad of downstream targets. One target is TBC1D1 a Rab-GTPase-activating protein that regulates glucose uptake in muscle cells by integrating insulin signalling with that promoted by muscle contraction. Ser in TBC1D1 is a target for phosphorylation by AMPK, an event which may be important in regulating glucose uptake.

Average symptom trajectories following incident radiographic knee osteoarthritis: data from the Osteoarthritis Initiative.

Introduction: Previous research has identified the existence of a prodromal phase of symptom worsening beginning on average 2-3 years prior to the first appearance of radiographic knee osteoarthritis (OA). The current study extends these observations to investigate the trajectory of self-reported pain, stiffness, function and other symptoms following the incidence of radiographic OA.

Methods: Data were from the incidence cohort of the Osteoarthritis Initiative public use data sets.

Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth.

Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation.

Use of qualitative integrative cycler PCR (qicPCR) to identify optimal therapeutic dosing time-points in a Respiratory Syncytial Virus Human Viral Challenge Model (hVCM).

Retroscreen (hVIVO) have developed an RSV human viral challenge model (hVCM) for testing the efficacy of novel antiviral therapies by monitoring changes in viral load and symptoms. The integrated cycler technology and Simplexa™ kits (Focus Diagnostics) currently provide fast, qualitative and sensitive diagnostic testing in hospitals and other healthcare facilities for patients with well-established respiratory illness. We have developed a novel use of qualitative integrated cycler PCR (qicPCR) technology to identify onset of RSV infection enabling an informed dosing clinical protocol in the RSV hVCM.

Investigations of Potential Phenotypes of Foot Osteoarthritis: Cross-Sectional Analysis From the Clinical Assessment Study of the Foot.

Objective: To investigate the existence of distinct foot osteoarthritis (OA) phenotypes based on pattern of joint involvement and comparative symptom and risk profiles.

Methods: Participants ages ≥50 years reporting foot pain in the previous year were drawn from a population-based cohort. Radiographs were scored for OA in the first metatarsophalangeal (MTP) joint, first and second cuneometatarsal, navicular first cuneiform, and talonavicular joints according to a published atlas.

Development and Validation of the Keele Musculoskeletal Patient Reported Outcome Measure (MSK-PROM).

Objective: To develop and validate a patient report outcome measure (PROM) for clinical practice that can monitor health status of patients with a range of musculoskeletal (MSK) disorders.

Methods: Constructs for inclusion in the MSK-PROM were identified from a consensus process involving patients with musculoskeletal conditions, clinicians, purchasers of healthcare services, and primary care researchers. Psychometric properties of the brief tool, including face and construct validity, repeatability and responsiveness were assessed in a sample of patients with musculoskeletal pain consulting physiotherapy services in the United Kingdom (n=425).

Maximising response from GPs to questionnaire surveys: do length or incentives make a difference?

Background: General Practitioners (GPs) respond poorly to postal surveys. Consequently there is potential for reduced data quality and bias in the findings. In general population surveys, response to postal questionnaires may be improved by reducing their length and offering incentives.

Pain at multiple body sites and health-related quality of life in older adults: results from the North Staffordshire Osteoarthritis Project.

Objectives: Number of pain sites (NPS) is a potentially important marker of health-related quality of life (HRQoL) but remains unexplored in older people. This cross-sectional study investigated whether, in older people including the oldest old, NPS was independently associated with poorer mental and physical HRQoL and if the association was moderated by age.

Methods: A postal questionnaire sent to a population sample of adults aged ≥50 years in North Staffordshire, UK, included the 12-item Short Form Health Survey (SF-12) mental component summary (MCS) and physical component summary (PCS), a blank body pain manikin, socio-demographic, health behaviour and morbidity questions.

Pain location matters: the impact of leg pain on health care use, work disability and quality of life in patients with low back pain.

Purpose: In low back pain (LBP) patients, those with radiating leg pain or sciatica have poorer pain and disability outcomes. Few studies have assessed the effect of leg pain on health care use and quality of life.

Methods: Prospective cohort study of 1,581 UK LBP primary care consulters.

The population prevalence of symptomatic radiographic foot osteoarthritis in community-dwelling older adults: cross-sectional findings from the clinical assessment study of the foot.

Objectives: To estimate the population prevalence of symptomatic radiographic osteoarthritis (OA) affecting the 1st metatarsophalangeal joint (MTPJ), 1st and 2nd cuneometatarsal joints (CMJs), navicular first cuneiform joint (NCJ) and talonavicular joint (TNJ) in community-dwelling older adults.

Methods: 9334 adults aged ≥50 years registered with four general practices were mailed a health survey. Responders reporting foot pain within the last 12 months were invited to undergo weight-bearing dorso-plantar and lateral radiographs of both feet.

Defining and mapping the person with osteoarthritis for population studies and public health.

Objective: To determine population-based estimates for the prevalence of the person with OA, predicted to be the single greatest cause of disability in the general population by 2030, in order to inform the planning and commissioning of health, social care and prevention services.

Methods: A postal survey to all adults ≥50 years of age registered with eight general practices in the UK. Self-reported data on chronic joint pain in four body regions (hand, hip, knee, foot) and the disabling nature of the pain was collected to determine gender and age-group specific prevalence estimates of clinical OA in the joint region and in the person.