Precision Dosing of Anti-TNF Therapy in Pediatric Inflammatory Bowel Disease.

PURPOSE OF THE REVIEW: This review focuses on recent advancements in anti-TNF therapeutic drug monitoring (TDM), pharmacogenetics and personalized drug selection for children with inflammatory bowel disease (IBD). RECENT FINDINGS: Several real-world studies and one clinical trial in children have demonstrated that proactive TDM, targeting higher exposure concentrations (> 5 µg/mL), can improve disease remission rates and enhance durability of the anti-TNF biologics. Recent data from both adult and pediatric IBD patients have revealed an association between a genetic polymorphism (HLA-DQA1*05) and the development of auto-drug antibodies. The impact of this association on clinical outcomes, considering more routine use proactive TDM and dose optimization in children, is still under investigation. Additionally, recent studies have identified potential inflammatory signatures and biomarkers that may serve as companion diagnostics for anti-TNF biologics. The effective management of anti-TNF therapies in children with IBD requires evidence-based precision dosing strategies, including routine TDM and proactive pharmacodynamic assessments.

Prospective risk of osteoporotic fractures in patients with advanced chronic obstructive pulmonary disease.

Despite the high prevalence of osteoporosis in chronic obstructive pulmonary disease (COPD) patients, the fracture risk prediction tools are not routinely undertaken in the management of COPD. We quantified fracture risk using a validated risk prediction tool (Fracture Risk Assessment (FRAX®)) and determined potential bone-protection treatment needs in patients with advanced COPD. The 10-year probability of major osteoporotic or hip fracture was calculated using the FRAX tool in a cohort of patients attending a hospital complex COPD service. Patients were identified to be at low, intermediate and high risk based on their FRAX scores, in accordance with the National Osteoporosis Guideline Group recommendations, to assess the number of patients requiring bone mineral density (BMD) testing or bone protection therapy. Two hundred forty-seven patients [mean (standard deviation (SD)) age 66 (9.1) years, 26% current smokers, 40% women and median (interquartile range (IQR)) Medical Research Council (MRC) breathlessness scale 4 (0)] had a 10-year probability of 9.5% (6.1) and 3.8% (4.6) for major osteoporotic and hip fractures, respectively. Thirty-six percentage of patients were identified to be at intermediate risk of developing fragility fracture, requiring BMD assessment, while 9% were at high risk, requiring treatment. Thirty-two percentage of high-risk patients were on bisphosphonates. The FRAX score can be used to assess the fracture risk within the COPD cohort and assist with decision-making about BMD measurement and provision of bone protection therapy.

Molecular hierarchy of mammary differentiation yields refined markers of mammary stem cells.

The partial purification of mouse mammary gland stem cells (MaSCs) using combinatorial cell surface markers (Lin(-)CD24(+)CD29(h)CD49f(h)) has improved our understanding of their role in normal development and breast tumorigenesis. Despite the significant improvement in MaSC enrichment, there is presently no methodology that adequately isolates pure MaSCs. Seeking new markers of MaSCs, we characterized the stem-like properties and expression signature of label-retaining cells from the mammary gland of mice expressing a controllable H2b-GFP transgene. In this system, the transgene expression can be repressed in a doxycycline-dependent fashion, allowing isolation of slowly dividing cells with retained nuclear GFP signal. Here, we show that H2b-GFP(h) cells reside within the predicted MaSC compartment and display greater mammary reconstitution unit frequency compared with H2b-GFP(neg) MaSCs. According to their transcriptome profile, H2b-GFP(h) MaSCs are enriched for pathways thought to play important roles in adult stem cells. We found Cd1d, a glycoprotein expressed on the surface of antigen-presenting cells, to be highly expressed by H2b-GFP(h) MaSCs, and isolation of Cd1d(+) MaSCs further improved the mammary reconstitution unit enrichment frequency to nearly a single-cell level. Additionally, we functionally characterized a set of MaSC-enriched genes, discovering factors controlling MaSC survival. Collectively, our data provide tools for isolating a more precisely defined population of MaSCs and point to potentially critical factors for MaSC maintenance.

BNP as a New Biomarker of Cardiac Thyroid Hormone Function.

BACKGROUND: Cardiac re-expression of fetal genes in patients with heart failure (HF) suggests the presence of low cardiac tissue thyroid hormone (TH) function. However, serum concentrations of T3 and T4 are often normal or subclinically low, necessitating an alternative serum biomarker for low cardiac TH function to guide treatment of these patients. The clinical literature suggests that serum Brain Natriuretic Peptide (BNP) levels are inversely associated with serum triiodo-L-thyronine (T3) levels. The objective of this study was to investigate BNP as a potential serum biomarker for TH function in the heart. METHODS: Two animal models of thyroid hormone deficiency: (1) 8-weeks of propyl thiouracil-induced hypothyroidism (Hypo) in adult female rats were subsequently treated with oral T3 (10 µg/kg/d) for 3, 6, or 14 days; (2) HF induced by coronary artery ligation (myocardial infarction, MI) in adult female rats was treated daily with low dose oral T3 (5 µg/kg/d) for 8 or 16 wks. RESULTS: Six days of T3 treatment of Hypo rats normalized most cardiac functional parameters. Serum levels of BNP increased 5-fold in Hypo rats, while T3 treatment normalized BNP by day 14, showing a significant inverse relationship between serum BNP and free or total T3 concentrations. Myocardial BNP mRNA was increased 2.5-fold in Hypo rats and its expression was decreased to normal values by 14 days of T3 treatment. Measurements of hemodynamic function showed significant dysfunction in MI rats after 16 weeks, with serum BNP increased by 4.5-fold and serum free and total T3 decreased significantly. Treatment with T3 decreased serum BNP while increasing total T3 indicating an inverse correlation between these two biologic factors (r 2 = 0.676, p < 0.001). Myocardial BNP mRNA was increased 5-fold in MI rats which was significantly decreased by T3 over 8 to 16 week treatment periods. CONCLUSIONS: Results from the two models of TH dysfunction confirmed an inverse relationship between tissue and serum T3 and BNP, such that the reduction in serum BNP could potentially be utilized to monitor efficacy and dosing of T3 treatment. Thus, serum BNP may serve as a reliable biomarker for cardiac TH function.

Model-informed Precision Dosing for Biologics Is Now Available at the Bedside for Patients With Inflammatory Bowel Disease.

It is increasingly recognized that inconsistent biologic therapeutic response is related to pharmacokinetic variability (drug clearance) between patients. This study highlights a multidisciplinary effort to integrate a precision dosing dashboard within the electronic health record to individualize biologic exposure starting and during induction.

Bilateral subtrochanteric fractures in tumour-induced osteomalacia caused by a nasal haemangiopericytoma.

Bilateral insufficiency fractures of the proximal femur often have a pathological basis. Diagnosis of rare causes of insufficiency fractures can be challenging. Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of mesenchymal tumours which leads to hypophosphataemia and osteomalacia. Suspected pathological fractures should be investigated thoroughly including a fasting serum phosphate level. Further investigations should include serum levels of fibroblast growth factor 23 (FGF23) which is a peptide hormone secreted by mesenchymal tumours. Available imaging modalities include Octreotide scanning which detects somatostatin receptors commonly expressed on mesenchymal tumours. After localisation and resection of the tumour, a full recovery from TIO is achievable.

Estrogen-induced osteogenesis in mice is associated with the appearance of Cbfa1-expressing bone marrow cells.

Cbfa1 is a transcription factor recognised as being involved in early osteoblast differentiation during embryonic skeletogenesis. To determine whether Cbfa1 plays a similar role in bone formation in the adult, we analysed whether its expression is altered during estrogen-induced osteogenesis, following our recent studies which suggest that this response involves the generation of early osteoblast precursors within bone marrow. To facilitate identification of Cbfa1-expressing cells, these studies were performed in mice heterozygous for a cbfa1 gene deletion (cbfa1(+/-)) using beta-galactosidase (lacZ) as a genetic marker. Cbfa1-expressing cells were identified by lacZ staining of longitudinal sections of the proximal tibial metaphysis. Treatment of cbfa1(+/-) mice with 17beta-estradiol 0.5 mg/week for 24 days led to the appearance of new cancellous bone surfaces. This response was associated with a marked increase in number of Cbfa1-expressing cells within the metaphysis, consisting not only of osteoblasts on bone surfaces but also of cells within the adjacent bone marrow. We subsequently enumerated Cbfa1-expressing cells at earlier time-points following estrogen, in sections co-stained for ALP activity. After 4 days of estrogen treatment, a population of cells appeared within the marrow cavity which expressed Cbfa1, but were negative for ALP. At later time-points, large numbers of Cbfa1 + bone marrow cells were still present, but the majority of these were close to new trabecular bone surfaces at sites which showed high levels of ALP activity. An equivalent distribution of Cbfa1-expressing cells was observed in further studies where Cbfa1 expression was analysed in wild-type mice by immunohistochemistry. We conclude that estrogen-induced osteogenesis is associated with the appearance of a population of Cbfa1-expressing cells within bone marrow, which we hypothesize to represent the osteoblast precursor population responsible for subsequent new bone formation.