Infliximab Can Be Effective in Pediatric Patients with Ulcerative Colitis and Primary Failure of Adalimumab.

OBJECTIVE: The FDA approved adalimumab, an anti-tumor necrosis factor alpha agent, for the treatment of moderate to severe pediatric ulcerative colitis (UC) in February 2021. There are no real-world publications, however, on adalimumab as the first-line biologic in pediatric UC, a form of chronic inflammatory bowel disease (IBD). METHODS: A retrospective review was conducted to characterize the clinical courses of nine patients with moderate to severe pediatric UC who received adalimumab as their first biologic and had documented drug monitoring trough levels. RESULTS: Seven of the nine patients, or 78%, were switched from adalimumab to another therapy due to continued symptoms or steroid-dependence at an average of 5 months from initiation. Six of these seven patients, or 86%, had adalimumab drug trough levels in the consensus therapeutic range. Three patients were successfully switched to infliximab. CONCLUSIONS: Both the Crohn's disease-based dosing and the new FDA-approved pediatric UC dosing of adalimumab were ineffective in inducing remission in the majority of patients in our case series. This study indicates that further real-world observations are needed to optimize and position adalimumab in the treatment paradigm of moderate to severe pediatric UC.

Developmental exposure to Pb2+ induces transgenerational changes to zebrafish brain transcriptome.

Lead (Pb2+) is a major public health hazard for urban children, with profound and well-characterized developmental and behavioral implications across the lifespan. The ability of early Pb2+ exposure to induce epigenetic changes is well-established, suggesting that Pb2+-induced neurobehavioral deficits may be heritable across generations. Understanding the long-term and multigenerational repercussions of lead exposure is crucial for clarifying both the genotypic alterations behind these behavioral outcomes and the potential mechanism of heritability. To study this, zebrafish (Danio rerio) embryos (<2 h post fertilization; EK strain) were exposed for 24 h to waterborne Pb2+ at a concentration of 10 µM. This exposed F0 generation was raised to adulthood and spawned to produce the F1 generation, which was subsequently spawned to produce the F2 generation. Previous avoidance conditioning studies determined that a 10 µM Pb2+ dose resulted in learning impairments persisting through the F2 generation. RNA was extracted from control- and 10 µM Pb2+-lineage F2 brains, (n = 10 for each group), sequenced, and transcript expression was quantified utilizing Quant-Seq. 648 genes were differentially expressed in the brains of F2 lead-lineage fish versus F2 control-lineage fish. Pathway analysis revealed altered genes in processes including synaptic function and plasticity, neurogenesis, endocrine homeostasis, and epigenetic modification, all of which are implicated in lead-induced neurobehavioral deficits and/or their inheritance. These data will inform future investigations to elucidate the mechanism of adult-onset and transgenerational health effects of developmental lead exposure.

Assessing the Feasibility and Effectiveness of Two Prenatal Breastfeeding Intervention Apps in Promoting Postpartum In-Hospital Exclusive Breastfeeding.

Purpose: To test the feasibility and possible effects of two iPad®-based breastfeeding interventions for expectant minority women and evaluate (1) the intervention effect on exclusive breastfeeding (EBF) intention, (2) intervention acceptability and satisfaction, and (3) follow-up rates of in-hospital EBF. Materials and Methods: This was a longitudinal survey study with follow-up chart review. Expectant women who completed clinically required breastfeeding education were eligible and were assigned to one of the following interventions by nonrandomized block design: the champion intervention utilized a free commercially available app to identify a supportive breastfeeding champion and the positive messaging intervention offered breastfeeding information in a question-answer format. Medical records were reviewed postpartum for in-hospital feeding choice. Data were analyzed using percentages, frequencies, chi-squared analyses, and McNemar's test. Results: We enrolled 243 publicly insured predominantly African American women: 132 and 111 completed the champion and positive messaging interventions, respectively. Thirty-two of 40 champion participants (80.03%) intended EBF and did in-hospital EBF; 39/86 champion participants (45.3%) not intending EBF did in-hospital EBF (p < 0.0001 for change). Similarly, 30/36 positive messaging participants (83.3%) intended EBF and did in-hospital EBF; 36/67 positive messaging participants (53.7%) not intending EBF did in-hospital EBF (p < 0.0001 for change). Conclusions: In this pilot of two brief, iPad-based prenatal interventions designed to promote in-hospital EBF among minority women, interventions were feasible and a statistically significant change in the proportion of women who intended (prenatally) and then chose (postpartum) EBF was noted. Additional controlled trials are needed to demonstrate the effectiveness of this approach.

Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity.

Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL-a re-engineered protein form of the antioxidant enzyme catalase-inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c.

Peroxisome biogenesis in mammalian cells: The impact of genes and environment.

The initiation and progression of many human diseases are mediated by a complex interplay of genetic, epigenetic, and environmental factors. As all diseases begin with an imbalance at the cellular level, it is essential to understand how various types of molecular aberrations, metabolic changes, and environmental stressors function as switching points in essential communication networks. In recent years, peroxisomes have emerged as important intracellular hubs for redox-, lipid-, inflammatory-, and nucleic acid-mediated signaling pathways. In this review, we focus on how nature and nurture modulate peroxisome biogenesis and function in mammalian cells. First, we review emerging evidence that changes in peroxisome activity can be linked to the epigenetic regulation of cell function. Next, we outline how defects in peroxisome biogenesis may directly impact cellular pathways involved in the development of disease. In addition, we discuss how changes in the cellular microenvironment can modulate peroxisome biogenesis and function. Finally, given the importance of peroxisome function in multiple aspects of health, disease, and aging, we highlight the need for more research in this still understudied field.

Collagen mimetic peptide engineered M13 bacteriophage for collagen targeting and imaging in cancer.

Collagens are over-expressed in various human cancers and subsequently degraded and denatured by proteolytic enzymes, thus making them a target for diagnostics and therapeutics. Genetically engineered bacteriophage (phage) is a promising candidate for the development of imaging or therapeutic materials for cancer collagen targeting due to its promising structural features. We genetically engineered M13 phages with two functional peptides, collagen mimetic peptide and streptavidin binding peptide, on their minor and major coat proteins, respectively. The resulting engineered phage functions as a therapeutic or imaging material to target degraded and denatured collagens in cancerous tissues. We demonstrated that the engineered phages are able to target and label abnormal collagens expressed on A549 human lung adenocarcinoma cells after the conjugation with streptavidin-linked fluorescent agents. Our engineered collagen binding phage could be a useful platform for abnormal collagen imaging and drug delivery in various collagen-related diseases.

Phage-based nanomaterials for biomedical applications.

Recent advances in nanotechnology enable us to manipulate and produce materials with molecular level control. In the newly emerging field of bionanomedicine, it is essential to precisely control the physical, chemical and biological properties of materials. Among other biological building blocks, viruses are a promising nanomaterial that can be functionalized with great precision. Since the production of viral particles is directed by the genetic information encapsulated in their protein shells, the viral particles create precisely defined sizes and shapes. In addition, the composition and surface properties of the particles can be controlled through genetic engineering and chemical modification. In this manuscript, we review the advances of virus-based nanomaterials for biomedical applications in three different areas: phage therapy, drug delivery and tissue engineering. By exploiting and manipulating the original functions of viruses, viral particles hold great possibilities in these biomedical applications to improve human health.