Delivering large genes using adeno-associated virus and the CRE-lox DNA recombination system.

Adeno-associated virus (AAV) is a safe and efficient gene delivery vehicle for gene therapies. However, its relatively small packaging capacity limits its use as a gene transfer vector. Here, we describe a strategy to deliver large genes that exceed the AAV's packaging capacity using up to four AAV vectors and the CRE-lox DNA recombination system.

The impact of storage, handling, and treatment on nutritional quality and safety of animal milk: A protocol for the systematic review and meta-analysis.

Objectives: Human milk has been shown to reduce severe morbidity in preterm/low-birth-weight infants and is therefore the recommended nutritional source. When infants cannot receive maternal milk, donor human milk (DHM) is recommended. The use of human milk banking facilities is increasing to meet the need for DHM.

The impact of donating milk on the health of milk donors and their infants: A systematic review and meta-analysis protocol.

Objectives: Breast milk is the recommended nutritional source for newborns and has been associated with decreased morbidity in low-birth-weight and preterm infants. In situations where breast milk is not available, donor breast milk is an alternative. Milk banking is becoming increasingly common worldwide to meet this need.

Molecular basis of CRX/DNA recognition and stoichiometry at the Ret4 response element.

Two retinal transcription factors, cone-rod homeobox (CRX) and neural retina leucine zipper (NRL), cooperate functionally and physically to control photoreceptor development and homeostasis. Mutations in CRX and NRL cause severe retinal diseases. Despite the roles of NRL and CRX, insight into their functions at the molecular level is lacking.

Foot offloading associated with carbon fiber orthosis use: A pilot study.

Background: Traumatic lower limb injuries can result in chronic pain. Orthotic interventions are a leading conservative approach to reduce pain, manage loading, and protect the foot. Robust carbon fiber custom dynamic orthoses (CDOs) designed for military service members have been shown to reduce foot loading.

Prevalence of Electrographic Seizures in Hospitalized Patients With Altered Mental Status With No Significant Seizure Risk Factors Who Underwent Continuous EEG Monitoring: A Retrospective Study.

Objectives: The objective of this study is to evaluate the prevalence of electrographic seizures in hospitalized patients with altered mental status and no significant risk factors for seizures.

Methods: We retrospectively reviewed over a six-year period (2013-2019) the medical records of all adults admitted at Ohio State University Wexner Medical Center (OSUWMC), who underwent continuous electroencephalography (cEEG) monitoring for > 48 hours. Our primary objective was to identify the prevalence of electrographic seizures in patients with altered mental status and no significant acute or remote risk factors for seizures.

Reconstitution of the phosphodiesterase 6 maturation process important for photoreceptor cell function.

The sixth family phosphodiesterases (PDE6) are principal effector enzymes of the phototransduction cascade in rods and cones. Maturation of nascent PDE6 protein into a functional enzyme relies on a coordinated action of ubiquitous chaperone HSP90, its specialized cochaperone aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), and the regulatory Pγ-subunit of PDE6. Deficits in PDE6 maturation and function underlie severe visual disorders and blindness.

Pathologic Peri-Implant Proximal Femur Fracture: Takeaways from Our Experience.

Pathologic fractures of the distal femur secondary to bone metastases are not as common as those in the proximal femur, and they are rarely reported on in the literature. Even in the absence of current metastatic lesions in the femoral neck, traditional orthopaedic teaching has stressed the importance of protecting the entire femur, while recent studies have shown that it may not be necessary to stabilize the entire femur in the event of future metastases. Thus, there is no consensus regarding optimal surgical treatment, making the choice of fixation often based on the experience of the surgeon.

The Role of Health Coaching in Pain and Palliative Care Pharmacy Practice.

Whole-person care is essential in the management of patients with chronic pain and serious illness. Pain, suffering, and comfort do not fall under typical chronic disease management and cannot be boxed nicely into algorithms of evidence-focused, biomarker-based goal achievement like hypertension or diabetes. Current therapies, including surgical, interventional, and analgesic modalities may be only marginally effective, and have brought with them questionable practices, high cost, and an opioid epidemic.

Let the Program Evaluation Committee SOAR: Applying the Strengths, Opportunities, Aspirations, and Results (SOAR) Framework for Program Evaluation.

Objective: Annual program evaluations are important activities of all graduate medical education programs. Although the Accreditation Council for Graduate Medical Education provides general guidelines, there is substantial scope for educational innovation. Strengths, opportunities, aspirations, and results (SOAR) is a strengths-based framework for strategic planning.

Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer.

Recent studies have demonstrated an important role for vitamin C in the epigenetic regulation of cancer-related genes via DNA demethylation by the ten-eleven translocation (TET) methylcytosine dioxygenase enzymes. DNA methyltransferase (DNMT) reverses this, increasing DNA methylation and decreasing gene expression. Dual oxidase (DUOX) enzymes produce hydrogen peroxide (HO) in normal pancreatic tissue but are silenced in pancreatic cancer (PDAC).

Hydrogen Peroxide Mediates Pharmacological Ascorbate Induced Radio-Sensitization of Pancreatic Cancer Cells by Enhancing G2-accumulation and Reducing Cyclin B1 Protein Levels.

Pharmacological ascorbate (P-AscH-, high dose, intravenous vitamin C) preferentially sensitizes human pancreas ductal adenocarcinoma (PDAC) cells to radiation-induced toxicity compared to non-tumorigenic epithelial cells. Radiation-induced G2-checkpoint activation contributes to the resistance of cancer cells to DNA damage induced toxicity. We hypothesized that P-AscH- induced radio-sensitization of PDAC cells is mediated by perturbations in the radiation induced activation of the G2-checkpoint pathway.

Contrasting roles of different mismatch repair proteins in basal-like breast cancer.

The mismatch repair (MMR) pathway is known as a tumor suppressive pathway and genes involved in MMR are commonly mutated in hereditary colorectal or other cancer types. However, the function of MMR genes/proteins in breast cancer progression and metastasis are largely unknown. We found that MSH2, but not MLH1, is highly enriched in basal-like breast cancer (BLBC) and that its protein expression is inversely correlated with overall survival time (OS).

INternational Soft Tissue saRcoma ConsorTium (INSTRuCT) consensus statement: Imaging recommendations for the management of rhabdomyosarcoma.

Rhabdomyosarcoma is the most common soft-tissue neoplasm in the pediatric population. The survival of children with rhabdomyosarcoma has only marginally improved over the past 25 years and remains poor for those with metastatic disease. A significant challenge to advances in treatment of rhabdomyosarcoma is the relative rarity of this disease, necessitating years to complete clinical trials.

Thermosensitive biomaterial gels with chemical permeation enhancers for enhanced microneedle delivery of naltrexone for managing opioid and alcohol dependency.

Naltrexone (NTX) can be transdermally delivered using microneedles (MN) to treat opioid and alcohol misuse disorders, but delivery is blunted by rapid micropore closure. Poloxamer (P407), a thermosensitive biocompatible hydrogel, sustains NTX delivery through MN-treated skin by generating a drug depot within the micropores. Optimizing P407 formulations could maintain sustained delivery after micropore closure while reducing required patch sizes, which would be more discreet and preferred by most patients.

The effect of icosapent ethyl on left atrial and left ventricular morphology.

Atrial fibrillation (AF) is a common arrhythmia associated with poor outcomes. N-3 fatty acids have been shown to provide significant cardiovascular risk reduction, but they may exacerbate the risk of AF. The pathway by which N-3 fatty acids may be arrhythmogenic is unknown.

GENE EXPRESSION WITHIN A HUMAN CHOROIDAL NEOVASCULAR MEMBRANE USING SPATIAL TRANSCRIPTOMICS.

Macular neovascularization is a relatively common and potentially visually devastating complication of age-related macular degeneration. In macular neovascularization, pathologic angiogenesis can originate from either the choroid or the retina, but we have limited understanding of how different cell types become dysregulated in this dynamic process. In this study, we performed spatial RNA sequencing on a human donor eye with macular neovascularization as well as a healthy control donor.

A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2's known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses.

Unique interface and dynamics of the complex of HSP90 with a specialized cochaperone AIPL1.

Photoreceptor phosphodiesterase PDE6 is central for visual signal transduction. Maturation of PDE6 depends on a specialized chaperone complex of HSP90 with aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1). Disruption of PDE6 maturation underlies a severe form of retina degeneration.

The role of mitochondria in pharmacological ascorbate-induced toxicity.

At pharmacological levels, ascorbate (P-AscH) acts as a pro-oxidant by generating HO, depleting ATP in sensitive cells leading to cell death. The aim of this study was to determine the role of ATP production by oxidative phosphorylation or glycolysis in mechanisms of resistance to P-AscHinduced cell death. Pancreatic cancer cells were used to generate ρ cells by mitochondrial overexpression of the Y147A mutant uracil-N-glycosylase or Herpes Simplex Virus protein.