Optimal delivery of endothelial progenitor cells in a rat model of critical-size bone defects.

Nonunion and segmental bone defects are complex issues in orthopedic trauma. The use of endothelial progenitor cells (EPCs), as part of a cell-based therapy for bone healing is a promising approach. In preclinical studies, culture medium (CM) is commonly used to deliver EPCs to the defect site, which has the potential for immunogenicity in humans.

Circulating microRNA expression signatures accurately discriminate myalgic encephalomyelitis from fibromyalgia and comorbid conditions.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and fibromyalgia (FM) are two chronic complex diseases with overlapping symptoms affecting multiple systems and organs over time. Due to the absence of validated biomarkers and similarity in symptoms, both disorders are misdiagnosed, and the comorbidity of the two is often unrecognized. Our study aimed to investigate the expression profiles of 11 circulating miRNAs previously associated with ME/CFS pathogenesis in FM patients and individuals with a comorbid diagnosis of FM associated with ME/CFS (ME/CFS + FM), and matched sedentary healthy controls.

Identification of , an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.

DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods.

Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306.

PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound was identified as a weak PKMYT1 inhibitor.

Screening for Inhibitors of YAP Nuclear Localization Identifies Aurora Kinase A as a Modulator of Lung Fibrosis.

Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts.

The induced membrane technique: Optimization of bone grafting in a rat model of segmental bone defect.

Introduction: The induced membrane technique (IMT) is a two-stage surgical procedure used to treat fracture nonunion and bone defects. Although there is an increasing number of animal studies investigating the IMT, few have examined the outcomes of bone healing after a second stage grafting procedure. This study aimed at comparing two bone grafting procedures, as part of the IMT, in order to establish a rat model providing consistent healing outcomes.

Assessing infant cognition in field settings using eye-tracking: a pilot cohort trial in Sierra Leone.

Objectives: To investigate the feasibility of eye-tracking-based testing of the speed of visual orienting in malnourished young children at rural clinics in Sierra Leone.

Design: Prospective dual cohort study nested in a cluster-randomised trial.

Setting: 8 sites participating in a cluster-randomised trial of supplementary feeding for moderate acute malnutrition (MAM).

Effect of electroencephalography-guided anesthesia on neurocognitive disorders in elderly patients undergoing major non-cardiac surgery: A trial protocol The POEGEA trial (POncd Elderly GEneral Anesthesia).

Introduction: The number of elderly patients undergoing major surgery is rapidly increasing. They are particularly at risk of developing postoperative neurocognitive disorders (NCD). Earlier studies suggested that processed electroencephalographic (EEG) monitors may reduce the incidence of postoperative NCD.

Treating high-risk moderate acute malnutrition using therapeutic food compared with nutrition counseling (Hi-MAM Study): a cluster-randomized controlled trial.

Background: There is a lack of consensus on what is the most appropriate treatment of moderate acute malnutrition (MAM).

Objectives: We aimed to determine if provision of ready-to-use-therapeutic food (RUTF) and antibiotics to "high-risk" MAM (HR-MAM) children in addition to nutritional counseling would result in higher recovery and less deterioration than nutrition counseling alone.

Methods: At the 11 intervention clinics, HR-MAM children were given RUTF and amoxicillin along with standard nutrition counseling, for 2-12 wk.

Systemically impaired fracture healing in small animal research: A review of fracture repair models.

Fracture healing is a complex process requiring mechanical stability, an osteoconductive matrix, and osteoinductive and osteogenic biology. This intricate process is easily disrupted by various patient factors such as chronic disease and lifestyle. As the medical complexity and age of patients with fractures continue to increase, the importance of developing relevant experimental models is becoming paramount in preclinical research.

The induced membrane technique for the management of long bone defects.

Aims: The purpose of this study was to: review the efficacy of the induced membrane technique (IMT), also known as the Masquelet technique; and investigate the relationship between patient factors and technique variations on the outcomes of the IMT.

Methods: A systematic search was performed in CINAHL, The Cochrane Library, Embase, Ovid MEDLINE, and PubMed. We included articles from 1 January 1980 to 30 September 2019.

Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease, rooted in multi-system dysfunctions characterized by unexplained debilitating fatigue. Post-exertional malaise (PEM), defined as the exacerbation of the patient's symptoms following minimal physical or mental stress, is a hallmark of ME/CFS. While multiple case definitions exist, there is currently no well-established biomarkers or laboratory tests to diagnose ME/CFS.

Treatment of severe acute malnutrition with oat or standard ready-to-use therapeutic food: a triple-blind, randomised controlled clinical trial.

Objective: We hypothesised that an alternative RUTF (ready-to-use therapeutic food) made with oats (oat-RUTF) would be non-inferior to standard RUTF (s-RUTF).

Design: This was a randomised, triple-blind, controlled, clinical non-inferiority trial comparing oat-RUTF to s-RUTF in rural Sierra Leone. Children aged 6-59 months with severe acute malnutrition (SAM) were randomised to oat-RUTF or s-RUTF.

Understanding Articular Cartilage Injury and Potential Treatments.

The goals of all orthopaedic surgeons treating articular cartilage injuries have been anatomic reduction and stable fixation of the articular cartilage surface with restoration of limb alignment and/or reestablishment of the joint stability, all while minimizing the risk of surgical complications. Recent developments in the study of articular cartilage injury have shown that there is a robust cellular response to joint injury. This response has been shown to involve the synoviocytes, chondrocytes, and osteocytes in and around the injured joint and if these responses are left unchecked, they can lead to the development of posttraumatic osteoarthritis (PTOA).

Experimental Validation of the Radiographic Union Score for Tibial Fractures (RUST) Using Micro-Computed Tomography Scanning and Biomechanical Testing in an in-Vivo Rat Model.

Background: The Radiographic Union Score for Tibial fractures (RUST) and the modified version of the system, mRUST, are popular standards for assessing fracture-healing progress with use of radiographs. To our knowledge, this is the first study to experimentally validate the ability of RUST and mRUST to accurately assess bone-healing progression with use of both micro-computed tomography (micro-CT) scanning and biomechanical testing.

Methods: Adult male rats (n = 29) underwent osteotomy with a midshaft fracture gap repaired with use of a polyetheretherketone plate.

Blood Pressure Measurement in Severely Obese Patients: Validation of the Forearm Approach in Different Arm Positions.

Background: Blood pressure measurement in severe obesity may be technically challenging as the cuff of the device may not fit adequately around the upper arm. The aim of the study was to assess the agreement between intra-arterial blood pressure values (gold standard) compared with forearm blood pressure measurements in severely obese patients in different arm positions.

Methods: Thirty-three severely obese patients and 21 controls participated in the study.

Diabetes and Healing Outcomes in Lower Extremity Fractures: A Systematic Review.

Objective: The purpose of this study was to review the rates of adverse healing outcomes following surgical fixation of lower extremity fractures in diabetic patients and matched controls.

Materials And Methods: Searches of PubMed, MEDLINE, CINAHL and Embase were performed for studies published between the date of database inception and July 6, 2015. Patient characteristics and the incidence of adverse healing outcomes (nonunion, malunion, delayed union, infection and reoperation) were extracted from each study.

Subtypes of endothelial progenitor cells affect healing of segmental bone defects differently.

Purpose: Treating fracture nonunion with endothelial progenitor cells (EPCs) is a promising approach. Nevertheless, the effect of different EPC-related cell populations remains unclear. In this study, we compared the therapeutic potential of early (E-EPCs) and late EPCs (L-EPCs).

Delayed Endothelial Progenitor Cell Therapy Promotes Bone Defect Repair in a Clinically Relevant Rat Model.

The repair of segmental bone defects remains a significant challenge for orthopaedic surgeons. Endothelial progenitor cells (EPCs) have successfully promoted the repair of acute defects in animal models; however, the ability of EPCs to induce the repair of chronic nonhealing defects, such as those often encountered clinically, has not been investigated. Therefore, the purpose of this study was to investigate the ability of EPCs delivered in delayed fashion to induce the repair of nonhealing defects in a clinically relevant model.

The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity.

Microtubule-targeting agents (MTAs) are widely used anticancer agents, but toxicities such as neuropathy limit their clinical use. MTAs bind to and alter the stability of microtubules, causing cell death in mitosis. We describe DZ-2384, a preclinical compound that exhibits potent antitumor activity in models of multiple cancer types.

Differences between the cell populations from the peritenon and the tendon core with regard to their potential implication in tendon repair.

The role of intrinsic and extrinsic healing in injured tendons is still debated. In this study, we characterized cell plasticity, proliferative capacity, and migration characteristics as proxy measures of healing potential in cells derived from the peritenon (extrinsic healing) and compared these to cells from the tendon core (intrinsic healing). Both cell populations were extracted from horse superficial digital flexor tendon and characterized for tenogenic and matrix remodeling markers as well as for rates of migration and replication.