Donor Limb Functional Restoration via a Novel Clinical Care Pathway following Fibula Free Flap Harvest for Head and Neck Reconstruction.

Patients undergoing head and neck skeletal reconstruction (HNR) often require free tissue transfer from the extremities to ensure proper restoration of form and function. This requires a team-based, highly reliable medical system centered around the patient needs. Surgical intervention across multiple sites and harvesting of donor tissue results in short- and long-term physical impairments.

Exosomes mediated fibrogenesis in dilated cardiomyopathy through a MicroRNA pathway.

Cardiac fibrosis is a hallmark in late-stage familial dilated cardiomyopathy (DCM) patients, although the underlying mechanism remains elusive. Cardiac exosomes (Exos) have been reported relating to fibrosis in ischemic cardiomyopathy. Thus, we investigated whether Exos secreted from the familial DCM cardiomyocytes could promote fibrogenesis.

Fall Prevention Training for Service Members With an Amputation or Limb Salvage Following Lower Extremity Trauma.

Introduction: Recent military conflicts have resulted in a significant number of lower extremity injuries to U.S. service members that result in amputation or limb preservation (LP) procedures.

Running footstrike pattern effect on lower extremity work in an individual with transtibial amputation.

Asymmetrical loading favoring the intact limb during running has been associated with increased prevalence of reported knee pain and potential risk factors of knee osteoarthritis in that limb for patients with amputation. Footstrike pattern alterations have been suggested to help alleviate some overloading of the knee, but little is known about how it affects the rest of the limb. The purpose of this case study was to evaluate the effect of footstrike pattern on the distribution of loading throughout the lower extremities during submaximal running of an individual with transtibial amputation (TTA).

Common fall-risk indicators are not associated with fall prevalence in a high-functioning military population with lower limb trauma.

Background: Persons with lower limb trauma are at high risk for falls. Although there is a wide range of measures used to assess stability and fall-risk that include performance measures, temporal-spatial gait parameters, and nonlinear dynamic stability calculations, these measures are typically derived from fall-prone populations, such as older adults. Thus, it is unclear if these commonly used fall-risk indicators are effective at evaluating fall-risk in a younger, higher-functioning population of Service members with lower limb trauma.

Altered sialidase expression in human myeloid cells undergoing apoptosis and differentiation.

To gain insight into sialic acid biology and sialidase/neuraminidase (NEU) expression in mature human neutrophil (PMN)s, we studied NEU activity and expression in PMNs and the HL60 promyelocytic leukemic cell line, and changes that might occur in PMNs undergoing apoptosis and HL60 cells during their differentiation into PMN-like cells. Mature human PMNs contained NEU activity and expressed NEU2, but not NEU1, the NEU1 chaperone, protective protein/cathepsin A(PPCA), NEU3, and NEU4 proteins. In proapoptotic PMNs, NEU2 protein expression increased > 30.

Comparative efficacy and mechanism of action of cardiac progenitor cells after cardiac injury.

Successful cell therapy requires cells to resist the hostile ischemic myocardium, be retained to continue secreting cardioprotective growth factors/exosomes, and resist immunological host responses. Clinically relevant stem/progenitor cells in a rodent model of acute myocardial infarction (MI) demonstrated that neonatal cardiac mesenchymal stromal cells (nMSCs) provide the most robust cardiac functional recovery. Transplanted nMSCs significantly increased the number of tissue reparative macrophages and regulatory T-cells and decreased monocyte-derived inflammatory macrophages and neutrophils in the host myocardium.

Activating STING1-dependent immune signaling in mutant and wild-type acute myeloid leukemia.

DNA methyltransferase inhibitors (DNMTis) reexpress hypermethylated genes in cancers and leukemias and also activate endogenous retroviruses (ERVs), leading to interferon (IFN) signaling, in a process known as viral mimicry. In the present study we show that in the subset of acute myeloid leukemias (AMLs) with mutations in , associated with poor prognosis, DNMTis, important drugs for treatment of AML, enable expression of ERVs and IFN and inflammasome signaling in a STING-dependent manner. We previously reported that in solid tumors poly ADP ribose polymerase inhibitors (PARPis) combined with DNMTis to induce an IFN/inflammasome response that is dependent on STING1 and is mechanistically linked to generation of a homologous recombination defect (HRD).

Correction: Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.

[This corrects the article DOI: 10.1371/journal.pone.

PARP1 PARylates and stabilizes STAT5 in FLT3-ITD acute myeloid leukemia and other STAT5-activated cancers.

Signal transducer and activator of transcription 5 (STAT5) signaling plays a pathogenic role in both hematologic malignancies and solid tumors. In acute myeloid leukemia (AML), internal tandem duplications of fms-like tyrosine kinase 3 (FLT3-ITD) constitutively activate the FLT3 receptor, producing aberrant STAT5 signaling, driving cell survival and proliferation. Understanding STAT5 regulation may aid development of new treatment strategies in STAT5-activated cancers including FLT3-ITD AML.

Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.

Radiation therapy plays a major role in the treatment of lung cancer patients. However, cancer cells develop resistance to radiation. Tumor radioresistance is a complex multifactorial mechanism which may be dependent on DNA damage and repair, hypoxic conditions inside tumor microenvironment, and the clonal selection of radioresistant cells from the heterogeneous tumor site, and it is a major cause of treatment failure in non-small cell lung cancer (NSCLC).

Military Service Members with Major Lower Extremity Fractures Return to Running with a Passive-dynamic Ankle-foot Orthosis: Comparison with a Normative Population.

Background: Lower extremity fractures represent a high percentage of reported injuries in the United States military and can devastate a service member's career. A passive dynamic ankle-foot orthosis (PD-AFO) with a specialized rehabilitation program was initially designed to treat military service members after complex battlefield lower extremity injuries, returning a select group of motivated individuals back to running. For high-demand users of the PD-AFO, the spatiotemporal gait parameters, agility, and quality of life is not fully understood with respect to uninjured runners.

Assessments of trunk postural control within a fall-prevention training program for service members with lower limb trauma and loss.

Background: Trunk postural control (TPC) is critical in maintaining balance following perturbations (i.e., avoiding falls), and impaired among persons with lower extremity trauma, contributing to elevated fall risk.

Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax.

Artemisinins are active against human leukemia cell lines and have low clinical toxicity in worldwide use as antimalarials. Because multiagent combination regimens are necessary to cure fully evolved leukemias, we sought to leverage our previous finding that artemisinin analogs synergize with kinase inhibitors, including sorafenib (SOR), by identifying additional synergistic antileukemic drugs with low toxicity. Screening of a targeted antineoplastic drug library revealed that B-cell lymphoma 2 (BCL2) inhibitors synergize with artemisinins, and validation assays confirmed that the selective BCL2 inhibitor, venetoclax (VEN), synergized with artemisinin analogs to inhibit growth and induce apoptotic cell death of multiple acute leukemia cell lines in vitro.

SIRT3, a metabolic target linked to ataxia-telangiectasia mutated (ATM) gene deficiency in diffuse large B-cell lymphoma.

Inactivation of Ataxia-telangiectasia mutated (ATM) gene results in an increased risk to develop cancer. We show that ATM deficiency in diffuse large B-cell lymphoma (DLBCL) significantly induce mitochondrial deacetylase sirtuin-3 (SIRT3) activity, disrupted mitochondrial structure, decreased mitochondrial respiration, and compromised TCA flux compared with DLBCL cells expressing wild type (WT)-ATM. This corresponded to enrichment of glutamate receptor and glutamine pathways in ATM deficient background compared to WT-ATM DLBCL cells.

The PAX-SIX-EYA-DACH network modulates GATA-FOG function in fly hematopoiesis and human erythropoiesis.

The GATA and PAX-SIX-EYA-DACH transcriptional networks (PSEDNs) are essential for proper development across taxa. Here, we demonstrate novel PSEDN roles in hematopoiesis and in human erythropoiesis Using genetics, we show that PSEDN members function with GATA to block lamellocyte differentiation and maintain the prohemocyte pool. Overexpression of human SIX1 stimulated erythroid differentiation of human erythroleukemia TF1 cells and primary hematopoietic stem-progenitor cells.

mTOR hyperactivity mediates lysosomal dysfunction in Gaucher's disease iPSC-neuronal cells.

Bi-allelic mutations cause Gaucher's disease (GD), the most common lysosomal storage disorder. Neuronopathic manifestations in GD include neurodegeneration, which can be severe and rapidly progressive. mutations are also the most frequent genetic risk factors for Parkinson's disease.

A Yeast Suppressor Screen Used To Identify Mammalian SIRT1 as a Proviral Factor for Middle East Respiratory Syndrome Coronavirus Replication.

Viral proteins must intimately interact with the host cell machinery during virus replication. Here, we used the yeast as a system to identify novel functional interactions between viral proteins and eukaryotic cells. Our work demonstrates that when the Middle East respiratory syndrome coronavirus (MERS-CoV) ORF4a accessory gene is expressed in yeast it causes a slow-growth phenotype.

MicroRNAs as regulators and effectors of hematopoietic transcription factors.

Hematopoiesis is a highly-regulated development process orchestrated by lineage-specific transcription factors that direct the generation of all mature blood cells types, including red blood cells, megakaryocytes, granulocytes, monocytes, and lymphocytes. Under homeostatic conditions, the hematopoietic system of the typical adult generates over 10 blood cells daily throughout life. In addition, hematopoiesis must be responsive to acute challenges due to blood loss or infection.

Estimating the Mass of Chemicals Associated with Ocean Plastic Pollution to Inform Mitigation Efforts.

Plastic pollution in the marine environment is well documented. What remains less recognized and understood are the chemicals associated with it. Plastics enter the ocean with unreacted monomers, oligomers, and additives, which can leach over time.

Are Gait Parameters for Through-knee Amputees Different From Matched Transfemoral Amputees?

Background: Through-knee amputation is a common amputation level after battlefield injuries during the medical evacuation process. However, there are limited data comparing through-knee amputation with transfemoral amputation as a definitive amputation level in terms of gait parameters.

Questions/purposes: (1) Does through-knee amputation result in improved gait velocity when compared with matched transfemoral amputees? (2) Do through-knee amputees have a faster gait cadence than matched transfemoral amputees? (3) Do through-knee amputees have a different stride length or stride width than matched transfemoral amputees? (4) Does through-knee amputation result in decreased work of ambulation when compared with matched transfemoral amputees?

Methods: Between January 2008 and December 2012, six male active-duty military patients who had undergone unilateral through-knee amputations as a result of trauma underwent gait studies at our institution.

Regulation of cancer stem cell properties by SIX1, a member of the PAX-SIX-EYA-DACH network.

The PAX-SIX-EYA-DACH network (PSEDN) is a central developmental transcriptional regulatory network from Drosophila to humans. The PSEDN is comprised of four conserved protein families; including paired box (PAX), sine oculis (SIX), eyes absent (EYA), and dachshund (DACH). Aberrant expression of PSEDN members, particularly SIX1, has been observed in multiple human cancers, where SIX1 expression correlates with increased aggressiveness and poor prognosis.

Measuring Abnormality in High Dimensional Spaces with Applications in Biomechanical Gait Analysis.

Accurately measuring a subject's abnormality using high dimensional data can empower better outcomes research. Utilizing applications in instrumented gait analysis, this article demonstrates how using data that is inherently non-independent to measure overall abnormality may bias results. A methodology is then introduced to address this bias and accurately measure abnormality in high dimensional spaces.

A Fluidic Culture Platform for Spatially Patterned Cell Growth, Differentiation, and Cocultures.

Stem cell cultures within perfusion bioreactors, while efficient in obtaining cell numbers, often lack the similarity to native tissues and consequently cell phenotype. We develop a three-dimensional (3D)-printed fluidic chamber for dynamic stem cell culture, with emphasis on control over flow and substrate curvature in a 3D environment, two physiologic features of native tissues. The chamber geometry, consisting of an array of vertical cylindrical pillars, facilitates actin-mediated localization of human mesenchymal stem cells (hMSCs) within ∼200 μm distance from the pillars, enabling spatial patterning of hMSCs and endothelial cells in cocultures and subsequent modulation of calcium signaling between these two essential cell types in the bone marrow microenvironment.