Wound Healing Progression Research Articles

Dual Roles of the AMP-Activated Protein Kinase Pathway in Angiogenesis.

Angiogenesis plays important roles in development, stress response, wound healing, tumorigenesis and cancer progression, diabetic retinopathy, and age-related macular degeneration. It is a complex event engaging many signaling pathways including vascular endothelial growth factor (VEGF), Notch, transforming growth factor-beta/bone morphogenetic proteins (TGF-β/BMPs), and other cytokines and growth factors. Almost all of them eventually funnel to two crucial molecules, VEGF and hypoxia-inducing factor-1 alpha (HIF-1α) whose expressions could change under both physiological and pathological conditions. Hypoxic conditions stabilize HIF-1α, while it is upregulated by many oncogenic factors under normaxia. HIF-1α is a critical transcription activator for VEGF. Recent studies have shown that intracellular metabolic state participates in regulation of sprouting angiogenesis, which may involve AMP-activated protein kinase (AMPK). Indeed, AMPK has been shown to exert both positive and negative effects on angiogenesis. On the one hand, activation of AMPK mediates stress responses to facilitate autophagy which stabilizes HIF-1α, leading to increased expression of VEGF. On the other hand, AMPK could attenuate angiogenesis induced by tumor-promoting and pro-metastatic factors, such as the phosphoinositide 3-kinase /protein kinase B (Akt)/mammalian target of rapamycin (PI3K/Akt/mTOR), hepatic growth factor (HGF), and TGF-β/BMP signaling pathways. Thus, this review will summarize research progresses on these two opposite effects and discuss the mechanisms behind the discrepant findings.

Spatial frequency domain imaging: a quantitative, noninvasive tool for in vivo monitoring of burn wound and skin graft healing.

.There is a need for noninvasive, quantitative methods to characterize wound healing in the context of longitudinal investigations related to regenerative medicine. Such tools have the potential to inform the assessment of wound status and healing progression and aid the development of new treatments. We employed spatial frequency domain imaging (SFDI) to characterize the changes in optical properties of tissue during wound healing progression in a porcine model of split-thickness skin grafts and also in a model of burn wound healing with no graft intervention. Changes in the reduced scattering coefficient measured using SFDI correlated with structural changes reported by histology of biopsies taken concurrently. SFDI was able to measure spatial inhomogeneity in the wounds and predicted heterogeneous healing. In addition, we were able to visualize differences in healing rate, depending on whether a wound was debrided and grafted, versus not debrided and left to heal without intervention apart from topical burn wound care. Changes in the concentration of oxy- and deoxyhemoglobin were also quantified, giving insight into hemodynamic changes during healing.

Synergistic Photodynamic and Photothermal Antibacterial Nanocomposite Membrane Triggered by Single NIR Light Source.

Herein, we developed a nanocomposite membrane with synergistic photodynamic therapy and photothermal therapy antibacterial effects, triggered by a single near-infrared (NIR) light illumination. First, upconversion nanoparticles (UCNPs) with a hierarchical structure (UCNPs@TiO2) were synthesized, which use NaYF4:Yb,Tm nanorods as the core and TiO2 nanoparticles as the outer shell. Then, nanosized graphene oxide (GO), as a photothermal agent, was doped into UCNPs@TiO2 core-shell nanoparticles to obtain UCNPs@TiO2@GO. Afterward, the mixture of UCNPs@TiO2@GO in poly(vinylidene) fluoride (PVDF) was applied for electrospinning to generate the nanocomposite membrane (UTG-PVDF). Generation of reactive oxygen species (ROS) and changes of temperature triggered by NIR action were both investigated to evaluate the photodynamic and photothermal properties. Upon a single NIR light (980 nm) irradiation for 5 min, the nanocomposite membrane could simultaneously generate ROS and moderate temperature rise, triggering synergistic antibacterial effects against both Gram-positive and -negative bacteria, which are hard to be achieved by an individual photodynamic or photothermal nanocomposite membrane. Additionally, the as-prepared membrane can effectively restrain the inflammatory reaction and accelerate wound healing, thus exhibiting great potentials in treating infectious complications in wound healing progress.

Experience of negative pressure wound therapy over sternal wound healing: A retrospective review

Objectives The aim of this study was to retrospectively review the effectiveness of negative pressure wound therapy (NPWT) in sternal wound healing with the use of the validated Bates-Jensen Wound Assessment Tool (BWAT), and explore the role of NPWT over sternal wounds and future treatment pathways. Methods Data was gathered from patients' medical records and the institution's database clinical management system. Seventeen subjects, who had undergone cardiothoracic surgeries and subsequently consulted the wound care team in one year were reviewed. Fourteen of them were included in the analysis. Healing improvement of each sternal wound under continuous NPWT and continuous conventional dressings was studied. In total, 23 continuous NPWT and 13 conventional dressing episodes were analysed with the BWAT. Results Among conventional dressing episodes, sternal wound improvement was 2.5–3% over 10 days to 3.5 weeks, whereas 4–5% sternal healing was achieved in 5 days to 2 weeks with sternal wire presence. Better healing at 11% in 1 week by conventional dressing was attained after sternal wire removal. In NPWT episodes, 8–29%, 13–24%, and 15–46% of healing was observed in 2 weeks, 3.5 to 5 weeks and 6 to 7 weeks, respectively. Only 39% wound healing was acquired at the 13th week of NPWT in one subject. With sternal wire present, 6%–29% wound healing progress was achieved by NPWT in 1–4 weeks, and 16–23% wound improvement in 2 to 4.5 weeks by NWPT after further surgical debridement. After sternal wire removal, 6–34% sternal wound healing occurred by continuous NPWT for 1–2 weeks, and maximum healing at 46% after 2.5 weeks of NPWT were observed. Conclusions Better wound healing was achieved in the NPWT group in comparison to conventional dressings alone. However, suboptimal sternal wound healing by NPWT alone was observed. Removal of sternal wire may improve the effectiveness of NPWT. Successful tertiary closure after NPWT among subjects supports the important bridging role of NPWT in sternal wound healing. Factors causing stagnant sternal wound healing by NPWT alone are discussed.

Dynamic changes of the extracellular matrix during corneal wound healing

The extracellular matrix (ECM) confers transparency to the cornea because of the precise organization of collagen fibrils and a wide variety of proteoglycans. We monitored the corneal wound healing process after alkali burns in rabbits. We analyzed the location and expression of collagens and proteoglycans, the clinical impact, and the recovery of optical transparency.After the animals received both general and ocular topical anesthesia, the central cornea of the left eye was burned by placing an 8-mm diameter filter paper soaked in 0.5 N NaOH for 60 s. The eyes were evaluated under a surgical microscope at 1, 3, and 6 months after burning. At each time point, the clinical conditions of the burned and control corneas were observed. The arrangement of collagen fibers in the corneal stroma was visualized by Picrosirius-red staining, Gomori's silver impregnation and transmission electronic microscopy. Corneal light transmittance was also measured. Myofibroblasts presence was analyzed by immunohistochemistry. mRNA expression levels of collagen types I and III, lumican, decorin, keratocan and alpha-smooth muscle actin were determined by quantitative real-time polymerase chain reaction.One month after alkali burn, the ECM was disorganized and filled with lacunae containing different types of cells and collagen type III fibers in the wound area. Corneal opacities were present with attendant loss of light transmittance. Collagen and proteoglycan mRNA expression levels were up-regulated. After three months, wound healing progress was indicated by reduced corneal opacity, increased light transmittance, reorganization of collagen fibers and only collagen type I expression levels were at control levels. After six months, the wound area ECM morphology was similar to controls, but transmittance values remained low, denoting incomplete restoration of the stromal architecture.This multidisciplinary study of the stromal wound healing process revealed changes in corneal transmittance, collagen organization, myofibroblasts presence and ECM composition at 1, 3, and 6 months after alkali burning. Documenting wound resolution during the six-month period provided reliable information that can be used to test new therapies.

Endoscopic resection of the pancreatic tail and subsequent wound healing mechanisms in a porcine model.

BACKGROUNDLaparoscopic resection of the pancreatic body and tail is the predominant methodology to remove lesions in these locations; its safety and surgical planning are relatively mature, but it remains a complex and high-precision surgical operation, requiring abundant experience and skills in laparoscopic surgery, with a 10% rate of complications.AIMTo verify the feasibility and safety, as well as to examine the complications of endoscopic pancreatectomy and healing mechanisms of pancreatic wounds after endoscopic resection.METHODSTransgastric endoscopic resections of varying sizes of pancreases were performed in 15 healthy Bama miniature pigs. The technical success rate, the incidence of serious complications, and the survival of the animals were studied. The healing of the wounds was evaluated by sacrificing the animals at various time points. Finally, the expression of transforming growth factor-β1 and Smad3/Smad7 in the surgical site was examined by immunohistochemistry to explore the role of these factors in wound healing of the pancreas.RESULTSPartial and total resections were successfully performed in two groups of animals, respectively. The technical success rate and the survival rate of the pigs were both 100%. We obtained 12 pancreatic tissue samples by endoscopic resection. The pancreatic wounds were closed with metal clips in one group and the wounds healed well by forming scars. There was a small amount of pancreatic leakage in the other group, but it can be fully encapsulated. The level of transforming growth factor-β1 (TGF-β1) in the wounds increased during the inflammatory and fibrous hyperplasia phases, and decreased in the scar phase. The expression of Smad3 paralleled that of TGF-β1, while the expression of Smad7 had an inverse relationship with the expression of TGF-β1.CONCLUSIONPurely transgastric endoscopic resection of the pancreas is a safe, effective, and feasible procedure, but the incidence of pancreatic leakage in total pancreatic tail resection is high. The expression of TGF-β1 and Smad3/Samd7 is related to the progression of pancreatic wound healing.

Wound healing properties of Epiphyllum oxypetalum (DC.) Haw. leaf extract in streptozotocin-induced diabetic mice by topical application

Abstract Diabetic foot ulcer is a serious complication of diabetes, resulting from peripheral neuropathy, macrovascular and microvascular disease, impaired angiogenesis and chronic inflammation. Epiphyllum oxypetalum leaves have been proven to be efficacious in incision wound healing. This project aimed to evaluate the wound healing properties of topical application of Epiphyllum oxypetalum leaves in diabetic mice. Diabetes was induced using streptozotocin. Wound healing activity was assessed by incision model. A total of 40 mice were used in this project, divided into four groups: WE10 and WE20 groups were treated topically with 10% and 20% Epiphyllum oxypetalum leaf extract ointment, respectively, while the diabetic control and non-diabetic groups were treated topically with the ointment base. The results showed significant wound healing progress in mice treated with Epiphyllum oxypetalum extract ointment, as assessed by wound contraction, number of macrophages and fibroblast count. In conclusion, topical application of 96% ethanol extract of Epiphyllum oxypetalum leaves could accelerate the wound healing time in diabetic mice, where the best activity was shown by 20% Epiphyllum oxypetalum extract.

On Force and Form: Mechano-Biochemical Regulation of Extracellular Matrix.

The extracellular matrix is well-known for its structural role in supporting cells and tissues, and its important biochemical role in providing signals to cells has increasingly become apparent. These structural and biochemical roles are closely coupled through mechanical forces: the biochemistry of the extracellular matrix determines its mechanical properties, mechanical forces control release or display of biochemical signals from the extracellular matrix, and the mechanical properties of the matrix in turn influence the mechanical set point at which signals are sent. In this Perspective, we explain how the extracellular matrix is regulated by strain and mechanical forces. We show the impact of biochemistry and mechanical forces on in vivo assembly of extracellular matrix and illustrate how matrix can be generated in vitro using a variety of methods. We cover how the matrix can be characterized in terms of mechanics, composition, and conformation to determine its properties and to predict interactions. Finally, we explore how extracellular matrix remodeling, ligand binding, and hemostasis are regulated by mechanical forces. These recently discovered mechano-biochemical interactions have important functions in wound healing and disease progression. It is likely that mechanically altered extracellular matrix interactions are a commonly recurring theme, but due to limited tools to generate extracellular matrix fibers in vitro and lack of high-throughput methods to detect these interactions, it is hypothesized that many of these interactions have yet to be discovered.

LXR\u03b1 limits TGF\u03b2-dependent hepatocellular carcinoma associated fibroblast differentiation

Transforming growth factor β (TGFβ) is deposited in the extracellular space of diverse tissues. Resident fibroblasts respond to TGFβ and undergo myofibroblastic differentiation during tissue wound healing and cancer progression. Cancer-associated fibroblasts (CAFs) communicate with tumor cells during cancer progression, under the guidance of TGFβ signaling. We report that agonist-activated liver X receptors (LXR) limit the expression of key components of myofibroblast differentiation, including the α-smooth muscle actin (αSMA) gene in liver cancer cells. CAFs derived from hepatocellular carcinoma (HCC) express high αSMA and low LXRα levels, whereas hepatocarcinoma cells exhibit an inverse expression pattern. All hepatoma cells analyzed responded to the LXRα agonist T0901317 by inducing fatty acid synthase (FASN) expression. On the other hand, T0901317 antagonized TGFβ-induced fibroblastic marker responses, such as fibronectin and calponin, in a subset of hepatoma cells and all CAFs analyzed. Mechanistically, LXRα antagonized TGFβ signaling at the transcriptional level. Smad3 and LXRα were recruited to adjacent DNA motifs of the ACTA2 promoter. Upon cloning the human ACTA2 promoter, we confirmed its transcriptional induction by TGFβ stimulation, and LXRα overexpression repressed the promoter activity. Hepatosphere formation by HCC cells was enhanced upon co-culturing with CAFs. T0901317 suppressed the positive effects exerted on hepatosphere growth by CAFs. Taken together, the data suggest that LXRα agonists limit TGFβ-dependent CAF differentiation, potentially limiting primary HCC growth.

Antimicrobial wound dressings with high mechanical conformability prepared through thiol-yne click photopolymerization reaction

Radical mediated photochemical thiol-yne click polymerization of thiol-terminated polyurethane prepolymers, with poly(ethylene glycol) soft segment at two different molecular weights, a propargyl terminated urethane crosslinker and silver salt was utilized to prepare versatile wound dressings containing well-dispersed Ag° nanoparticles produced via in situ reduction of Ag+ ions. The dressings with optimized chemical structure showed desirable fluid handling capacity (up to 4.84 g/10 cm2 d−1) to provide moist environment over damaged tissue. They were permeable to oxygen and carbon dioxide, therefore, the processes related to tissue regeneration of wound bed could be continued without problem. Their appropriate tensile strength (up to 3.87 MPa) and suitable conformability (less than 0.1% permanent set) enabled protection of damaged skin tissue from external physical forces during the healing process, even for wounds present at organs with a high degree of freedom. The proper cytocompatibility of the prepared dressings and their ability to support growth and proliferation of fibroblast cells as determined by wound scratch healing assay showed the potential utility of the dressings to motivate wound healing progression by migration of cells to the damaged area. In addition, these dressings with in situ formed silver nanoparticles exhibited promising antimicrobial activity against different bacterial and fungal strains, and consequently could encourage wound healing process by prevention from infection in the wound site.

Mesenchymal stem cells: From regeneration to cancer.

Mesenchymal stem cells (MSCs) are multipotent tissue stem cells that differentiate into a number of mesodermal tissue types, including osteoblasts, adipocytes, chondrocytes and myofibroblasts. MSCs were originally identified in the bone marrow (BM) of humans and other mammals, but recent studies have shown that they are multilineage progenitors in various adult organs and tissues. MSCs that localize at perivascular sites function to rapidly respond to external stimuli and coordinate with the vascular and immune systems to accomplish the wound healing process. Cancer, considered as wounds that never heal, is also accompanied by changes in MSCs that parallels the wound healing response. MSCs are now recognized as key players at distinct steps of tumorigenesis. In this review, we provide an overview of the function of MSCs in wound healing and cancer progression with the goal of providing insight into the development of novel MSC-manipulating strategies for clinical cancer treatment.

Transforming Growth Factor Beta Induces Fibroblasts to Express and Release the Immunomodulatory Protein PD‐L1 into Extracellular Vesicles

Transforming growth factor beta (TGF‐β) is an enigmatic protein with various roles in normal tissue homeostasis/development as well as the development and/or progression of cancer, wound healing, fibrotic disorders, and immune modulation, to name a few. As TGF‐β is causal to various fibroproliferative disorders featuring localized or systemic tissue/organ fibrosis as well as the activated stroma observed in numerous malignancies, characterizing the pathways and players mediating its action is fundamental. To that end, in the current study we found that (i) TGF‐β induces the expression of the immunoinhibitory molecule Programmed Death‐Ligand 1 (PD‐L1) in human and murine fibroblasts in a Smad2/3‐dependent manner; (ii) profibrotic TGF‐β signaling is dependent upon PD‐L1 expression; and (iii) following treatment with TGF‐β, human lung fibroblasts secrete PD‐L1 into extracellular vesicles (EVs) capable of inhibiting T‐cell proliferation in response to T cell receptor stimulation. These findings provide new insights and potential targets for a variety of fibrotic and/or malignant diseases.Support or Funding InformationThis work was supported by Public Health Service grants GM‐55816 and GM‐54200 from the National Institute of General Medical Sciences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Differential Gene Expression in Erlotinib-Treated Fibroblasts.

Therapies targeting the epidermal growth factor receptor (EGFR) result in a painful rash, the most common and debilitating toxicity among patients with non-small cell lung cancer (NSCLC) who take EGFR tyrosine kinase inhibitor (TKI) therapy; however, predicting the development and the severity of the rash is difficult. The aim of this study was to examine how erlotinib-an EGFR TKI that NSCLC patients take to stop or slow tumor growth-altered the transcriptome of dermal fibroblasts. Dermal fibroblasts (ATCC PCS-201-012) were seeded in cell culture flasks, grown under standard conditions, and transferred to cell culture dishes. Cells were treated once daily for 3 days with erlotinib 100 nM (n = 5), erlotinib 1 μM (n = 5), vehicle 1 μM (dimethyl sulfoxide) (n = 5), or no treatment (n = 5). Total RNA was extracted using a standard TRIzol method and hybridized using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Raw intensities generated from the arrays were normalized using a Robust Multiarray Average method and analyzed using analysis of variance in Limma R software. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis to identify canonical or noncanonical signaling pathways enriched in this dataset. We selected genes for investigation based on their potential role in wound healing (AQP3), rash development (CCL2), fibroblast activation (PALLD), cancer and cancer progression (GDF-15, SLC7A11, MMP12, and DIRAS3), and cell cycle control (CDC6). We were able to validate four of these genes by both Western blot analysis and quantitative polymerase chain reaction (MMP12, CCL2, CDC6, and SLC7A11). If found predictive of rash in future studies using patient samples, our findings may help to identify those at risk for severe rash so that (a) the dose of EGFR TKI therapy may be adjusted; (b) additional treatments for the rash can be developed; and/or (c) precise, patient-centered interventions can be developed so that patients with cancer can better self-manage their rash and adhere to EGFR TKI treatment.

Abstract P2-06-11: Sortilin targeted therapy in breast cancer with elevated progranulin expression

Abstract Background: A major challenge concerning breast cancer therapy is the occasional lack of effects using drugs that target cancer cells unspecifically. One possible explanation for this treatment failure is the existence of the small subpopulation of breast cancer stem cells that are believed to be more resistant towards conventional therapy and possesses the ability to drive tumor formation and disease progression. Cytokines secreted by nearby cells and other factors in the surrounding tumor microenvironment further stimulate the cancer cells, contributing to a heterogeneous and potentially more treatment resistant tumor. Thus, a more specific treatment approach targeting the breast cancer stem cell niche is crucial in preventing disease recurrences. In a cytokine screen, we identified progranulin as one of the main compounds secreted from cells exposed to hypoxia, leading to cancer stem cell propagation. Progranulin is involved in biological processes such as wound healing, inflammation and cancer progression. Progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and are further associated with a clinically aggressive phenotype. Methods/Results: By carrying out a number of in vitro and in vivo like screening assays, we demonstrate that progranulin influences the stem cell population in breast cancer and is responsible for spreading a cancer stem cell promoting signal to normoxic tumor areas. In breast cancer, progranulin induces a dedifferentiation process in the receiving cancer cells and expression of cancer stem cell markers together with an EMT-associated gene expression profile, leading to cancer stem cell expansion. By using siRNA and pharmacological inhibition of sortilin, we show that sortilin is a functional receptor of progranulin and is responsible for driving progranulin induced breast cancer stem cell propagation. Supporting the role of progranulin in cancer progression, administration of progranulin in immunocompromised mice induce lung metastasis in our breast cancer xenograft models. The use of different approaches for blocking sortilin, such as sortilin inhibitors, down-modulators or sortilin-targeted antibodies can prevent this dedifferentiation process, both in vitro and in vivo, making the tumor cells less aggressive and metastatic. Conclusion: Targeting progranulin through its associated receptors is a potential therapeutic strategy for the treatment of patients with breast tumors having elevated progranulin or sortilin expression. By inhibiting the secretion based breast cancer progression, we could possibly block the formation of metastasis and cancer cell infiltration. Citation Format: Berger K, Rhost S, Hughes E, Harrison H, Rafnsdottir S, Jacobsson H, Gregersson P, Magnusson Y, Fitzpatrick P, Andersson D, Ståhlberg A, Landberg G. Sortilin targeted therapy in breast cancer with elevated progranulin expression [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-11.

Impact of an educational intervention on postpartum perineal wound care among antenatal mothers in Jos: A quasi-experimental study

Most women with stitched perineum after vaginal birth suffer some forms of postpartum complications. Pain is one of the distressing short term morbidity which interferes with the mother’s ability to carry out activities of daily living and care for her baby. Wound infection and dehiscence are usually seen in some cases. Supportive information on postpartum perineal wound care was given less attention during Antenatal health education sessions thereby making parturient unable to know and practice proper wound care that will aid healing. The aim of this study was to carry out an educational intervention then evaluate the impact of this intervention on practice of postpartum perineal wound care and wound healing. The design used for this study was quasi-experimental. A total of 200 mothers (100 interventions and 100 controls) were serially recruited purposively in antenatal Clinics. Instruments used for data collection consisted of a questionnaire and assessment tool. The instrument was reliable at Cronbach co-efficient alpha 78. Descriptive statistics such as frequency tables, percentages, bar chart, mean and standard deviations were used in analysis and Inferential statistics such as Chi-square and Pearson correlation were used in testing hypotheses. Participants in intervention group were given instructions on postpartum perineal wound care while those in control group received routine teaching on postpartum perineal wound care. The study lasted for 12 weeks. Findings indicate that mothers in intervention group on day 1 practiced perineal wound care; 91.88% implemented hygiene, 93.75% nutrition, 32.29% pain relief measures. On day seven, 92.50% practiced hygiene, 96.88% nutrition, 62.50% pain relief measures, 100% took their medications. Subjects in control group inadequately implemented the practice of postpartum self perineal wound care as seen in day 1; implementation of comfort measure was 3.3%, with 99.33% did not practice hygiene and none practiced eating food that prevents constipation but 99.67% adhered to their prescribed drugs because drugs are usually prescribed within 24 hours of delivery. Practice was found to influenced pain reduction in both group because as practice increased day 1 in intervention group, there was a decrease in pain intensity (r=-0.910; p<0.05) even though drugs are usually prescribed on discharge also, in control group as practice increased the second day, there was also decrease in pain intensity (r=-0.547; p=0.002). Women in the intervention group showed better wound healing process as 12.5% had severe pain on day 1 postpartum as against 20% in control group. On day 7 none in intervention group had gaped wound but 66.70% of them had gaped wound in control group. In conclusion, women who were taught postpartum perineal wound care practiced it and this resulted in better wound healing progress, therefore, it is recommended that postpartum self-perineal wound care be introduced to antenatal mother, guidelines on perineal wound care be made available in delivery centers, Midwives should encourage parturient to practice care while on admission and encourage mothers to practice care when discharged home.

Cell Signaling Pathways Related to Epithelial Mesenchymal Transition in Cancer Metastasis.

The epithelial mesenchymal transition (EMT) is a highly complex and dynamic morphogenetic process in which epithelial cells change their cellular characteristics and transform to mesenchymal cells. It plays a key role in tissue remodeling, not only during embryonic development and stem cell biology but also during wound healing, fibrosis, and cancer progression. In EMT, under different extracellular cell signals and stimuli, epithelial cells undergo an orchestrated series of morphological, cellular, biochemical, and molecular changes. The mechanism of cancer cell metastasis is similar to embryonic development, like epithelial cells migrating and differentiating into all tissues of the embryo. In this period, epithelial cells differentiate into mesenchymal cells, migrate, and return to the epithelial cells when necessary. The important cell signaling pathways in embryonic development, such as growth factor receptor tyrosine kinases (FGF, HGF, TGF-α), TGF-β, Wnt, NOTCH, MAPK, JAK/STAT and inflammatory cytokines such as NF-κB, TNF-α, IL6, cathepsin and HIF-1α. All play crucial roles in EMT during cancer cell invasion and metastasis. In cancer progression, similar cell signaling pathways and molecular activation occur in embryonic development; therefore, it is important to understand the molecular mechanisms of cell signaling pathways related to cancer metastasis and improve new diagnostic and therapeutic approaches for resistance to drugs.

Role of infrared thermography in the assessment of burn wounds treated with and without hyperbaric oxygen therapy

Aim: The aim is to study the role of infrared thermography in the assessment of burns wound treated with and without hyperbaric oxygen (HBO) therapy. Burn wound progression is assessed with clinical evaluation and infrared thermography for the patients subjected to HBO therapy with controls. Materials and Methods: This study was carried out in the plastic surgery department, from November 2018 to February 2019. A total of 21 patients with Burns were subjected to clinical evaluation and thermographic study. All patients were treated according to standard burns treatment protocol, and photographic data of clinical and thermographic imagings were sequentially recorded. These clinical and radiographic images were preserved for analysis. In 10 patients, HBO therapy was used as an adjunct for burns wound management and results were evaluated and rest of the patients was used as control. Results: Of 21 patients, with all patients' burns patients assessment done clinically and infrared thermography, 10 patients were subjected to hyperbaric therapy in random fashion and 11 patients were not subjected to HBO therapy. The duration of wound healing and wound progression to deeper planes were reduced in the patients subjected to hyperbaric therapy, which was evident both clinically and, by thermographic assessment. No complications were noted in patients subjected to HBO therapy. Conclusions: Infrared thermography can be used in association with clinical examination to assess the various types of burns wound and could be utilized for understanding the dynamic changes that happen in burns wound due to changes in the treatment protocol with evolving adjunct managements.

Fine-grained diabetic wound depth and granulation tissue amount assessment using bilinear convolutional neural network.

Diabetes mellitus is a serious chronic disease that affects millions of people worldwide. In patients with diabetes, ulcers occur frequently and heal slowly. Grading and staging of diabetic ulcers is the first step of effective treatment and wound depth and granulation tissue amount are two important indicators of wound healing progress. However, wound depths and granulation tissue amount of different severities can visually appear quite similar, making accurate machine learning classification challenging. In this paper, we innovatively adopted the fine-grained classification idea for diabetic wound grading by using a Bilinear CNN (Bi-CNN) architecture to deal with highly similar images of five grades. Wound area extraction, sharpening, resizing and augmentation were used to pre-process images before being input to the Bi-CNN. Innovative modifications of the generic Bi-CNN network architecture are explored to improve its performance. Our research generated a valuable wound dataset. In collaboration with wound experts from University of Massachusetts Medical School, we collected a diabetic wound dataset of 1639 images and annotated them with wound depth and granulation tissue grades as labels for classification. Deep learning experiments were conducted using holdout validation on this diabetic wound dataset. Comparisons with widely used CNN classification architectures demonstrated that our Bi-CNN fine-grained classification approach outperformed prior work for the task of grading diabetic wounds.

Fluorescence Imaging of Mitochondrial Redox State to Assess Diabetic Wounds.

Background: Diabetes is known to cause delayed wound healing, and chronic non-healing lower extremity ulcers may end with lower limb amputations and mortalities. Given the increasing prevalence of diabetes mellitus worldwide, it is critical to focus on underlying mechanisms of these debilitating wounds to find novel therapeutic strategies and thereby improve patient outcome. Methods: This study aims to design a label-free optical fluorescence imager that captures metabolic indices (NADH and FAD autofluorescence) and monitors the in vivo wound healing progress noninvasively. Furthermore, 3D optical cryo-imaging of the mitochondrial redox state was utilized to assess the volumetric redox state of the wound tissue. Results: The results from our in vivo fluorescence imager and the 3D cryo-imager quantify the differences between the redox state of wounds on diabetic mice in comparison with the control mice. These metabolic changes are associated with mitochondrial dysfunction and higher oxidative stress in diabetic wounds. A significant correlation was observed between the redox state and the area of the wounds. Conclusion: The results suggest that our developed novel optical imaging system can successfully be used as an optical indicator of the complex wound healing process noninvasively.

Integrin CD11b activation drives anti-tumor innate immunity

Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression. Recruitment of these cells is regulated by integrins, a family of adhesion receptors that includes integrin CD11b. Here we report that, unexpectedly, integrin CD11b does not regulate myeloid cell recruitment to tumors but instead controls myeloid cell polarization and tumor growth. CD11b activation promotes pro-inflammatory macrophage polarization by stimulating expression of microRNA Let7a. In contrast, inhibition of CD11b prevents Let7a expression and induces cMyc expression, leading to immune suppressive macrophage polarization, vascular maturation, and accelerated tumor growth. Pharmacological activation of CD11b with a small molecule agonist, Leukadherin 1 (LA1), promotes pro-inflammatory macrophage polarization and suppresses tumor growth in animal models of murine and human cancer. These studies identify CD11b as negative regulator of immune suppression and a target for cancer immune therapy.