Toward understanding scarless skin wound healing and pathological scarring

The efficient healing of skin wounds is crucial for securing the vital barrier function of the skin, but pathological wound healing and scar formation are major medical problems causing both physiological and psychological challenges for patients. A number of tightly coordinated regenerative responses, including haemostasis, the migration of various cell types into the wound, inflammation, angiogenesis, and the formation of the extracellular matrix, are involved in the healing process. In this article, we summarise the central mechanisms and processes in excessive scarring and acute wound healing, which can lead to the formation of keloids or hypertrophic scars, the two types of fibrotic scars caused by burns or other traumas resulting in significant functional or aesthetic disadvantages. In addition, we discuss recent developments related to the functions of activated fibroblasts, the extracellular matrix and mechanical forces in the wound environment as well as the mechanisms of scarless wound healing. Understanding the different mechanisms of wound healing is pivotal for developing new therapies to prevent the fibrotic scarring of large skin wounds.publishedVersio

Haavan paraneminen - diabetes sekä muut esteet ja hidasteet

Krooniset haavat ja haavan paranemisen pitkittyminen ovat merkittäviä kliinisiä ongelmia. Haavan paraneminen on monimutkainen biologinen prosessi, joka voidaan jakaa neljään vaiheeseen: verenvuodon tyrehtymiseen sekä sitä seuraaviin tulehdus-, korjaus- ja kypsymisvaiheisiin, joita säätelevät paikalliset olosuhteet. Haavan paranemiseen vaikuttaa myös yksilön yleistila kaikkine sairauksineen ja lääkityksineen. Paikallisista tekijöistä muun muassa tulehdusreaktiovaiheen pitkittyminen ja huono verenkierto edistävät haavojen kroonistumista. Diabetekseen liittyy huonontunut haavojen paranemistaipumus. Hyperglykemia heikentää haavan paranemista useilla eri mekanismeilla, joista yksi keskeinen perustuu hyperglykemian seurauksena kudoksiin ylimäärin kertyneiden, ei-entsymaattisesti liikaglykosyloituneiden molekyylien (advanced glycosylation end-products, AGE) käynnistämiin solubiologisiin häiriöihin. Paras keino estää hyperglykemian haitallinen vaikutus on tavoitella suositusten mukaista verenglukoosipitoisuutta

Molecular alterations in pediatric brainstem gliomas

BackgroundDiffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group. MethodsWe studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long-term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next-generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC). ResultsH3 K27 was mutated in NGS or IHC in 20 patients, excluding both long-term survivors. One of these long-term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPAR, PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies. ConclusionsEighty-seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27-mutated diffuse midline gliomas. Both long-term survivors lacked this alteration. Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas.Peer reviewe

Upregulated integrin α11 in the stroma of cutaneous squamous cell carcinoma promotes skin carcinogenesis

Integrin α11β1 is a collagen-binding integrin that is needed to induce and maintain the myofibroblast phenotype in fibrotic tissues and during wound healing. The expression of the α11 is upregulated in cancer-associated fibroblasts (CAFs) in various human neoplasms. We investigated α11 expression in human cutaneous squamous cell carcinoma (cSCC) and in benign and premalignant human skin lesions and monitored its effects on cSCC development by subjecting α11-knockout (Itga11−/−) mice to the DMBA/TPA skin carcinogenesis protocol. α11-deficient mice showed significantly decreased tumor cell proliferation, leading to delayed tumor development and reduced tumor burden. Integrin α11 expression was significantly upregulated in the desmoplastic tumor stroma of human and mouse cSCCs, and the highest α11 expression was detected in high-grade tumors. Our results point to a reduced ability of α11-deficient stromal cells to differentiate into matrix-producing and tumor-promoting CAFs and suggest that this is one causative mechanism underlying the observed decreased tumor growth. An unexpected finding in our study was that, despite reduced CAF activation, the α11-deficient skin tumors were characterized by the presence of thick and regularly aligned collagen bundles. This finding was attributed to a higher expression of TGFβ1 and collagen crosslinking lysyl oxidases in the Itga11-/- tumor stroma. In summary, our data suggest that α11β1 operates in a complex interactive tumor environment to regulate ECM synthesis and collagen organization and thus foster cSCC growth. Further studies with advanced experimental models are still needed to define the exact roles and molecular mechanisms of stromal α11β1 in skin tumorigenesis.publishedVersio

Mutation analysis of the ATR gene in breast and ovarian cancer families

INTRODUCTION: Mutations in BRCA1, BRCA2, ATM, TP53, CHK2 and PTEN account for only 20–30% of the familial aggregation of breast cancer, which suggests the involvement of additional susceptibility genes. The ATR (ataxia-telangiectasia- and Rad3-related) kinase is essential for the maintenance of genomic integrity. It functions both in parallel and cooperatively with ATM, but whereas ATM is primarily activated by DNA double-strand breaks induced by ionizing radiation, ATR has been shown to respond to a much broader range of DNA damage. Upon activation, ATR phosphorylates several important tumor suppressors, including p53, BRCA1 and CHK1. Based on its central function in the DNA damage response, ATR is a plausible candidate gene for susceptibility to cancer. METHODS: We screened the entire coding region of the ATR gene for mutations in affected index cases from 126 Finnish families with breast and/or ovarian cancer, 75 of which were classified as high-risk and 51 as moderate-risk families, by using conformation sensitive gel electrophoresis and direct sequencing. RESULTS: A large number of novel sequence variants were identified, four of which – Glu254Gly, Ser1142Gly, IVS24-48G>A and IVS26+15C>T – were absent from the tested control individuals (n = 300). However, the segregation of these mutations with the cancer phenotype could not be confirmed, partly because of the lack of suitable DNA samples. CONCLUSION: The present study does not support a major role for ATR mutations in hereditary susceptibility to breast and ovarian cancer

The role of <em>BACH1</em>, <em>BARD1</em> and <em>TOPBP1</em> genes in familial breast cancer

Abstract Approximately 5–10% of all breast cancer cases are estimated to result from a hereditary predisposition to the disease. Currently no more than 25–30% of these familial cases can be explained by mutations in the known susceptibility genes, BRCA1 and BRCA2 being the major ones. Additional predisposing genes are therefore likely to be discovered. This study evaluates whether germline alterations in three BRCA1-associated genes, BACH1 (i.e. BRIP1/FANCJ), BARD1 and TOPBP1, contribute to familial breast cancer. Altogether 214 Finnish patients having breast and/or ovarian cancer were analysed for germline mutations in the BACH1 gene. Nine alterations were observed, four of which located in the protein-encoding region. The previously unidentified Pro1034Leu was considered a possible cancer-associated alteration as it appeared with two-fold higher frequency among cancer cases compared to controls. All the other observed alterations were classified as harmless polymorphisms. Mutation analysis of the BARD1 gene among 126 Finnish patients having family history of breast and/or ovarian cancer revealed seven alterations in the protein-encoding region. The Cys557Ser alteration was seen at an elevated frequency among familial cancer cases compared to controls (p = 0.005, odds ratio [OR] 4.2, 95% confidence interval [CI] 1.7–10.7). The other alterations appeared to be harmless polymorphisms. To evaluate further the possible effect of Cys557Ser on cancer risk, a large case-control study was performed, consisting of 3,956 cancer patients from the Nordic countries. The highest prevalence of Cys557Ser was found among breast and ovarian cancer patients from BRCA1/BRCA2 mutation-negative families (p &lt; 0.001, OR 2.6, 95% CI 1.7–4.0). In contrast, no significant association with male breast cancer, ovarian, colorectal or prostate cancer was observed. The current study is the first evaluating the role of TOPBP1 mutations in familial cancer predisposition. The analysis of 125 Finnish patients having breast and/or ovarian cancer revealed one putative pathogenic alteration. The commonly occurring Arg309Cys allele was observed at a significantly higher frequency among familial cancer cases compared to controls (p = 0.002, OR 2.4, 95% CI 1.3–4.2). The other 18 alterations observed were classified as harmless polymorphisms

Musiikin merkitys postoperatiivisessa toipumisessa: kuvaileva kirjallisuuskatsaus

Opinnäytetyön tarkoituksena oli kuvailla musiikin merkitystä postoperatiivisessa toipumisessa ja sitä, miten musiikkia voidaan käyttää hoitotyössä sekä millaisia tuloksia musiikilla on saatu postoperatiivisten potilaiden hoidossa. Opinnäytetyön tavoitteena oli tuottaa tietoa terveydenhuollon ammattilaisille ja opiskelijoille musiikin käyttämisestä postoperatiivisessa hoitotyössä ja musiikin vaikutuksista postoperatiivisten potilaiden hoidossa, mitä voidaan tulevaisuuden hoitotyössä hyödyntää. Opinnäytetyö toteutettiin kuvailevana kirjallisuuskatsauksena. Aineisto kerättiin Cinahl-PubMed- ja Medic-tietokannoista käyttäen sisäänotto- ja poissulkukriteereitä sekä laadunarviointia. Tutkimukseen valikoitui 10 hoitotieteellistä alkuperäistutkimusta, jotka analysoitiin induktiivisella sisällönanalyysilla. Tulokset osoittivat, että musiikki voi edistää postoperatiivista toipumista. Musiikin kuuntelu vähensi erityisesti postoperatiivista kipua ja ahdistusta. Musiikin vaikutukset vitaalielintoimintoihin ovat lähinnä ristiriitaisia tai vaikutusta ei todettu, mutta verenpaineeseen sillä todettiin olevan alentava vaikutus. Musiikilla todettiin olevan myös joitakin kognitiivista toimintaa edistäviä vaikutuksia. Sairaalassaoloaikaan musiikilla ei todettu olevan vaikutusta. Tulosten mukaan postoperatiivisessa toipumisessa musiikkia kuunnellaan tavallisimmin kuulokkeilla, MP3-soittimella, CD-soittimella ja kaiuttimella. Useimmiten postoperatiivisessa toipumisvaiheessa kuunnellaan rauhallista musiikkia. Tutkimusten perusteella voidaan todeta, että musiikki olisi hyvä yhdistää osaksi postoperatiivista hoitotyötä, sillä se on lääkkeetön, noninvasiivinen, edullinen sekä helposti toteutettava hoitomuoto. Jatkossa tulisi tutkia vaikuttavatko musiikin kuuntelutapa ja musiikkityyli postoperatiivisen toipumiseen. Lisäksi opinnäytetyön tulokset musiikin vaikutuksista postoperatiiviseen toipumiseen olivat osittain ristiriitaisia. Osassa tutkimuksia musiikki vaikutti toipumiseen ja osassa ei, vaikka tutkittiin samaa postoperatiiviseen toipumiseen liittyvää tekijää, kuten sykettä. Ristiriitaisuuden vuoksi aihetta tulisi tutkia lisää

Haavan paraneminen - diabetes sekä muut esteet ja hidasteet

Vertaisarvioitu. Teema : krooninen haava. English summary.Krooniset haavat ja haavan paranemisen pitkittyminen ovat merkittäviä kliinisiä ongelmia. Haavan paraneminen on monimutkainen biologinen prosessi, joka voidaan jakaa neljään vaiheeseen: verenvuodon tyrehtymiseen sekä sitä seuraaviin tulehdus-, korjaus- ja kypsymisvaiheisiin, joita säätelevät paikalliset olosuhteet. Haavan paranemiseen vaikuttaa myös yksilön yleistila kaikkine sairauksineen ja lääkityksineen. Paikallisista tekijöistä muun muassa tulehdusreaktiovaiheen pitkittyminen ja huono verenkierto edistävät haavojen kroonistumista. Diabetekseen liittyy huonontunut haavojen paranemistaipumus. Hyperglykemia heikentää haavan paranemista useilla eri mekanismeilla, joista yksi keskeinen perustuu hyperglykemian seurauksena kudoksiin ylimäärin kertyneiden, ei-entsymaattisesti liikaglykosyloituneiden molekyylien (advanced glycosylation end-products, AGE) käynnistämiin solubiologisiin häiriöihin. Paras keino estää hyperglykemian haitallinen vaikutus on tavoitella suositusten mukaista verenglukoosipitoisuutta.Peer reviewe

Toward understanding scarless skin wound healing and pathological scarring

The efficient healing of skin wounds is crucial for securing the vital barrier function of the skin, but pathological wound healing and scar formation are major medical problems causing both physiological and psychological challenges for patients. A number of tightly coordinated regenerative responses, including haemostasis, the migration of various cell types into the wound, inflammation, angiogenesis, and the formation of the extracellular matrix, are involved in the healing process. In this article, we summarise the central mechanisms and processes in excessive scarring and acute wound healing, which can lead to the formation of keloids or hypertrophic scars, the two types of fibrotic scars caused by burns or other traumas resulting in significant functional or aesthetic disadvantages. In addition, we discuss recent developments related to the functions of activated fibroblasts, the extracellular matrix and mechanical forces in the wound environment as well as the mechanisms of scarless wound healing. Understanding the different mechanisms of wound healing is pivotal for developing new therapies to prevent the fibrotic scarring of large skin wounds

Haavan paraneminen ja arpeutumisen häiriöt

Tiivistelmä Ihohaavan nopea paraneminen on yksilön selviytymisen kannalta ratkaisevaa ihon elintärkeän suojaustehtävän vuoksi. Haavan paranemiseen liittyy useita kudosta korjaavia biologisia vasteita kuten hemostaasi, tulehdus, erilaisten solujen migraatio haava-alueelle, niiden jakautuminen ja erilaistuminen, angiogeneesi sekä sidekudoksen muodostus ja muokkaus. Häiriöt näissä tapahtumissa johtavat haavan kroonistumiseen tai liiallisen arpikudoksen muodostumiseen. Tarkastelemme akuutin haavan paranemisen vaiheita sekä arpeutumisen häiriöitä eli hypertrofisia arpia ja keloideja, jotka voivat aiheuttaa merkittävää toiminnallista ja kosmeettista haittaa. Haavan paranemiseen ja arven muodostumiseen liittyvien solu- ja molekyylitason mekanismien ymmärtäminen on ensiarvoisen tärkeää kehiteltäessä uusia hoitomenetelmiä palovammoista tai muista traumoista johtuvien laajojen ihoalueiden arpeutumisen ehkäisemiseen.Summary Wound healing and pathological scarring Efficient healing of skin wounds is crucial because of the vital barrier function of the skin. Multiple tightly coordinated regenerative responses are involved in the healing process, including hemostasis, migration of various cell types into the wound, inflammation, angiogenesis, and formation of the extracellular matrix. This review summarizes the phases of acute wound healing and excessive scarring which can lead to formation of hypertrophic scars or keloids, the two types of fibrotic scars that can cause significant functional or aesthetic disadvantage. Understanding of the mechanisms of wound healing is pivotal for developing new therapies to prevent fibrotic scarring of large skin wounds caused by burns or other traumas