Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis

Purpose Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab. Methods We collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004-3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3(+) T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1(+)-immunosuppressive macrophage density in their primary tumours. Conclusion Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.Peer reviewe

Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis

Purpose Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab. Methods We collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004-3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3(+) T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1(+)-immunosuppressive macrophage density in their primary tumours. Conclusion Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.Peer reviewe

Draamakasvatus tunne- ja vuorovaikutustaitojen tukena 0–6-vuotiailla

Tiivistelmä. Tutkielmamme tavoitteena on koota yhteen, miten draamakasvatuksella voidaan tukea ja kehittää lasten tunne- ja vuorovaikutustaitoja. Tutkielmamme on kuvaileva kirjallisuuskatsaus, jossa syvennymme draamakasvatukseen tunne- ja vuorovaikutustaitojen tukena. Pyrimme myös tutkielmallamme tuomaan lisää ymmärrystä varhaiskasvatuksen henkilöstölle draamakasvatuksen tuomasta tuesta lasten tunne- ja vuorovaikutustaitoihin. Aiheemme on ajankohtainen ja etenkin tunnetaitojen harjoittaminen on isossa roolissa varhaiskasvatuksessa ja esiopetuksessa. Teoreettisen viitekehyksemme keskeisimmät käsitteet ovat draamakasvatus, tunne- ja vuorovaikutustaidot ja varhaiskasvatus. Vastaamme kirjallisuuden ja eri aineistojen avulla tutkimuskysymykseemme, “Miten draamakasvatuksella voidaan tukea 0–6-vuotiaiden lasten tunne- ja vuorovaikutustaitoja?”. Yhdistämme ja arvioimme tutkimuksessamme jo olemassa olevaa tietoa draamakasvatuksen vaikutuksesta lasten tunne- ja vuorovaikutustaitoihin ja millä draamakasvatuksen keinoilla niitä voidaan tukea. Lopuksi pohdimme ja arvioimme aineistojen perusteella saatuja tutkimustuloksiamme. Aineistona pyrimme käyttämään mahdollisimman tuoreita lähteitä, mutta tutkimuksia aiheesta on vielä vähän, joten olemme myös hyödyntäneet kirjallisuutta ja muuta aineistoa aikaisemmilta vuosilta. Aineistomme koostuu suomalaisista kirjoista ja artikkeleista sekä muusta aineistosta. Olemme myös käyttäneet lähteinä ulkomaisia artikkeleita. Aineiston perusteella draamakasvatuksella voidaan tukea lapsen tunne- ja vuorovaikutustaitoja, ja varhaiskasvatuksen henkilöstön tulisi tuntea draamakasvatuksen työtapoja, joita he voisivat toteuttaa tietoisesti ja suunnitelmallisesti. Kirjallisuudessa ja artikkeleissa tulee ilmi, että opettajan tulee olla tietoinen erilaisista draamakasvatuksen toimintatavoista ja käsitteistä. Jokainen varhaiskasvatuksessa työskentelevä voi omassa työssään rohkeasti soveltaa ja kehittää draaman genrejä omalle ryhmälle sopivaksi

Pharmacological Preconditioning with Diazoxide in the Experimental Hypothermic Circulatory Arrest Model

Background: Hypothermic circulatory arrest includes a remarkable risk for neurological injury. Diazoxide, a mitochondrial adenosine triphosphate-dependent potassium ion (K+ATP) channel opener, is known to have cardioprotective effects. We assessed its efficacy in preventing ischemic injury in a clinically relevant animal model.Methods: Eighteen piglets were randomized into a diazoxide group (n = 9) and a control group (n = 9). Animals underwent 60 minutes of hypothermic circulatory arrest at 18 degrees C. Diazoxide (5 mg/kg + 10 mL NaOH + 40 mL NaCl) was infused during the cooling phase. Metabolic and hemodynamic data were collected throughout the experiment. After 24-hour follow-up, whole brain, heart, and kidney biopsy specimens were collected for analysis.Results: Cerebellar Cytochrome-C and caspase-3 activation was higher in the control group (P = .02 and P = .016, respectively). Antioxidant activity tended to be higher in the diazoxide group (P = .099). Throughout the experiment, the oxygen consumption ratio was higher in the control animals (P-g = .04), as were the lactate levels (P-g = .02). Cardiac function tended to be better in diazoxide-treated animals.Conclusion: Diazoxide might confer neuroprotective effect as implied by the immunohistochemical analysis of the brain. Additionally, the circulatory effects of diazoxide were beneficial, supporting its neuroprotective effect

Down-Regulation of NDRG1 Promotes Migration of Cancer Cells during Reoxygenation

One characteristic of tumor microenvironment is oxygen fluctuation, which results from hyper-proliferation and abnormal metabolism of tumor cells as well as disorganized neo-vasculature. Reoxygenation of tumors can induce oxidative stress, which leads to DNA damage and genomic instability. Although the cellular responses to hypoxia are well known, little is known about the dynamic response upon reoxygenation. In order to investigate the transcriptional responses of tumor adaptation to reoxygenation, breast cancer MCF-7 cells were cultured under 0.5% oxygen for 24 h followed by 24 h of reoxygenation in normoxia. Cells were harvested at 0, 1, 4, 8, 12, and 24 h during reoxygenation. The transcriptional profile of MCF-7 cells upon reoxygenation was examined using Illumina Human-6 v3 BeadChips. We identified 127 differentially expressed genes, of which 53.1% were up-regulated and 46.9% were down-regulated upon reoxygenation. Pathway analysis revealed that the HIF-1-alpha transcription factor network and validated targets of C-MYC transcriptional activation were significantly enriched in these differentially expressed genes. Among these genes, a subset of interest genes was further validated by quantitative reverse-transcription PCR. In particular, human N-MYC down-regulated gene 1 (NDRG1) was highly suppressed upon reoxygenation. NDRG1 is associated with a variety of stress and cell growth-regulatory conditions. To determine whether NDRG1 plays a role in reoxygenation, NDRG1 protein was overexpressed in MCF-7 cells. Upon reoxygenation, overexpression of NDRG1 significantly inhibited cell migration. Our results revealed the dynamic nature of gene expression in MCF-7 cells upon reoxygenation and demonstrated that NDRG1 is involved in tumor adaptation to reoxygenation