RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate natural killer (NK) cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both innate and adaptive immune elimination, we performed parallel genome-wide CRISPR-Cas9 knockout screens under NK and CD8+ T cell pressure. We identify all components, RNF31, RBCK1, and SHARPIN, of the linear ubiquitination chain assembly complex (LUBAC). Genetic and pharmacologic ablation of RNF31, an E3 ubiquitin ligase, strongly sensitizes cancer cells to NK and CD8+ T cell killing. This occurs in a tumor necrosis factor (TNF)-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF receptor complex I. A small-molecule RNF31 inhibitor sensitizes colon carcinoma organoids to TNF and greatly enhances bystander killing of MHC antigen-deficient tumor cells. These results merit exploration of RNF31 inhibition as a clinical pharmacological opportunity for immunotherapy-refractory cancers

Ambulatory Arterial Stiffness Index Is Not Associated With Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease in Lacunar Stroke Patients

Ambulatory arterial stiffness index (AASI) is associated with microvascular damage in other organs, but the association with microvascular brain damage is unknown. The association of AASI with magnetic resonance imaging (MRI) markers of cerebral small vessel disease in 143 patients with lacunar stroke was investigated. We performed 24‐hour ambulatory blood pressure monitoring and scored the presence of lacunes, white matter hyperintensities, perivascular spaces, and cerebral microbleeds on brain MRI. In logistic regression analyses, AASI was associated with white matter hyperintensities, but, after adjustment for age and sex, this association lost significance. AASI was not associated with lacunes, microbleeds, or perivascular spaces. Systolic and diastolic 24‐hour blood pressure values were associated with lacunes, perivascular spaces, and microbleeds independent of age and sex. Despite its significance and growing interest as a possible prognostic and therapeutic target in (micro)vascular diseases, AASI seems to have no added value over standard 24‐hour blood pressure in cerebral small vessel disease

Ambulatory Arterial Stiffness Index Is Not Associated With Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease in Lacunar Stroke Patients

Denne masteroppgaven setter søkelyset på kulturskolelærere og kulturskolerektors beskrivelser av kulturskolens utfordringer. Problemstillingen lyder: Hvordan beskriverkulturskolelærere og kulturskolerektor ledelses-og styringsutfordringer i sin kulturskole?Kulturskolen som organisasjon står i "skvis"mellom kulturfeltet og skolefeltet. Norsk kulturskoleråds visjon for kulturskolen er "kulturskole for alle". Rammeplanen fra 2016 Mangfold og fordypning, beskriver at kulturskolen skal kjennetegnes av høy kvalitet, rikt mangfold og ivareta både bredde og talent. Hensikten med studien er å undersøke hvordan kulturskolens egenart som organisasjon, identiteten til kulturskolelærere og rektor, samt kulturskolens samfunnsoppdragbeskrives av forskningsdeltakerne, og hvordan disse har sammenheng med ledelses-og styringsutfordringer.Masteroppgaven bygger på en kvalitativ studie, der datamaterialet er generert gjennom refleksjonsskriv.Refleksjonsskrivet er besvart av fire kulturskolelærere, og en rektor fra samme kulturskole.Gjennom en narrativ analyse, i dialog med datamaterialet og teori om profesjon og ledelse, undersøkes forskningsdeltakernes refleksjoner fra hermeneutisk-fenomenologisk perspektiv. En viktig oppdagelse i denne undersøkelsen er kulturskolelærernes ønske om et samlende fellesskap med verdiforankring i lærernes profesjonsidentitet

Association between Perivascular Spaces and Progression of White Matter Hyperintensities in Lacunar Stroke Patients

Perivascular spaces are associated with MRI markers of cerebral small vessel disease, including white matter hyperintensities. Although perivascular spaces are considered to be an early MRI marker of cerebral small vessel disease, it is unknown whether they are associated with further progression of MRI markers, especially white matter hyperintensities. We determined the association between perivascular spaces and progression of white matter hyperintensities after 2-year follow-up in lacunar stroke patients.In 118 lacunar stroke patients we obtained brain MRI and 24-hour ambulatory blood pressure measurements at baseline, and a follow-up brain MRI 2 years later. We visually graded perivascular spaces and white matter hyperintensities at baseline. Progression of white matter hyperintensities was assessed using a visual white matter hyperintensity change scale. Associations with white matter hyperintensity progression were tested with binary logistic regression analysis.Extensive basal ganglia perivascular spaces were associated with progression of white matter hyperintensities (OR 4.29; 95% CI: 1.28-14.32; p<0.05), after adjustment for age, gender, 24-hour blood pressure and vascular risk factors. This association lost significance after additional adjustment for baseline white matter hyperintensities. Centrum semiovale perivascular spaces were not associated with progression of white matter hyperintensities.Our study shows that extensive basal ganglia perivascular spaces are associated with progression of white matter hyperintensities in cerebral small vessel disease. However, this association was not independent of baseline white matter hyperintensities. Therefore, presence of white matter hyperintensities at baseline remains an important determinant of further progression of white matter hyperintensities in cerebral small vessel disease

Association between baseline ambulatory 24-hour blood pressure levels and progression of WMH by binary logistic regression analysis.

<p>Results binary logistic regression analysis presented as OR per 10 mmHg increase in systolic blood pressure (SBP) or 5 mmHg in diastolic blood pressure (DBP). Model 1 adjusted for age, gender and vascular risk factors (diabetes mellitus, hypercholesterolemia and smoking). Model 2 adjusted for age, gender and baseline white matter hyperintensities. OR: odds ratio; CI: confidence interval; WMH: white matter hyperintensities; 24-h BP: 24-hour ambulatory blood pressure;</p><p>*p<0.05.</p><p>Association between baseline ambulatory 24-hour blood pressure levels and progression of WMH by binary logistic regression analysis.</p

MRI characteristics.

<p>WMH: white matter hyperintensities; PVS: perivascular spaces.</p><p>MRI characteristics.</p

Examples of the categories of perivascular spaces by using a semi-quantitative three-category severity scale.

<p>(A-C): Perivascular spaces (PVS) in the basal ganglia; respectively none-to-mild, moderate and extensive. (D-F): PVS in the centrum semiovale; respectively none-to-mild, moderate and extensive.</p

Higher ambulatory blood pressure relates to enlarged Virchow-Robin spaces in first-ever lacunar stroke patients

Enlarged Virchow-Robin spaces (EVRS) are considered to be a sign of cerebral small vessel disease. Hypertension is an important risk factor for cerebral small vessel disease, whereas ambulatory blood pressure (BP) is the strongest predictor of hypertension-related brain damage. However, the association between ambulatory BP levels and EVRS has never been investigated. The aim of this study was to determine the association between ambulatory BP levels and EVRS. In 143 first-ever lacunar stroke patients, we performed 24-h ambulatory BP monitoring after the acute stroke phase. On brain MRI we counted EVRS in the basal ganglia and the centrum semiovale. We graded the number of EVRS at each level into a three-category severity scale. We assessed the association between BP levels and EVRS by ordinal regression analysis. After adjusting for age, sex, extensive white matter lesions, and asymptomatic lacunar infarcts, higher day systolic (OR 1.21; 95 % CI 1.00–1.46 per 10 mmHg), day diastolic (1.18; 95 % CI 1.02–1.37 per 5 mmHg) and 24-h diastolic (OR 1.18; 95 % CI 1.01–1.37 per 5 mmHg) ambulatory BP levels were associated with EVRS at the basal ganglia level. No relation was found between ambulatory BP levels and EVRS in the centrum semiovale. Higher day ambulatory BP levels are associated with EVRS in the basal ganglia. This association was independent of the presence of extensive white matter lesions and asymptomatic lacunar infarcts. Our results imply that basal ganglia EVRS should be regarded as a separate manifestation of BP-related brain damage