• Publikační typ
• abstrakty MeSH

Maintaining genomic integrity is critical to avoid life-threatening disorders, such as premature aging, neurodegeneration and cancer. A multiprotein cascade operates at sites of DNA double-strand breaks (DSBs) to recognize, signal and repair damage. RNF168 (ring-finger nuclear factor) contributes to this emerging pathway of several E3 ubiquitin ligases that perform sequential ubiquitylations on damaged chromosomes, chromatin modifications essential for aggregation of repair complexes at the DSB sites. Here, we report the clinical and cellular phenotypes associated with a newly identified homozygous nonsense mutation in the RNF168 gene of a patient with a syndrome mimicking ataxia-telangiectasia. The mutation eliminated both of RNF168's ubiquitin-binding motifs, thus blocking progression of the ubiquitylation cascade and retention of repair proteins including tumor suppressors 53BP1 and BRCA1 at DSB sites, consistent with the observed defective DNA damage checkpoints/repair and pronounced radiosensitivity. Rapid screening for RNF168 pathway deficiency was achieved by scoring patients' lymphoblastoid cells for irradiation-induced nuclear foci containing 53BP1, a robust assay we propose for future diagnostic applications. The formation of radiation-induced DSB repair foci was rescued by ectopic expression of wild-type RNF168 in patient's cells, further causally linking the RNF168 mutation with the pathology. Clinically, this novel syndrome featured ataxia, telangiectasia, elevated alphafetoprotein, immunodeficiency, microcephaly and pulmonary failure and has implications for the differential diagnosis of autosomal recessive ataxias.

• MeSH
• diferenciální diagnóza MeSH
• homozygot MeSH
• intracelulární signální peptidy a proteiny genetika   metabolismus   MeSH
• lidé MeSH
• mladiství MeSH
• nesmyslný kodon * MeSH
• poruchy růstu genetika   parazitologie   MeSH
• protein BRCA1 genetika   metabolismus   MeSH
• syndrom MeSH
• teleangiektatická ataxie * diagnóza   genetika   metabolismus   patofyziologie   MeSH
• tolerance záření genetika   MeSH
• ubikvitin genetika   metabolismus   MeSH
• ubikvitinligasy * nedostatek   genetika   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH

OBJECTIVES: The aim of this study was to identify the risk factors associated with early mortality after postcardiotomy venoarterial extracorporeal membrane oxygenation. METHODS: This is an analysis of the postcardiotomy extracorporeal membrane oxygenation registry, a retrospective multicenter cohort study including 781 patients aged more than 18 years who required venoarterial extracorporeal membrane oxygenation for cardiopulmonary failure after cardiac surgery from 2010 to 2018 at 19 cardiac surgery centers. RESULTS: After a mean venoarterial extracorporeal membrane oxygenation therapy of 6.9 ± 6.2 days, hospital and 1-year mortality were 64.4% and 67.2%, respectively. Hospital mortality after venoarterial extracorporeal membrane oxygenation therapy for more than 7 days was 60.5% (P = .105). Centers that had treated more than 50 patients with postcardiotomy venoarterial extracorporeal membrane oxygenation had a significantly lower hospital mortality than lower-volume centers (60.7% vs 70.7%, adjusted odds ratio, 0.58; 95% confidence interval, 0.41-0.82). The postcardiotomy extracorporeal membrane oxygenation score was derived by assigning a weighted integer to each independent pre-venoarterial extracorporeal membrane oxygenation predictors of hospital mortality as follows: female gender (1 point), advanced age (60-69 years, 2 points; ≥70 years, 4 points), prior cardiac surgery (1 point), arterial lactate 6.0 mmol/L or greater before venoarterial extracorporeal membrane oxygenation (2 points), aortic arch surgery (4 points), and preoperative stroke/unconsciousness (5 points). The hospital mortality rates according to the postcardiotomy extracorporeal membrane oxygenation score was 0 point, 45.6%; 1 point, 40.5%; 2 points, 51.1%; 3 points, 57.8%; 4 points, 70.7%; 5 points, 68.3%; 6 points, 77.5%; and 7 points or more, 89.7% (P < .0001). CONCLUSIONS: Age, female gender, prior cardiac surgery, preoperative acute neurologic events, aortic arch surgery, and increased arterial lactate were associated with increased risk of early mortality after postcardiotomy venoarterial extracorporeal membrane oxygenation. Center experience with postcardiotomy venoarterial extracorporeal membrane oxygenation may contribute to improved results.

• MeSH
• hemodynamika fyziologie   MeSH
• kardiochirurgické výkony mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mimotělní membránová oxygenace mortalita   MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

BACKGROUND: We hypothesized that cannulation strategy in venoarterial extracorporeal membrane oxygenation (VA-ECMO) could play a crucial role in the perioperative survival of patients affected by postcardiotomy shock. METHODS: Between January 2010 and March 2018, 781 adult patients receiving VA-ECMO for postcardiotomy shock at 19 cardiac surgical centers were retrieved from the Postcardiotomy Veno-arterial Extracorporeal Membrane Oxygenation study registry. A parallel systematic review and meta-analysis (PubMed/MEDLINE, Embase, and Cochrane Library) through December 2018 was also accomplished. RESULTS: Central and peripheral VA-ECMO cannulation were performed in 245 (31.4%) and 536 (68.6%) patients, respectively. Main indications for the institution VA-ECMO were failure to wean from cardiopulmonary bypass (38%) and heart failure following cardiopulmonary bypass weaning (48%). The doubly robust analysis after inverse probability treatment weighting by propensity score demonstrated that central VA-ECMO was associated with greater hospital mortality (odds ratio 1.54; 95% confidence interval, 1.09-2.18), reoperation for bleeding/tamponade (odds ratio, 1.96; 95% confidence interval, 1.37-2.81), and transfusion of more than 9 RBC units (odds ratio, 2.42; 95% confidence interval, 1.59-3.67). The systematic review provided a total of 2491 individuals with postcardiotomy shock treated with VA-ECMO. Pooled prevalence of in-hospital/30-day mortality in overall patient population was 66.6% (95% confidence interval, 64.7-68.4%), and pooled unadjusted risk ratio analysis confirmed that patients undergoing peripheral VA-ECMO had a lower in-hospital/30-day mortality than patients undergoing central cannulation (risk ratio, 0.92; 95% confidence interval, 0.87-0.98). Adjustments for important confounders did not alter our results. CONCLUSIONS: In patients with postcardiotomy shock treated with VA-ECMO, central cannulation was associated with greater in-hospital mortality than peripheral cannulation.

• MeSH
• dospělí MeSH
• kardiochirurgické výkony škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mimotělní membránová oxygenace * škodlivé účinky   metody   mortalita   MeSH
• pooperační komplikace chirurgie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• šok chirurgie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH

AIMS : Veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) support for post-cardiotomy cardiogenic shock (PCS) after adult cardiac surgery is associated with satisfactory hospital survival. However, data on long-term survival of these critically ill patients are scarce. METHODS AND RESULTS: Between January 2010 and March 2018, 665 consecutive patients received VA-ECMO for PCS at 17 cardiac surgery centres and herein we evaluated their 5-year survival. The mean follow-up of this cohort was 1.7 ± 2.7 years (for hospital survivors, 4.6 ± 2.5 years). In this cohort, 240 (36.1%) patients survived to hospital discharge. Five-year survival of all patients was 27.7%. The PC-ECMO score was predictive of 5-year survival in these patients (0 point, 50.9%; 1 point, 44.9%; 2 points, 40.0%; 3 points, 34.7%; 4 points, 21.0%; 5 points, 17.6%; ≥6 points, 10.7%; P < 0.0001). Age was among factors independently associated with late survival, patients >70 years old having a remarkably poor 5-year survival (<60 years: 39.2%; 60-69 years: 29.9%; 70-79 years: 12.3%; ≥80 years: 13.0%, P < 0.0001). Implantation of a ventricular assist device or heart transplant was performed in 3.2% of patients and their 5-year survival was 42.9% (for heart transplant, 63.6%). CONCLUSION : Veno-arterial extracorporeal membrane oxygenation for PCS is associated with satisfactory 5-year survival in young patients without critical pre-ECMO conditions. The use of VA-ECMO for PCS in patients >70 years should be considered only after a judicious scrutiny of patient's life expectancy. Future studies should evaluate whether satisfactory mid-term survival of these patients translates into a good functional outcome. TRIAL REGISTRATION: Clinicaltrials.gov-NCT03508505.

• MeSH
• dospělí MeSH
• kardiochirurgické výkony * MeSH
• kardiogenní šok etiologie   terapie   MeSH
• lidé MeSH
• mimotělní membránová oxygenace * MeSH
• podpůrné srdeční systémy * MeSH
• retrospektivní studie MeSH
• senioři MeSH
• transplantace srdce * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

Caloric Restriction (CR) has established anti-cancer effects, but its clinical relevance and molecular mechanism remain largely undefined. Here, we investigate CR's impact on several mouse models of Acute Myeloid Leukemias, including Acute Promyelocytic Leukemia, a subtype strongly affected by obesity. After an initial marked anti-tumor effect, lethal disease invariably re-emerges. Initially, CR leads to cell-cycle restriction, apoptosis, and inhibition of TOR and insulin/IGF1 signaling. The relapse, instead, is associated with the non-genetic selection of Leukemia Initiating Cells and the downregulation of double-stranded RNA (dsRNA) sensing and Interferon (IFN) signaling genes. The CR-induced adaptive phenotype is highly sensitive to pharmacological or genetic ablation of LSD1, a lysine demethylase regulating both stem cells and dsRNA/ IFN signaling. CR + LSD1 inhibition leads to the re-activation of dsRNA/IFN signaling, massive RNASEL-dependent apoptosis, and complete leukemia eradication in ~90% of mice. Importantly, CR-LSD1 interaction can be modeled in vivo and in vitro by combining LSD1 ablation with pharmacological inhibitors of insulin/IGF1 or dual PI3K/MEK blockade. Mechanistically, insulin/IGF1 inhibition sensitizes blasts to LSD1-induced death by inhibiting the anti-apoptotic factor CFLAR. CR and LSD1 inhibition also synergize in patient-derived AML and triple-negative breast cancer xenografts. Our data provide a rationale for epi-metabolic pharmacologic combinations across multiple tumors.

• MeSH
• akutní myeloidní leukemie * patologie   MeSH
• histondemethylasy genetika   MeSH
• inzuliny * MeSH
• kalorická restrikce MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: To investigate the frequency, predictors, and outcomes of neurologic injury in adults treated with postcardiotomy extracorporeal membrane oxygenation (PC-ECMO). DESIGN: A retrospective multicenter registry study. SETTING: Twenty-one European institutions where cardiac surgery is performed. PARTICIPANTS: A total of 781 adult patients who required PC-ECMO during 2010 to 2018 were divided into patients with neurologic injury (NI) and patients without neurologic injury (NNI). MEASUREMENTS AND MAIN RESULTS: Baseline and operative data, in-hospital outcomes, and long-term survival were compared between the NI and the NNI groups. Predictors of neurologic injury were identified. A subgroup analysis according to the type of neurologic injury was performed. Overall, NI occurred in 19% of patients in the overall series, but the proportion of patients with NI ranged from 0% to 65% among the centers. Ischemic stroke occurred in 84 patients and hemorrhagic stroke in 47 patients. Emergency procedure was the sole independent predictor of NI. In-hospital mortality was higher in the NI group than in the NNI group (79% v 61%, p < 0.001). The one-year survival was lower in the NI group (17%) compared with the NNI group (37%). Long-term survival did not differ between patients with ischemic stroke and those with hemorrhagic stroke. CONCLUSION: Neurologic injury during PC-ECMO is common and associated with a dismal prognosis. There is considerable interinstitutional variation in the proportion of neurologic injury in PC-ECMO-treated adults. Well-known risk factors for stroke are not associated with neurologic injury in this setting.

• MeSH
• cévní mozková příhoda MeSH
• dospělí MeSH
• kardiochirurgické výkony * škodlivé účinky   MeSH
• kardiogenní šok diagnóza   epidemiologie   etiologie   MeSH
• lidé MeSH
• mimotělní membránová oxygenace * MeSH
• mortalita v nemocnicích MeSH
• retrospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

OBJECTIVE: There is a paucity of sex-specific data on patients' postcardiotomy venoarterial extracorporeal membrane oxygenation (VA-ECMO). The present study sought to assess this issue in a multicenter study. DESIGN: Retrospective, propensity score-matched analysis of an international registry. SETTING: Multicenter study, tertiary university hospitals. PARTICIPANTS: Data on adult patients undergoing postcardiotomy VA-ECMO. MEASUREMENTS AND MAIN RESULTS: Between January 2010 and March 2018, patients treated with postcardiotomy VA-ECMO at 17 cardiac surgery centers were analyzed. Index procedures considered were coronary artery bypass graft surgery, isolated valve surgery, their combination, and proximal aortic root surgery. Hospital and five-year mortality constituted the endpoints of interest. Propensity score matching was adopted with logistic regression. A total of 358 patients (mean age: 63.3 ± 12.3 years; 29.6% female) were identified. Among 94 propensity score-matched pairs, women had a higher hospital mortality (70.5% v 56.4%, p = 0.049) compared with men. Logistic regression analysis showed that women (odds ratio [OR], 1.87; 95% confidence interval [CI] 1.10-3.16), age (OR, 1.06; 95%CI 1.04-1.08) and pre-ECMO arterial lactate (OR, 1.09; 95%CI 1.04-1.16) were independent predictors of hospital mortality. No differences between female and male patients were observed for other outcomes. Among propensity score-matched pairs, one-, three-, and five-year mortality were 60.6%, 65.0%, and 65.0% among men, and 71.3%, 71.3%, and 74.0% among women, respectively (p = 0.110, adjusted hazard ratio, 1.27; 95%CI 0.96-1.66). CONCLUSIONS: In postcardiotomy VA-ECMO, female patients demonstrated higher hospital mortality than men. Morbidity and late mortality were similar between the two groups.

• MeSH
• dospělí MeSH
• kardiochirurgické výkony * škodlivé účinky   MeSH
• kardiogenní šok etiologie   MeSH
• koronární bypass MeSH
• lidé středního věku MeSH
• lidé MeSH
• mimotělní membránová oxygenace * metody   MeSH
• mortalita v nemocnicích MeSH
• retrospektivní studie MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

OBJECTIVES: To compare the outcomes of patients with postcardiotomy shock treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO) only compared with VA-ECMO and intra-aortic balloon pump (IABP). DESIGN: A retrospective multicenter registry study. SETTING: At 19 cardiac surgery units. PARTICIPANTS: A total of 615 adult patients who required VA-ECMO from 2010 to 2018. The patients were divided into 2 groups depending on whether they received VA-ECMO only (ECMO only group) or VA-ECMO plus IABP (ECMO-IABP group). MEASUREMENTS AND MAIN RESULTS: The overall series mean age was 63 ± 13 years, and 33% were female. The ECMO-only group included 499 patients, and 116 patients were in the ECMO-IABP group. Urgent and/or emergent procedures were more common in the ECMO-only group. Central cannulation was performed in 47% (n = 54) in the ECMO-IABP group compared to 27% (n = 132) in the ECMO-only group. In the ECMO-IABP group, 58% (n = 67) were successfully weaned from ECMO, compared to 46% (n = 231) in the ECMO-only group (p = 0.026). However, in-hospital mortality was 63% in the ECMO-IABP group compared to 65% in the ECMO-only group (p = 0.66). Among 114 propensity score-matched pairs, ECMO-IABP group had comparable weaning rates (57% v 53%, p = 0.51) and in-hospital mortality (64% v 58%, p = 0.78). CONCLUSIONS: This multicenter study showed that adjunctive IABP did not translate into better outcomes in patients treated with VA-ECMO for postcardiotomy shock.

• MeSH
• dospělí MeSH
• intraaortální balónková pumpa metody   MeSH
• kardiochirurgické výkony * škodlivé účinky   MeSH
• kardiogenní šok etiologie   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mimotělní membránová oxygenace * metody   MeSH
• podpůrné srdeční systémy * MeSH
• retrospektivní studie MeSH
• senioři MeSH
• šok * etiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

OBJECTIVE: Data on patients requiring a second run of venoarterial extracorporeal membrane oxygenation (VA-ECMO) support in patients affected by postcardiotomy cardiogenic shock (PCS) are very limited. The authors aimed to investigate the effect of a second run of VA-ECMO on PCS patient survival. DESIGN: Retrospective analysis of an international registry. SETTING: Multicenter study, tertiary university hospitals. PARTICIPANTS: Data on adult PCS patients receiving a second run of VA-ECMO. MEASUREMENTS AND MAIN RESULTS: A total of 674 patients with a mean age of 62.9 ± 12.7 years were analyzed, and 21 (3.1%) patients had a second run of VA-ECMO. None of them required more than two VA-ECMO runs. The median duration of VA-ECMO therapy was 135 hours (interquartile range [IQR] 61-226) in patients who did not require a VA-ECMO rerun. In the rerun VA-ECMO group the median overall duration of VA-ECMO therapy was 183 hours (IQR 107-344), and the median duration of the first run was 114 hours (IQR 66-169). Nine (42.9%) of the patients who required a second run of VA-ECMO died during VA-ECMO therapy, whereas five (23.8%) survived to hospital discharge. No differences between patients treated with single or second VA-ECMO runs were observed in terms of hospital mortality and late survival. In patients requiring a second VA-ECMO run, the actuarial survival estimates at three and 12 months after VA-ECMO weaning were 23.8% ± 9.3% and 19.6% ± 6.4%, respectively. CONCLUSIONS: Repeat VA-ECMO therapy is a valid treatment strategy for PCS patients. Early and late survivals are similar between patients who have undergone a single or second run of VA-ECMO.

• MeSH
• dospělí MeSH
• kardiogenní šok etiologie   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mimotělní membránová oxygenace * škodlivé účinky   MeSH
• mortalita v nemocnicích MeSH
• registrace MeSH
• retrospektivní studie MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH