a multicenter cardiovascular magnetic resonance imaging (CMR) study

Chronic activation of the sympathetic nervous system is supposed to play a crucial role in the pathogenesis of therapy resistant hypertension (RH). Renal sympathetic denervation (RDN) is under investigation as a treatment option in patients with RH. Determinants of arterial compliance may, however, help to predict the blood pressure (BP) response to therapy. Aortic distensibility (AD) is a well-established parameter of aortic stiffness and can reliably be obtained by cardiac magnetic resonance tomography (CMR). This analysis sought to investigate the effects of RDN on AD and to assess the predictive value of pre-treatment AD for BP response. We analyzed data of 65 patients with RH included in a multicenter trial. RDN was performed in all participants. A standardized CMR protocol was utilized at baseline and at six-month follow-up. AD was determined as the change in cross-sectional aortic area per unit change in BP. Office BP decreased significantly from 173/92 ± 24/16 mmHg at baseline to 151/85 ± 24/17 mmHg (p<0.001) six months after RDN. Maximum aortic areas increased from 604.7 ± 157.7 mm² to 621.1 ± 157.3 mm² (p = 0.011). AD improved significantly by 33% from 1.52 ± 0.82 10-3 mmHg-1 to 2.02 ± 0.93 10-3 mmHg-1 (p<0.001). Increase of AD at follow-up was significantly more pronounced in younger patients (p = 0.005) and responders to RDN (p = 0.002). Patients with high baseline AD were significantly younger (61.4 ± 10.1 years vs. 67.1 ± 8.4 years, p = 0.022). However, there was no significant correlation of baseline AD to response to RDN. AD improved after RDN across all age groups. Importantly, these improvements appear to be unrelated to observed BP changes, suggesting that RDN may have direct effects on the central vasculature through modulation of the sympathetic tone.Ein erhöhter Sympathikotonus wird als eine der Ursachen für die Entstehung einer therapieresistenten arteriellen Hypertonie (RH) angesehen. Die renale Denervierung (RDN) kann bei Patienten mit RH zur Blutdrucksenkung beitragen. Bislang ist nicht bekannt, in welcher Weise Faktoren der Gefäßsteifigkeit den Erfolg dieser Intervention vorhersagen. Als etablierter Parameter für lokal gemessene Gefäßsteifigkeit der Aorta kann die Aortic distensibility (AD) zuverlässig mittels kardialer Magnetresonanztomographie (MRT) bestimmt werden. Ziel der vorliegenden Arbeit war es, die Veränderungen der AD nach RDN zu untersuchen sowie den prädiktiven Voraussagewert der AD für eine Blutdruckänderung zu erfassen. Wir analysierten Daten von 65 Patienten mit RH, die sich an vier unterschiedlichen Zentren einer RDN unterzogen. Eine MRT wurde sowohl vor als auch sechs Monate nach der Intervention durchgeführt. Die AD wurde aus Flächenänderungen im Querschnitt der Aorta während des Herzzyklus und der Blutdruckamplitude während der MRT errechnet. Der Praxisblutdruck reduzierte sich nach sechs Monaten signifikant von 173/92 ± 24/16 mmHg auf 151/85 ± 24/17 mmHg (p < 0.001). Die maximalen Querschnittsflächen der Aorta erhöhten sich von 604,7 ± 157,7 mm² auf 621,1 ± 157,3 mm² (p = 0,011). Die AD stieg signifikant um 33 % von 1,52 ± 0,82 · 10-3 mmHg-1 auf 2,02 ± 0,93 · 10-3 mmHg-1 (p < 0,001). Vor allem jüngere Patienten (p = 0,005) und Patienten mit einer signifikanten Blutsenkung nach RDN (p = 0,002) verzeichneten einen deutlichen Anstieg der AD. Patienten mit hohen Ausgangswerten für AD waren deutlich jünger (61,4 ± 10,1 Jahre vs. 67,1 ± 8,4 Jahre, p = 0,022), jedoch konnte eine Verbesserung der AD nach RDN in allen Altersgruppen beobachtet werden. Die Höhe der AD vor RDN hatte keinen statistischen Einfluss auf ein Therapieansprechen. Die beobachtete Zunahme der AD war unabhängig von einer Veränderung des arteriellen Blutdrucks sechs Monate nach Intervention. Diese Tatsache illustriert die direkten Effekte der RDN auf das zentrale Gefäßsystem durch eine Modulation des Sympathikotonus

STAT3β is a tumor suppressor in acute myeloid leukemia

Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3α and STAT3β. Although truncated STAT3β was originally postulated to act as a dominant-negative form of STAT3α, it has been shown to have various STAT3α-independent regulatory functions. Recently, STAT3β gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3β in AML remains elusive. Therefore, we analyzed the STAT3β/α messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3β/α mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3β in AML, we engineered a transgenic mouse allowing for balanced Stat3β expression. Transgenic Stat3β expression resulted in decelerated disease progression and extended survival in PTEN- and MLL-AF9-dependent AML mouse models. Our findings further suggest that the antitumorigenic function of STAT3β depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3β plays an essential tumor-suppressive role in AML

Renal sympathetic denervation restores aortic distensibility in patients with resistant hypertension: data from a multi-center trial

Renal sympathetic denervation (RDN) is under investigation as a treatment option in patients with resistant hypertension (RH). Determinants of arterial compliance may, however, help to predict the BP response to therapy. Aortic distensibility (AD) is a well-established parameter of aortic stiffness and can reliably be obtained by CMR. This analysis sought to investigate the effects of RDN on AD and to assess the predictive value of pre-treatment AD for BP changes. We analyzed data of 65 patients with RH included in a multicenter trial. RDN was performed in all participants. A standardized CMR protocol was utilized at baseline and at 6-month follow-up. AD was determined as the change in cross-sectional aortic area per unit change in BP. Office BP decreased significantly from 173/92 ± 24/16 mmHg at baseline to 151/85 ± 24/17 mmHg (p < 0.001) 6 months after RDN. Maximum aortic areas increased from 604.7 ± 157.7 to 621.1 ± 157.3 mm2 (p = 0.011). AD improved significantly by 33% from 1.52 ± 0.82 to 2.02 ± 0.93 × 10-3 mmHg-1 (p < 0.001). Increase of AD at follow-up was significantly more pronounced in younger patients (p = 0.005) and responders to RDN (p = 0.002). Patients with high-baseline AD were significantly younger (61.4 ± 10.1 vs. 67.1 ± 8.4 years, p = 0.022). However, there was no significant correlation of baseline AD to response to RDN. AD is improved after RDN across all age groups. Importantly, these improvements appear to be unrelated to observed BP changes, suggesting that RDN may have direct effects on the central vasculature

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL

The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma.

Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK+ and ALK- anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17/group 3 innate lymphoid cells (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORγt. Elevated IL-17A and IL-17F levels were detected in a subset of children and adolescents with ALK+ ALCL. Furthermore, a comprehensive analysis of primary lymphoma data confirms TH17-, and in particular ILC3-skewing in ALCL compared with PTCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK+ ALCL. Our data highlight the crucial role of AP-1/BATFs in ALCL and lead to the concept that some ALCL might originate from ILC3

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa

Correction: Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

CMR stress testing in a patient with morbid obesity (BMI 58 kg/m2) and suspected coronary artery disease

Abstract Background Severe obesity is asscociated with an increased risk of coronary artery disease (CAD) but non-invasive cardiac imaging modalities have important technical limits. Case presentation We report a case of a 58-year old patient with suspected CAD and severely elevated BMI of 58 kg/m2. Conclusions Stress-CMR was able to non-invasively stratify risk with good imaging quality despite the body dimensions of the patient

Targeting Wnt/Beta-Catenin Signaling in HPV-Positive Head and Neck Squamous Cell Carcinoma

Wnt/Beta-Catenin signaling is involved in the carcinogenesis of different solid malignant tumors. The interaction of Creb-binding protein (CBP) with Beta-Catenin is a pivotal component of the Wnt/Beta-Catenin signaling pathway. The first aim of this study was to evaluate the association of CBP expression with survival in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC). Second, the in vitro effects of the inhibition of CBP/Beta-Catenin interaction were analyzed. In particular, the effects of ICG-001, an inhibitor of CBP/Beta-Catenin interaction, on proliferation, cell death, modulation of Wnt/Beta-Catenin target expression, and cell migration were examined in vitro. High CBP expression is significantly associated with better survival on mRNA and protein levels. Furthermore, we observed cytotoxic as well as anti-migratory effects of ICG-001. These effects were particularly more potent in the HPV-positive than in the -negative cell line. Mechanistically, ICG-001 treatment induced apoptosis and led to a downregulation of CBP, c-MYC, and Cyclin D1 in HPV-positive cells, indicating inhibition of Wnt/Beta-Catenin signaling. In conclusion, high CBP expression is observed in HPV-positive HNSCC patients with a good prognosis, and ICG-001 showed a promising antineoplastic potential, particularly in HPV-positive HNSCC cells. Therefore, ICG-001 may potentially become an essential component of treatment de-escalation regimens for HPV-positive HNSCC. Further studies are warranted for additional assessment of the mechanistic background of our in vitro findings

The Intraventricular Hemodynamic Forces Estimated Using Routine CMR Cine Images: A New Marker of the Failing Heart

Nowadays huge efforts are being made to identify sensitive markers suitable to detect subclinical myocardial failure. Despite great breakthroughs in myocardial deformation analysis, myocardial strain does not represent the end of the story and new measures allowing detection of failing hearts are highly desirable