High/low cortisol reactivity and food intake in people with obesity and healthy weight

Increased food intake, termed “comfort eating”, is a pathologic coping mechanism in chronic stress. Cortisol reactivity under stress is a potent predictor of stress-induced eating behavior affecting the body mass index (BMI). However, cortisol reactivity and food intake under stress in people with obesity has not been evaluated. The aim of this study was to investigate the effect of high/low cortisol reactivity on food intake in people with obesity and healthy weight test controls, following standardized stress induction and a resting condition. Thirty-six men and women with obesity (BMI: 33.00 ± 3.23 kg/m²), as well as 36 age- and gender-matched healthy weight controls (BMI: 21.98 ± 1.81 kg/m²) were categorized into high cortisol reactors (HCR) and low cortisol reactors (LCR) in the Trier Social Stress Test (TSST). Following the TSST and a resting condition, the food intake of all participants was recorded in a standardized laboratory meal. Obese HCR demonstrated a significantly higher food intake than LCR (t (34) = −2.046, p ≤ 0.05). However, there were no significant differences between HCR and LCR in the healthy weight controls (p = 0.26). In addition, HCR of the people with obesity showed lower values in the emotion coping strategy of cognitive reappraisal than obese LCR (t (32) = 2.087, p ≤ 0.05). In conclusion, the magnitude of the cortisol reactivity to stress predicts stress-induced food intake in people with obesity, but not in the healthy weight controls. Limited use of cognitive reappraisal in emotion regulation in the obese HCR may be a marker of vulnerability to stress-induced eating. © 2020, The Author(s)

Casein kinase 2 (CK2) phosphorylates the deubiquitylase OTUB1 at Ser¹⁶to trigger its nuclear localization

The deubiquitylating enzyme OTUB1 is present in all tissues and targets a multitude of substrates, both in the cytosol and nucleus. Here, we found that the phosphorylation of OTUB1 at Ser(16) and its subsequent nuclear accumulation is mediated by casein kinase 2 (CK2). Whereas unphosphorylated OTUB1 was detected mainly in the cytosol, Ser(16)-phosphorylated OTUB1 was detected only in the nucleus. Pharmacological inhibition or genetic ablation of CK2 blocked the phosphorylation of OTUB1 at Ser(16) and its nuclear localization in various cells. The phosphorylation of OTUB1 at Ser(16) did not alter its catalytic activity in vitro, its ability to bind K63-linked ubiquitin chains in vitro and its ability to interact with the E2 enzyme UBE2N in vitro. The phosphorylation at Ser(16) and subsequent nuclear localization of OTUB1 was essential for cells to repair ionizing radiation-induced DNA damage in osteosarcoma U2OS cells

CXCR4-targeted PET imaging of central nervous system B-cell lymphoma

C-X-C chemokine receptor 4 is a transmembrane chemokine receptor involved in growth, survival, and dissemination of cancer, including aggressive B-cell lymphoma. Magnetic resonance imaging (MRI) is the standard imaging technology for central nervous system involvement of B-cell lymphoma and provides high sensitivity but moderate specificity. Therefore, novel molecular and functional imaging strategies are urgently required. METHODS: In this proof-of-concept study, 11 patients with lymphoma of the CNS (CNSL, n = 8 primary and n = 3 secondary involvement) were imaged with the CXCR4-directed positron emission tomography (PET) tracer (68)Ga-Pentixafor. To evaluate the predictive value of this imaging modality, treatment response, as determined by MRI, was correlated with quantification of CXCR4 expression by (68)Ga-Pentixafor PET in vivo before initiation of treatment in 7 of 11 patients. RESULTS: (68)Ga-Pentixafor-PET showed excellent contrast characteristics to the surrounding brain parenchyma in all patients with active disease. Furthermore, initial CXCR4 uptake determined by PET correlated with subsequent treatment response as assessed by MRI. CONCLUSION: (68)Ga-Pentixafor-PET represents a novel diagnostic tool for central nervous system lymphoma with potential implications for theranostic approaches as well as response and risk assessment

Nivolumab and doxorubicin, vinblastine, and dacarbazine in early-stage unfavorable Hodgkin Lymphoma: final analysis of the randomized german Hodgkin study group phase II NIVAHL trial

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the investigator-sponsored randomized phase II NIVAHL trial for early-stage unfavorable classical Hodgkin lymphoma (HL), two schedules of four cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine followed by 30 Gy involved-site radiotherapy resulted in high complete remission rates and an unprecedented 1-year progression-free survival in 109 patients. In this article, we report the preplanned final analysis conducted three years after the registration of the last patient including long-term safety results. No survival events were observed since the primary analysis, and after a median follow-up (FU) of 41 months, the overall survival was 100% in both treatment groups. The progression-free survival was 98% and 100% in the sequential and concomitant nivolumab, doxorubicin, vinblastine, and dacarbazine treatment groups, respectively. At last FU, the mean forced expiratory pressure in one second was 95.5% (standard deviation 12.7%), the mean diffusion capacity for carbon monoxide adjusted for hemoglobin was 82.8% (standard deviation 15.4%), and the left ventricular ejection fraction was in the normal range in 95% of patients. Hypothyroidism requiring long-term medication occurred in 15% of patients, who were nearly exclusively female (87%). No second primary malignancies occurred, and no patient required corticosteroid treatment at last FU. Patient-reported normalized global quality-of-life score measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 improved over time. This preplanned FU analysis of the largest anti-programmed death protein 1 HL first-line trial to date confirms the outstanding efficacy and relatively favorable safety profile of this therapeutic approach

Dual targeting of acute leukemia and supporting niche by CXCR4-directed theranostics.

C-X-C chemokine receptor 4 (CXCR4) is a transmembrane receptor with pivotal roles in cell homing and hematopoiesis. CXCR4 is also involved in survival, proliferation and dissemination of cancer, including acute lymphoblastic and myeloid leukemia (ALL, AML). Relapsed/refractory ALL and AML are frequently resistant to conventional therapy and novel highly active strategies are urgently needed to overcome resistance. Methods: We used patient-derived (PDX) and cell line-based xenograft mouse models of ALL and AML to evaluate the efficacy and toxicity of a CXCR4-targeted endoradiotherapy (ERT) theranostic approach. Results: The positron emission tomography (PET) tracer 68 Ga-Pentixafor enabled visualization of CXCR4 positive leukemic burden. In xenografts, CXCR4-directed ERT with 177 Lu-Pentixather distributed to leukemia harboring organs and resulted in efficient reduction of leukemia. Despite a substantial in vivo cross-fire effect to the leukemia microenvironment, mesenchymal stem cells (MSCs) subjected to ERT were viable and capable of supporting the growth and differentiation of non-targeted normal hematopoietic cells ex vivo. Finally, three patients with refractory AML after first allogeneic hematopoietic stem cell transplantation (alloSCT) underwent CXCR4-directed ERT resulting in leukemia clearance, second alloSCT, and successful hematopoietic engraftment. Conclusion: Targeting CXCR4 with ERT is feasible and provides a highly efficient means to reduce refractory acute leukemia for subsequent cellular therapies. Prospective clinical trials testing the incorporation of CXCR4 targeting into conditioning regimens for alloSCT are highly warranted