Development of combination therapies with BTK inhibitors and dasatinib to treat CNS-infiltrating E2A-PBX1+/preBCR+ ALL.

ABSTRACT: The t(1;19) translocation, encoding the oncogenic fusion protein E2A (TCF3)-PBX1, is involved in acute lymphoblastic leukemia (ALL) and associated with a pre-B-cell receptor (preBCR+) phenotype. Relapse in patients with E2A-PBX1+ ALL frequently occurs in the central nervous system (CNS). Therefore, there is a medical need for the identification of CNS active regimens for the treatment of E2A-PBX1+/preBCR+ ALL. Using unbiased short hairpin RNA (shRNA) library screening approaches, we identified Bruton tyrosine kinase (BTK) as a key gene involved in both proliferation and dasatinib sensitivity of E2A-PBX1+/preBCR+ ALL. Depletion of BTK by shRNAs resulted in decreased proliferation of dasatinib-treated E2A-PBX1+/preBCR+ cells compared with control-transduced cells. Moreover, the combination of dasatinib with BTK inhibitors (BTKi; ibrutinib, acalabrutinib, or zanubrutinib) significantly decreased E2A-PBX1+/preBCR+ human and murine cell proliferation, reduced phospholipase C gamma 2 (PLCG2) and BTK phosphorylation and total protein levels and increased disease-free survival of mice in secondary transplantation assays, particularly reducing CNS-leukemic infiltration. Hence, dasatinib with ibrutinib reduced pPLCG2 and pBTK in primary ALL patient samples, including E2A-PBX1+ ALLs. In summary, genetic depletion and pharmacological inhibition of BTK increase dasatinib effects in human and mouse with E2A-PBX1+/preBCR+ ALL across most of performed assays, with the combination of dasatinib and BTKi proving effective in reducing CNS infiltration of E2A-PBX1+/preBCR+ ALL cells in vivo.

Cosmetic surgery and associated chronic postsurgical pain: A cross-sectional study from Norway.

OBJECTIVES: Chronic postsurgical pain (CPSP) is a common postoperative sequela. Despite the increasing popularity of cosmetic surgeries, there is a notable lack of research on CPSP in this context, with existing studies focusing on breast surgeries only. To address existing gaps in knowledge, the objective of the present study was to investigate the self-reported prevalence of cosmetic surgery and associated CPSP among Norwegian adults. METHODS: An online questionnaire consisting of three questions inquiring prior cosmetic surgeries, associated CPSP, and whether participants had sought for pain management was constructed and distributed among adults residing in Norway. RESULTS: Between November 30, 2022 and December 16, 2022, 1,746 participants were recruited. 10% of respondents, 73.3% of which were female, affirmed to have undergone cosmetic surgery. About 1 in 4 of these was aged 18-29 years. The prevalence of CPSP was 12.6%. CPSP was five times more common among male, compared to female respondents. While about two thirds of participants indicating to have experienced CPSP were aged 18-29 years, CPSP was much less common among individuals of other ages. CONCLUSION: Consistent with international trends, there appears to be a young and growing population of cosmetic surgery consumers in Norway. According to our results, about 1 in 8 of these might be affected by CPSP, a condition that is notoriously hard to treat and weighting heavily on public healthcare and social welfare systems. Large-scale longitudinal studies further investigating the topic are thus urgently needed.

A cross-sectional study of fear of surgery in female breast cancer patients: Prevalence, severity, and sources, as well as relevant differences among patients experiencing high, moderate, and low fear of surgery.

BACKGROUND: Fear of surgery has been associated with more postoperative pain, disability, and a lower quality of life among patients undergoing various surgical procedures. While qualitative studies indicate breast cancer patients to be afraid of surgery, detailed quantitative analyses are lacking. The present research aimed at investigating the prevalence, severity, and sources of fear of surgery in this patient group and to compare patients reporting different degrees of such fear. METHODS: This cross-sectional study included 204 breast cancer patients, 18-70 years old, and scheduled for surgery at Oslo University Hospital, Norway. Following their preoperative visit participants completed validated psychological questionnaires online. Among these, the primary outcome measure, the Surgical Fear Questionnaire (SFQ; scores: 0-10 per item, 0-80 overall). Patients were grouped based on SFQ-percentiles (<25th = little, 25th-75th = moderate and >75th percentile = high fear) and compared on psychological (anxiety, depression, experienced injustice, optimism and expected postsurgical pain), sociodemographic, and medical outcomes. RESULTS: 195 patients completed the SFQ. On average fear of surgery was low (M = 26.41, SD = 16.0, median = 26, min-max = 0-80), but omnipresent. Only 1.5% (n = 3) indicated no fear at all. Overall, patients feared surgery itself the most (M = 3.64, SD = 2.8). Groups differed significantly (p < .001) in their experience of anxiety, depression, and injustice, as well as their disposition to be optimistic, and expectance of postsurgical pain. Differences between groups concerning demographic and medical information were largely insignificant. DISCUSSION: This study was the first to demonstrate fear of surgery to be prevalent and relevant among female breast cancer patients. The higher a patients' fear group, the poorer their preoperative psychological constitution. This, largely irrespective of their current diagnoses or treatments, medical history, and demographics. Fear of surgery might thus cater as a prognostic marker and treatment target in this patient group. However, given the cross-sectional character of the present data, prognostic studies are needed to evaluate such claims.

PATAN-domain regulators interact with the Type IV pilus motor to control phototactic orientation in the cyanobacterium Synechocystis.

Many prokaryotes show complex behaviors that require the intricate spatial and temporal organization of cellular protein machineries, leading to asymmetrical protein distribution and cell polarity. One such behavior is cyanobacterial phototaxis which relies on the dynamic localization of the Type IV pilus motor proteins in response to light. In the cyanobacterium Synechocystis, various signaling systems encompassing chemotaxis-related CheY- and PatA-like response regulators are critical players in switching between positive and negative phototaxis depending on the light intensity and wavelength. In this study, we show that PatA-type regulators evolved from chemosensory systems. Using fluorescence microscopy and yeast two-hybrid analysis, we demonstrate that they localize to the inner membrane, where they interact with the N-terminal cytoplasmic domain of PilC and the pilus assembly ATPase PilB1. By separately expressing the subdomains of the response regulator PixE, we confirm that only the N-terminal PATAN domain interacts with PilB1, localizes to the membrane, and is sufficient to reverse phototactic orientation. These experiments established that the PATAN domain is the principal output domain of PatA-type regulators which we presume to modulate pilus extension by binding to the pilus motor components.