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.

The energy savings-oxidative cost trade-off for migratory birds during endurance flight.

Elite human and animal athletes must acquire the fuels necessary for extreme feats, but also contend with the oxidative damage associated with peak metabolic performance. Here, we show that a migratory bird with fuel stores composed of more omega-6 polyunsaturated fats (PUFA) expended 11% less energy during long-duration (6 hr) flights with no change in oxidative costs; however, this short-term energy savings came at the long-term cost of higher oxidative damage in the omega-6 PUFA-fed birds. Given that fatty acids are primary fuels, key signaling molecules, the building blocks of cell membranes, and that oxidative damage has long-term consequences for health and ageing, the energy savings-oxidative cost trade-off demonstrated here may be fundamentally important for a wide diversity of organisms on earth.

Multiple leading edge vortices of unexpected strength in freely flying hawkmoth.

The Leading Edge Vortex (LEV) is a universal mechanism enhancing lift in flying organisms. LEVs, generally illustrated as a single vortex attached to the wing throughout the downstroke, have not been studied quantitatively in freely flying insects. Previous findings are either qualitative or from flappers and tethered insects. We measure the flow above the wing of freely flying hawkmoths and find multiple simultaneous LEVs of varying strength and structure along the wingspan. At the inner wing there is a single, attached LEV, while at mid wing there are multiple LEVs, and towards the wingtip flow separates. At mid wing the LEV circulation is ~40% higher than in the wake, implying that the circulation unrelated to the LEV may reduce lift. The strong and complex LEV suggests relatively high flight power in hawmoths. The variable LEV structure may result in variable force production, influencing flight control in the animals.

Elytra boost lift, but reduce aerodynamic efficiency in flying beetles.

Flying insects typically possess two pairs of wings. In beetles, the front pair has evolved into short, hardened structures, the elytra, which protect the second pair of wings and the abdomen. This allows beetles to exploit habitats that would otherwise cause damage to the wings and body. Many beetles fly with the elytra extended, suggesting that they influence aerodynamic performance, but little is known about their role in flight. Using quantitative measurements of the beetle's wake, we show that the presence of the elytra increases vertical force production by approximately 40 per cent, indicating that they contribute to weight support. The wing-elytra combination creates a complex wake compared with previously studied animal wakes. At mid-downstroke, multiple vortices are visible behind each wing. These include a wingtip and an elytron vortex with the same sense of rotation, a body vortex and an additional vortex of the opposite sense of rotation. This latter vortex reflects a negative interaction between the wing and the elytron, resulting in a single wing span efficiency of approximately 0.77 at mid downstroke. This is lower than that found in birds and bats, suggesting that the extra weight support of the elytra comes at the price of reduced efficiency.

The role of wind-tunnel studies in integrative research on migration biology.

Wind tunnels allow researchers to investigate animals' flight under controlled conditions, and provide easy access to the animals during flight. These increasingly popular devices can benefit integrative migration biology by allowing us to explore the links between aerodynamic theory and migration as well as the links between flight behavior and physiology. Currently, wind tunnels are being used to investigate many different migratory phenomena, including the relationship between metabolic power and flight speed and carry-over effects between different seasons. Although biotelemetry is also becoming increasingly common, it is unlikely that it will be able to completely supplant wind tunnels because of the difficulty of measuring or varying parameters such as flight speed or temperature in the wild. Wind tunnels and swim tunnels will therefore continue to be important tools we can use for studying integrative migration biology.

The use of tunable diode laser absorption spectroscopy for rapid measurements of the delta13C of animal breath for physiological and ecological studies.

In this study we introduce the use of tunable diode laser absorption spectroscopy (TDLAS) as a technique for making measurements of the delta13C of animal 'breath' in near real time. The carbon isotope ratios (delta13C) of breath CO2 trace the carbon source of the materials being metabolized, which can provide insight into the use of specific food resources, e.g. those derived from plants using C3 versus C4 or CAM photosynthetic pathways. For physiological studies, labeled substrates and breath analyses provide direct evidence of specific physiological (e.g. fermentative digestion) or enzymatic (e.g. sucrase activity) processes. Although potentially very informative, this approach has rarely been taken in animal physiological or ecological research. In this study we quantify the utilization of different plant resources (photosynthetic types--C3 or C4) in arthropod herbivores by measuring the delta13C of their 'breath' and comparing it with bulk tissue values. We show that breath delta13C values are highly correlated with bulk tissues and for insect herbivores reflect their dietary guild, in our case C3-specialists, C4-specialists, or generalists. TDLAS has a number of advantages that will make it an important tool for physiologists, ecologists and behaviorists: it is non-invasive, fast, very sensitive, accurate, works on animals of a wide range of body sizes, per-sample costs are small, and it is potentially field-deployable.

Energy expenditure during flight in relation to body mass: effects of natural increases in mass and artificial load in Rose Coloured Starlings.

Rose Coloured Starlings (Sturnus roseus) flew repeatedly for several hours in a wind tunnel while undergoing spontaneous variation in body mass. The treatments were as follows: flying unrestrained (U), with a control harness of 1.2% of their body mass (C), or with a harness of 7.4% of their body mass, which was either applied immediately before the flight (LS) or at least 9 days in advance (LL). Energy expenditure during flight (ef in W) was measured with the Doubly Labelled Water method. Flight costs in L(S) and LL were not significantly different and therefore were pooled (L). The harness itself did not affect ef, i.e. U and C flights were not different. ef was allometrically related with body mass m (in g). The slopes were not significantly different between the treatments, but ef was increased by 5.4% in L compared to C flights (log10(ef) = 0.050 + 0.47 x log10(m) for C, and log10(ef) = 0.073 + 0.47 x log10(m) for L). The difference in ef between C, LS and LL was best explained by taking the transported mass m transp (in g) instead of m into account (log10(ef) = -0.08 + 0.54 x log10(m transp)). Flight costs increased to a lesser extent than expected from interspecific allometric comparison or aerodynamic theory, regardless of whether the increase in mass occurred naturally or artificially. We did not observe an effect of treatment on breast muscle size and wingbeat frequency. We propose that the relatively low costs at a high mass are rather a consequence of immediate adjustments in physiology and/or flight behaviour than of long-term adaptations.

Respiratory water loss during rest and flight in European Starlings (Sturnus vulgaris).

Respiratory water loss in Starlings (Sturnus vulgaris) at rest and during flight at ambient temperatures (T(amb)) between 6 and 25 degrees C was calculated from respiratory airflow and exhaled air temperature. At rest, breathing frequency f (1.4+/-0.3 Hz) and tidal volume Vt (1.9+/-0.4 ml) were independent of T(amb), but negatively correlated with each other. Mean ventilation at rest was 156+/-28 ml min(-1) at all T(amb). Exhaled air temperature (T(exh)) at rest increased with T(amb) (T(exh) = 0.92.T(amb)+12.45). Respiratory water loss at rest averaged 0.18+/-0.09 ml h(-1) irrespective of T(amb). In flying Starlings f was 4.0+/-0.4 Hz and independent of T(amb). Vt during flight averaged 3.6+/-0.4 ml and increased with T(amb) (Vt = 0.06.T(amb)+2.83) as, correspondingly, did ventilation. T(exh) during flight increased with T(amb) (T(exh) = 0.85.T(amb)+17.29). Respiratory water loss during flight (average REWL(f) = 0.74+/-0.22 ml h(-1)) was significantly higher than at rest and increased with T(amb). Our measurements suggest that respiratory evaporation accounts for most water loss in flying Starlings and increases more than cutaneous evaporation with rising ambient temperature.

Water and heat balance during flight in the rose-colored starling (Sturnus roseus).

Water imbalance during flight is considered to be a potentially limiting factor for flight ranges in migrating birds, but empirical data are scarce. We studied flights under controlled ambient conditions with rose-colored starlings in a wind tunnel. In one experiment, we measured water fluxes with stable isotopes at a range of flight speeds (9-14 m s(-1)) at constant temperature (15 degrees C). In a second experiment, we measured evaporation rates at variable ambient temperatures (Ta = 5 deg -27 deg C) but constant speed (12 m s(-1)). During all flights, the birds experienced a net water loss. On average, water influx was 0.98 g h(-1) (SD = 0.16; n = 8), and water efflux was 1.29 g h(-1) (SD = 0.14; n = 8), irrespective of flight speed. Evaporation was related to temperature in a biphasic pattern. At temperatures below 18.2 degrees C, net evaporation was constant at 0.36 g h(-1) (SD = 0.18; n = 10), rising at higher temperatures with a slope of 0.11 per degree to about 1.5 g h(-1) at 27 degrees C. We calculated the relative proportion of dry and evaporative heat loss during flight. Evaporative heat loss at Ta < 18.2 deg C was 14% of total heat production during flight, and dry heat loss accounted for 84%. At higher temperatures, evaporative heat loss increased linearly with T(a) to about 25% at 27 degrees C. Our data suggest that for prolonged flights, rose-colored starlings should adopt behavioral water-saving strategies and that they cannot complete their annual migration without stopovers to replenish their water reserves.

Exhaled air temperature as a function of ambient temperature in flying and resting ducks.

Exhaled air temperature (T (exh)) has a paramount effect on respiratory water loss during flight. For migratory birds, low T (exh) potentially reduces water loss and increases flight range. However, only three studies provide empirical data on T (exh) during flight. The aim of this study was to record T (exh) of birds during rest and flight at a range of controlled ambient temperatures (T (amb)). One wigeon and two teal flew a total of 20 times in a wind tunnel at T (amb) ranging from 1 degrees to 24 degrees C. T (exh) during flight did not differ between the two species and was strongly correlated with T (amb) (T (exh)=1.036 T (amb) + 13.426; R2=0.58). In addition, body temperature had a weak positive effect on T (exh). At a given T (amb), T (exh )was about 5 degrees C. higher during flight than at rest.

Metabolic costs of avian flight in relation to flight velocity: a study in Rose Coloured Starlings (Sturnus roseus, Linnaeus).

The metabolic costs of flight at a natural range of speeds were investigated in Rose Coloured Starlings (Sturnus roseus, Linnaeus) using doubly labelled water. Eight birds flew repeatedly and unrestrained for bouts of 6 h at speeds from 9 to 14 m s(-1) in a low-turbulence wind tunnel, corresponding to travel distances between 200 and 300 km, respectively. This represents the widest speed range where we could obtain voluntarily sustained flights. From a subset of these flights, data on the wing beat frequency (WBF) and intermittent flight behaviour were obtained. Over the range of speeds that were tested, flight costs did not change with velocity and were on an average 8.17+/-0.64 W or 114 W kg(-1). Body mass was the only parameter with a significant (positive) effect on flight costs, which can be described as EE(f)=0.741 M(0.554). WBF changed slightly with speed, but correlated better with body mass. Birds showed both types of intermittent flight, undulating and bounding, but their frequencies did not systematically change with flight speed.