The potential of pirtobrutinib in multiple B-cell malignancies

Bruton’s tyrosine kinase (BTK) is a critical downstream signaling element from the B-cell receptor (BCR) that has been effectively inhibited in B-cell cancers by irreversible, covalent inhibitors including ibrutinib and acalabrutinib. All FDA-approved covalent BTK inhibitors rely on binding to the cysteine 481 (C481) amino acid within the active site of BTK, thus rendering it inert. While covalent BTK inhibitors have been very successful in multiple B-cell malignancies, improving both overall survival and progression-free survival relative to chemoimmunotherapy in phase 3 trials, they can be limited by intolerance and disease progression. Pirtobrutinib is a novel, highly selective, and non-covalent BTK inhibitor that binds independently of C481, and in a recent, first-in-human phase 1/2 clinical trial was shown to be extremely well tolerated and lead to remissions in relapsed/refractory patients with multiple B-cell malignancies. Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of pirtobrutinib, which has the potential to fulfill multiple areas of unmet clinical need for patients with B-cell malignancies

Adaptation of Autocatalytic Fluctuations to Diffusive Noise

Evolution of a system of diffusing and proliferating mortal reactants is analyzed in the presence of randomly moving catalysts. While the continuum description of the problem predicts reactant extinction as the average growth rate becomes negative, growth rate fluctuations induced by the discrete nature of the agents are shown to allow for an active phase, where reactants proliferate as their spatial configuration adapts to the fluctuations of the catalysts density. The model is explored by employing field theoretical techniques, numerical simulations and strong coupling analysis. For d<=2, the system is shown to exhibits an active phase at any growth rate, while for d>2 a kinetic phase transition is predicted. The applicability of this model as a prototype for a host of phenomena which exhibit self organization is discussed.Comment: 6 pages 6 figur

What is animal happiness?

Today, we see a growing concern for the quality of life of nonhuman animals and an accompanying call for viable means of assessing how well animals thrive. Past research focused on minimizing negatives such as stress, while more recent endeavors strive to promote positives such as happiness. But what is animal happiness? Although often mentioned, the term lacks a clear definition. With recent advances in the study of animal emotion, current interest into positive rather than negative experiences, and the call for captive and domesticated animals to have good lives, the time is ripe to examine the concept of animal happiness. We draw from the human and animal literature to delineate a concept of animal happiness and propose how to assess it. We argue that animal happiness depends on how an individual feels generally—that is, a typical level of affect

Chopped or long roughage: what do calves prefer? Using cross point analysis of double demand functions

The present study aimed to quantify calves'(Bos taurus) preference for long versus chopped hay and straw, and hay versus straw, using cross point analysis of double demand functions, in a context where energy intake was not a limiting factor. Nine calves, fed milk replacer and concentrate, were trained to work for roughage rewards from two simultaneously available panels. The cost (number of muzzle presses) required on the panels varied in each session (left panel/right panel): 7/35, 14/28, 21/21, 28/14, 35/7. Demand functions were estimated from the proportion of rewards achieved on one panel relative to the total number of rewards achieved in one session. Cross points (cp) were calculated as the cost at which an equal number of rewards was achieved from both panels. The deviation of the cp from the midpoint (here 21) indicates the strength of the preference. Calves showed a preference for long versus chopped hay (cp ¿=¿14.5; P ¿=¿0.004), and for hay versus straw (cp ¿=¿38.9; P¿=¿0.004), both of which improve rumen function. Long hay may stimulate chewing more than chopped hay, and the preference for hay versus straw could be related to hedonic characteristics. No preference was found for chopped versus long straw (cp ¿=¿20.8; P¿=¿0.910). These results could be used to improve the welfare of calves in production systems; for example, in systems where calves are fed hay along with high energy concentrate, providing long hay instead of chopped could promote roughage intake, rumen development, and rumination