PLCG2 (Phospholipase C Gamma 2)

In patients with cBTKi-pretreated relapsed/refractory (R/R) CLL, the BRUIN-CLL-321 trial demonstrated improved progression-free survival (PFS) and time to next treatment (TTNT) compared with idelalisib/rituximab or bendamustine/rituximab, accompanied by a favorable tolerability profile. Data from randomized phase III BRUIN-CLL-313 and BRUIN-CLL-314 trials demonstrate the superiority of pirtobrutinib over chemoimmunotherapy in untreated patients and non-inferiority to ibrutinib in untreated patients or in patients with R/R disease who had no prior exposure to cBTKis. These data are not sufficient to justify a change in clinical practice; however, they lay the groundwork for a potential future repositioning of pirtobrutinib from the treatment of R/R CLL to earlier lines of therapy. In this review, we address a range of current and prospective aspects of pirtobrutinib-based therapies: (1) the strengths and limitations of the trial datasets; (2) the biological rationale for frontline noncovalent BTK inhibition; (3) sequencing trade-offs; and (4) prospective scenarios, including combination strategies and time-limited regimens.

Our data suggest a common precursor in these two cases of composite lymphoma. The shared somatic variants we identified may represent early events in lymphomagenesis and potential therapeutic targets.

These results demonstrate that cross-species exome capture provides a means to identify genomic alterations that may play a role in the molecular pathogenesis of UGC in the CSL and adds to the body of evidence for an association between OtHV-1 and UGC in this species.

This review focus on the mechanism of BTKi resistance, the role of the TME and its components in drug resistance. It emphasized that targeting TME remodeling and combined the inhibition of multiple pathways may provide a new strategy for overcoming drug resistance, optimizing the treatment paradigm of B-cell lymphoma.

For perturbation, the EZH2 inhibitor tazemetostat was evaluated in the CRPC-relevant C42 cell line with H3K27me3 readouts and transcriptomic profiling, with key changes validated by RT-qPCR...This multi-layer integrative analysis suggests that EZH2 is associated with proliferative malignant states and immunosuppressive microenvironment features in advanced PCa, including Treg-linked crosstalk. Transcriptomic profiling following EZH2 inhibition supports modulation of these programs by EZH2-targeted perturbation, while functional and causal mechanisms warrant further investigation.

Rescue experiments were performed with the MAPK inhibitor trametinib...We reveal a novel oncogenic axis in which MYBL2 and SUMOylation cooperatively increase UBE2C expression and stability, promoting HCC progression via MAPK pathway activation. Targeting the MYBL2/UBE2C/MAPK axis represents a potential therapeutic strategy for treating HCC.

This study is the first to demonstrate that calycosin effectively prevents platelet activation and thrombus formation, partly by targeting glycoprotein VI-mediated signaling, without affecting hemostasis. These findings highlight the therapeutic potential of calycosin for cardiovascular diseases.

Covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) irreversibly bind the C481 residue and have produced high response rates and durable disease control, often replacing chemoimmunotherapy in the relapsed setting and, for some entities, even in the first line. Non-covalent BTK inhibitors (e.g., pirtobrutinib) bind BTK independently of C481, can overcome classic C481-mediated resistance, and extend BTK pathway targeting into later lines of therapy. Overall, BTK inhibition has evolved into a versatile platform enabling long-term, often chemo-free management strategies.

While PLCG2 represents a promising nexus for intervention, urgent mechanistic gaps and translational priorities remain. We argue that future efforts must prioritize the development of precise, variant-directed targeting strategies and systematic phenotype-genotype mapping to successfully translate PLCG2 research into tangible patient benefits.

We have characterized in vivo signatures of three genetic candidates for late-onset Alzheimer's disease (LOAD), identifying alterations in specific LOAD-related pathways for each variant. Our study highlights that assembling multi-omics measurements reveals interrelated pathway alterations in Alzheimer's Disease (AD) and enables the identification of biomarker combinations that may inform clinical practice. Our approach provides a platform for further exploration into the causes and progression of AD by assessing animal models at different ages and/or with different combinations of LOAD risk variants.

Mechanistically, xanthone inhibited NF-κB activation, phosphorylation of ERK1/2 and p38, calcium mobilization, and platelet procoagulant activity. These findings indicate that xanthone impairs platelet activation and both arterial and venous thrombus formation, suggesting its potential as a novel agent for treating thrombotic or cardiovascular diseases.

Moreover, upon ibrutinib treatment, REL DNA-binding activity decreased in 2pWT CLL cells but remained sustained in 2p+ CLL cells following BCR stimulation, suggesting that persistent NF-κB activation contributes to resistance...Altogether, our study identifies REL overexpression as a novel 2p+-driven mechanism of BTKi resistance in CLL, complementing the well described BTK and PLCG2 mutations. These findings support the clinical relevance of detecting 2p gain to guide treatment strategies and improve outcomes in CLL.