Utilizing risk factors to guide treatment decisions in chronic lymphocytic leukemia.

INTRODUCTION: In the era of chemo-immunotherapy, high-risk factors unequivocally predicted inferior outcomes for patients with CLL. The widespread adoption of BTK inhibitors has challenged the practical implications of such testing, as many patients have improved outcomes despite the presence of high-risk features. The impact of adverse prognostic factors, such as unmutated IGHV, on survival has been ameliorated by continuous treatment with BTK inhibitors, but not by finite-duration therapy with venetoclax-based combinations. Furthermore, TP53 abnormalities continue to be associated with worse outcomes in the era of novel agents. New treatment modalities, such as pirtobrutinib, lisocabtagene maraleucel, and ongoing studies combining BTK inhibitors with venetoclax, raise new questions on the significance of prognostic factors of survival for patients with CLL. AREAS COVERED: Herein, we summarized the available literature on patients with CLL harboring high-risk biomarkers, with a focus on data from key clinical trials. EXPERT OPINION: Testing for prognostic biomarkers will remain relevant to identify patients who may have increased benefit from novel therapeutic strategies, such as combination therapies and novel agents. Patients with high-risk disease should be encouraged to participate in clinical trials.

Bioinformatics analysis of BTK expression in lung adenocarcinoma: implications for immune infiltration, prognostic biomarkers, and therapeutic targeting.

In recent years, as more and more lung-cancer patients have been treated with immunotherapeutic agents, their survival has been prolonged compared to before. It is well known that BTK (Bruton's tyrosine kinase) is predominantly found in cells of the hematopoietic system. However, there is a distinct lack of literature on BTK expression in lung adenocarcinoma (LUAD) patients and its effect on the immune microenvironment. Consequently, the main goal of this investigation was to analyze how BTK expression in lung adenocarcinoma affects its progression, along with its prognostic significance, through the utilization of bioinformatics online resources and publicly available databases. Data on the sequencing results and clinical records of lung adenocarcinoma patients were gathered from The Cancer Genome Atlas (TCGA) database. Based on the expression level of BKT, TCGA categorized lung adenocarcinoma patients into BTK high-expression and low-expression groups. We investigated the effects of BKT on clinicopathologic, genomic, and immunologic characteristics of lung adenocarcinoma patients. We analyzed BTK mRNA expression in tumors and normal tissues using two key resources: Tumor Immuno Estimation Resource 2.0 (TIMER 2.0) and Gene Expression Profiling Interactive Analysis 2 (GEPIA 2). We analyzed the prognosis of the patients using GEPIA2 and validated the results using univariate and multivariate analyses. In addition, we assessed BTK protein expression by Human Protein Atlas (HPA). We sought to elucidate the clinical prognostic significance of BTK in The TCGA using the online tool GEPIA 2. Furthermore, to clarify the biologic roles and pathways linked to BTK, we conducted a genomic enrichment analysis of the information. To predict the proportion of various immune cell infiltrations in the immune microenvironment of lung adenocarcinoma patients diagnosed in the TCGA database, we performed an analysis using the TIMER online tool. Using TIMER and CIBERSORT, the correlation between genes co-expressed with BTK and the corresponding tumor-infiltrating immune cells was explored; finally, the relationship between BTK expression and immune infiltration and immune checkpoints in the TMB group and the high and low groups was analyzed by R language analysis using the TCGA database. The expression of BTK provides some hints about the prognosis of the patients. The high expression of BTK is involved in immune response regulation signaling pathways, leukocyte-mediated immunity, leukocyte intercellular adhesion, graft rejection, and complement. Analysis of the GEPIA 2 database showed that BTK was co-expressed with the genes FGD2, SASH3, NCKAP1L, CD53, ARHGAP30 and LPXN. Increased expression of the above-mentioned genes resulted in increased proportions of CD8 + T cells, memory CD4 + T cells, B cells, macrophages, and dendritic cells, and decreased proportions of Treg cells and TH2 cells. In addition, our study revealed a strong positive correlation between various key immune checkpoints (e.g., PDCD1, CD274, PDCD1LG2, CTLA4, HAVCR2, LAG3, TIGIT, and SIGLEC15) and BTK expression. In conclusion, increased BTK expression in lung adenocarcinoma is closely associated with prolonged survival of lung-cancer patients. Moreover, the genes classified under the BTK high-expression group exhibit significant enrichment in immune-related pathways, suggesting a potential impact on the tumor microenvironment. We investigated the potential of BTK as a tumor suppressor gene in predicting prolonged patient survival. In addition, we further investigated the possibility that BTK further affects the immunotherapeutic response of patients by influencing the microenvironment of tumor immune infiltration, but the relevant mechanisms remain to be further studied.

Trends in covalent drug discovery: a 2020-23 patent landscape analysis focused on select covalent reacting groups (CRGs) found in fda-approved drugs.

INTRODUCTION: Covalent drugs contain electrophilic groups that can react with nucleophilic amino acids located in the active sites of proteins, particularly enzymes. Recently, there has been considerable interest in using covalent drugs to target non-catalytic amino acids in proteins to modulate difficult targets (i.e. targeted covalent inhibitors). Covalent compounds contain a wide variety of covalent reacting groups (CRGs), but only a few of these CRGs are present in FDA-approved covalent drugs. AREAS COVERED: This review summarizes a 2020-23 patent landscape analysis that examined trends in the field of covalent drug discovery around targets and organizations. The analysis focused on patent applications that were submitted to the World International Patent Organization and selected using a combination of keywords and structural searches based on CRGs present in FDA-approved drugs. EXPERT OPINION: A total of 707 patent applications from > 300 organizations were identified, disclosing compounds that acted at 71 targets. Patent application counts for five targets accounted for ~ 63% of total counts (i.e. BTK, EGFR, FGFR, KRAS, and SARS-CoV-2 Mpro). The organization with the largest number of patent counts was an academic institution (Dana-Farber Cancer Institute). For one target, KRAS G12C, the discovery of new drugs was highly competitive (>100 organizations, 186 patent applications).

Chronic Lymphocytic Leukemia: Prognostic Factors in the Era of Novel Drugs.

Novel drugs have profoundly changed the outcomes in chronic lymphocytic leukemia (CLL) patients, and the traditional prognostic factors that were identified in the era of chemoimmunotherapy need to be validated in the context of these new targeted therapies. Currently, the most important prognostic genetic biomarkers are the immunoglobulin heavy chain variable (IGHV) mutational status, genetic aberrations including del(17p)/TP53 abnormalities, and the complex karyotype. In this review, we discuss the prognostic role of these genomic markers in relation to novel treatments. Moreover, we present and discuss new scoring systems that were elaborated and validated in the era of new drugs. In routine clinical practice, the application of an extensive genomic work-up with validated prognostic markers could improve the identification of "very high-risk" CLL patients who could benefit from novel, more effective targeted treatments.

Prolonged Responses in Central Nervous System Relapsed Diffuse Large B-Cell Lymphoma After Chimeric Antigen Receptor T-Cell Therapy Using Targeted Treatments.

The introduction of chimeric antigen receptor T-cell (CAR-T cell) therapy has changed the treatment landscape of diffuse large B-cell lymphoma (DLBCL). However, the optimal treatment strategy after relapse after this therapy still needs to be elucidated. In this report, we describe the case of a 67-year-old male who relapsed after treatment with tisagenlecleucel as a third-line therapy. We present our approach to treatment after relapse, in which we tried to sustain the circulating chimeric antigen receptor T-cells. This is reflected by the kinetics of the chimeric antigen receptor T-cells during these treatments.

Evaluation of infectious morbidity due to BTK inhibitors in indolent B-cell lymphomas: latest research findings and systematic analysis.

INTRODUCTION: Randomized clinical trials (RCTs) have suggested that BTK inhibitors (BTKis) might increase infectious disease (ID) risk. Systematic analysis of this topic as derived from RCTs and clinical practice is needed. AREAS COVERED: An extensive Medline, Embase, and Cochrane search of peer-reviewed sources reporting on ID morbidity in patients on BTKis was performed (1 January 2014 - 31 December 2013). Contribution of intrinsic immune defects in indolent B-cell lymphomas to this morbidity was carefully considered. EXPERT OPINION: Patients with indolent B-cell lymphomas display a wide range of innate and adaptive immune defects. In addition, BTKi use is linked with an increased signal of upper respiratory tract infections (URTIs) and pneumonias, mainly grade 1-2. These agents also increase the risk of rare invasive fungal infections (IFIs), mainly due to Cryptococcus and Aspergillus spp. with a peak within several months after the start of therapy. More than half of these IFIs are fatal. Research suggests a similar ID risk across 1st, 2nd and 3rd generations of BTKis, all causing B-cell dysfunction due to BTK inhibition, along with off-target functional neutrophil/macrophage alterations. Expanding the knowledge base on ID morbidity in patients on BTKis would facilitate timely diagnosis and treatment, and improve clinical outcomes.

Current and future therapies for follicular lymphoma.

Follicular lymphoma (FL) is an indolent, germinal center B cell-derived lymphoid neoplasm, for which recent advances in treatment have substantially improved patient survival. However, FL remains an incurable and heterogeneous disease, with groups of patients experiencing early disease progression, histologic transformation, or a high risk of treatment-related toxicity. Additionally, FL is a continually relapsing disease, and response rates and disease-control intervals decrease with each subsequent line of therapy. In this review, we explore the current treatment landscape for relapsed or refractory FL and promising therapies in development, highlighting the efficacy and potential risks of each treatment. We provide a real-world perspective on the unmet needs of patients with FL. Novel therapeutic approaches in development offer a wide array of options for clinicians when treating relapsed or refractory FL. A nuanced approach is required to address the needs of individual patients, taking into consideration both the risks and benefits of each treatment option, as well as patient preferences.

Dialog between mantle cell lymphoma cells and lymphoma-associated macrophages underlies ibrutinib resistance.

INTRODUCTION: Patients with mantle cell lymphoma (MCL) frequently develop resistance to ibrutinib. Lymphoma-associated macrophages (LAMs) may play a causal role in this resistance but remain underexplored in current literature. OBJECTIVES: To elucidate the role of LAMs in mediating ibrutinib resistance in MCL. METHODS: We investigated macrophage polarization through multiparameter flow cytometry (MPFC) using antibodies against CD206 and CD86 in blood and tissue samples from patients with MCL, both resistant and sensitive to ibrutinib. Subsequently, we developed an in vitro co-culture model utilizing MCL cell lines to identify cytokines associated with ibrutinib resistance and macrophage M2 polarization. The mechanisms underlying resistance were examined using MPFC, RNA sequencing, and Western blot analysis. Additionally, we assessed whether SB225002, a CXCR2 inhibitor, could reverse ibrutinib resistance through CCK-8 and caspase-3 assays, as well as in a mouse xenograft model involving an ibrutinib-resistant MCL cell line. RESULTS: In patients exhibiting ibrutinib resistance, the ratio of M2 to M1 LAMs was significantly higher compared to sensitive patients. In co-cultures of LAMs and MCL cells, the percentage of M2 macrophages, the IC50 value for ibrutinib, and the concentrations of IL-8 and CXCL5 were significantly elevated. Mechanistically, CXCL5 secreted by LAMs interacted with the CXCR2 on MCL cells, leading to the activation of the Akt, p38, and STAT3 signaling pathways in the presence of ibrutinib; this activity was diminished upon blockade of the CXCL5/CXCR2 axis. The combination of SB225002 and ibrutinib significantly enhanced MCL cell apoptosis, suppressed lymphoma growth in the xenograft model, and reprogrammed macrophage phenotype compared to treatment with ibrutinib alone. CONCLUSION: Our data indicate that M2-polarized LAMs are associated with ibrutinib resistance in a model of MCL, and that a CXCR2 inhibitor can reverse this resistance. These findings suggest a potential new therapeutic strategy.

Three-year cardiovascular and non-cardiovascular adverse events in patients with chronic lymphocytic leukemia or small cell lymphocytic lymphoma treated with Bruton tyrosine kinase inhibitors acalabrutinib or ibrutinib: a real-world analysis.

Bruton tyrosine kinase (BTK) inhibitors play an important role in targeted treatment of B-cell lymphoproliferative disorders. However, adverse events may limit the proper course of treatment in many patients. The purpose of this study is to compare the risk of cardiovascular and non-cardiovascular adverse events in patients with chronic lymphocytic leukemia (CLL) or small cell lymphocytic lymphoma (SLL) treated with the first-generation BTK inhibitor ibrutinib versus second-generation acalabrutinib, using real-world data from a collaborative multinational network. We used data from the network (TriNetX), which encompasses more than 100 healthcare organizations worldwide. We queried the database for patients aged ≥ 18 years with chronic lymphocytic leukemia or small-cell lymphomas treated with ibrutinib or acalabrutinib in the past ten years before the analysis. We used propensity score matching to balance the cohorts. The 3-year cumulative incidences and hazard ratios for the following outcomes were calculated: atrial flutter or fibrillation, other arrhythmias, heart failure, ischemic stroke or peripheral embolism, acute coronary syndrome, bleeding, and sepsis. We compared 2,107 patients in each group. Atrial fibrillation or flutter occurred in 150 (7.1%) patients with acalabrutinib and 310 (14.7%) patients with ibrutinib during the 3-year follow-up (hazard ratio, 0.68, 95% CI 0.55-0.84). New-onset hypertension occurred in 342 (16.3%) patients in the acalabrutinib group and 584 (27.7%) patients in the ibrutinib group (hazard ratio 0.81, 95% CI 0.66-0.98). Sepsis was diagnosed in 136 (6.5%) patients in the acalabrutinib group versus 239 (11.3%) patients in the ibrutinib group (hazard ratio 0.77, 95 CI 0.60-0.98). The two groups had no significant differences concerning the other adverse events. In a large retrospective cohort using real-world data from electronic medical registers, patients with CLL or SLL treated with acalabrutinib had a better cardiovascular and non-cardiovascular safety profile than those treated with ibrutinib, with lower risks of atrial flutter or fibrillation, new-onset arterial hypertension, and sepsis.

BTK inhibitors: moving the needle on the treatment of chronic lymphocytic leukemia.

INTRODUCTION: Bruton's tyrosine kinaseinhibitors (BTKis) changed the trajectory of upfront and relapsed/refractory chronic lymphocytic leukemia (CLL) treatment. However, BTKis are plagued by a spectrum of toxicities. Zanubrutinib was developed to circumvent challenges with prolonged tolerability by increasing BTK selectivity and maximizing efficacy through pharmacokinetic/pharmacodynamic optimization. However, with the availability of ibrutinib, acalabrutinib, and zanubrutinib, limited data exists to guide sequencing of BTKi therapy in the relapsed/refractory setting. AREAS COVERED: We review the first head-to-head trial (ALPINE) of zanubrutinib versus ibrutinib for the treatment of relapsed/refractory CLL and compare zanubrutinib's clinical efficacy and toxicities, including in patients with del(17p) and/or TP53 mutations to ibrutinib and acalabrutinib. EXPERT OPINION: Zanubrutinibrepresents one of the new standards of care for relapsed/refractory CLL based on superior progression-free survival and response rates over ibrutinib. Whilezanubrutinib is associated with fewer cardiac toxicities, similar rates of neutropenia and hypertension are noted. Ongoing studies are pushing the envelope, utilizing targeted drug combinations and minimal residual disease markers as well as receptor tyrosine kinase-like orphan receptor 1 inhibitors, chimeric antigen receptor T-cells, and novel BTK degraders. However, zanubrutinibrepresents a strong contender in the arsenal of treatment options for relapsed/refractory CLL.

Targeting Bruton's tyrosine kinase (BTK) as a signaling pathway in immune-mediated diseases: from molecular mechanisms to leading treatments.

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, plays a remarkable role in the transmission and amplification of extracellular signals to intracellular signaling pathways. Various types of cells use the BTK pathway to communicate, including hematopoietic cells particularly B cells and T cells. The BTK pathway plays a role in controlling the proliferation, survival, and functions of B cells as well as other myeloid cells. First, second, and third-generation BTK inhibitors are currently being evaluated for the treatment of immune-mediated diseases in addition to B cell malignancies. In this article, the available evidence on the action mechanisms of BTK inhibitors is reviewed. Then, the most recent data obtained from preclinical studies and ongoing clinical trials for the treatment of autoimmune diseases, such as pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, systemic lupus erythematosus, Sjögren's disease, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, myasthenia gravis, and inflammatory diseases such as psoriasis, chronic spontaneous urticaria, atopic dermatitis, and asthma are discussed. In addition, adverse effects and complications associated with BTK inhibitors as well as factors predisposing patients to BTK inhibitors complications are discussed.

Benefits and Challenges of Drug-Coated Balloons in Peripheral Artery Disease: From Molecular Mechanisms to Clinical Practice.

Multiple clinical trials have reported favorable outcomes after drug-coated balloon therapy for peripheral artery disease in above-the-knee and below-the-knee lesions and in both de novo and in-stent restenosis. However, there are still insufficient data to identify and tackle the risk factors associated with a higher risk of restenosis, which is the primary concern for patients who are treated with an endovascular approach. A modern armamentarium, which includes improved lesion preparation techniques such as plaque modification balloons, mechanical atherectomy, intravascular lithotripsy, and imaging, is crucial for obtaining better long-term clinical outcomes. Moreover, a better understanding of the molecular properties of drug-coated balloons has led to improved devices that could tackle the shortcomings of previous generations. This comprehensive review focuses on drug-coated balloon technology as a tool to treat peripheral artery disease and the effects of the molecular mechanisms involved in preventing vascular restenosis.

Successful treatment of hemophagocytic intravascular large B-cell lymphoma with CNS involvement with BTK inhibitor combined with rituximab and high-dose methotrexate.

This is a case of hemophagocytic intravascular large B-cell lymphoma (IVLBCL) with central nervous system (CNS) involvement. Although R-CHOP chemotherapy regimen has been shown significant improvement in survival rate. The prognosis and outcomes remain unsatisfactory, which is identified as outstanding challenges and need solutions. Gene and molecular profiling studies may provide new therapeutic strategies, especially the BCR/TLR/IL-1R/NF-κB signaling pathway in IVLBCL. Here, we treated the hemophagocytic IVLBCL CNS-involved patient with the Bruton tyrosine kinase inhibitor (BTKi) to block NF-κB pathway, and indicated that the second-generation BTKi zanubrutinib-based treatment was feasible and efficient.

Evidence-based expert consensus on clinical management of safety of Bruton's tyrosine kinase inhibitors (2024).

Bruton's tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of B-cell lymphomas. However, safety issues related to the use of BTKis may hinder treatment continuity and further affect clinical efficacy. A comprehensive and systematic expert consensus from a pharmacological perspective is lacking for safety issues associated with BTKi treatment. A multidisciplinary consensus working group was established, comprising 35 members from the fields of hematology, cardiovascular disease, cardio-oncology, clinical pharmacy, and evidence-based medicine. This evidence-based expert consensus was formulated using an evidence-based approach and the Delphi method. The Joanna Briggs Institute Critical Appraisal (JBI) tool and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach were used to rate the quality of evidence and grade the strength of recommendations, respectively. This consensus provides practical recommendations for BTKis medication based on nine aspects within three domains, including the management of common adverse drug events such as bleeding, cardiovascular events, and hematological toxicity, as well as the management of drug-drug interactions and guidance for special populations. This multidisciplinary expert consensus could contribute to promoting a multi-dimensional, comprehensive and standardized management of BTKis.

Therapeutic potential and recent progression of BTK inhibitors against rheumatoid arthritis.

Rheumatoid arthritis (RA) is a complex chronic inflammatory illness that affects the entire physiology of human body. It has become one of the top causes of disability worldwide. The development and progression of RA involves a complex interplay between an individual's genetic background and various environmental factors. In order to effectively manage RA, a multidisciplinary approach is required, as this disease is complicated and its pathophysiological mechanism is not fully understood yet. In majority of arthritis patients, the presence of abnormal B cells and autoantibodies, primarily anti-citrullinated peptide antibodies and rheumatoid factor affects the progression of RA. Therefore, drugs targeting B cells have now become a hot topic in the treatment of RA which is quite evident from the recent trends seen in the discovery of various B cell receptors (BCRs) targeting agents. Bruton's tyrosine kinase (BTK) is one of these recent targets which play a role in the upstream phase of BCR signalling. BTK is an important enzyme that regulates the survival, proliferation, activation and differentiation of B-lineage cells by preventing BCR activation, FC-receptor signalling and osteoclast development. Several BTK inhibitors have been found to be effective against RA during the in vitro and in vivo studies conducted using diverse animal models. This review focuses on BTK inhibition mechanism and its possible impact on immune-mediated disease, along with the types of RA currently being investigated, preclinical and clinical studies and future prospective.

Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition.

BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

BTK inhibitors: past, present, and future.

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment landscape for B cell lymphomas such as chronic lymphocytic leukemia (CLL). The first-in-class BTK inhibitor ibrutinib has recently been succeeded by covalent BTK inhibitors that are safer but still face challenges of resistance mutations. The noncovalent BTK inhibitor pirtobrutinib was recently approved for relapsed and refractory CLL, and whether noncovalent BTK inhibitors will supplant covalent BTK inhibitors as upfront treatment options either alone or in combination will be determined. Meanwhile, newer BTK inhibitors and BTK degraders are vying for their place in the potential future landscape of B cell cancers as well as autoimmune diseases. This review will cover the latest progress in BTK inhibitor development and where the field is moving in light of these recent discoveries.

The Evolving Role of Bruton's Tyrosine Kinase Inhibitors in B Cell Lymphomas.

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase crucial for B cell development and function, acts downstream of the B cell receptor (BCR) in the BCR pathway. Other kinases involved downstream of the BCR besides BTK such as Syk, Lyn, PI3K, and Mitogen-activated protein (MAP) kinases also play roles in relaying signals from the BCR to provide pro-survival, activation, and proliferation cues. BTK signaling is implicated in various B-cell lymphomas such as mantle cell lymphoma, Waldenström Macroglobulinemia, follicular lymphoma, and diffuse large B cell lymphoma, leading to the development of transformative treatments like ibrutinib, the first-in-class covalent BTK inhibitor, and pirtobrutinib, the first-in-class noncovalent BTK inhibitor. However, kinase-deficient mutations C481F, C481Y, C481R, and L528W in the BTK gene confer resistance to both covalent and non-covalent BTK inhibitors, facilitating B cell survival and lymphomagenesis despite kinase inactivation. Further studies have revealed BTK's non-catalytic scaffolding function, mediating the assembly and activation of proteins including Toll-like receptor 9 (TLR9), vascular cell adhesion protein 1 (VCAM-1), hematopoietic cell kinase (HCK), and integrin-linked kinase (ILK). This non-enzymatic role promotes cell survival and proliferation independently of kinase activity. Understanding BTK's dual roles unveils opportunities for therapeutics targeting its scaffolding function, promising advancements in disrupting lymphomagenesis and refining B cell lymphoma treatments.

Investigating the molecular mechanisms underlying the co-occurrence of Parkinson's disease and inflammatory bowel disease through the integration of multiple datasets.

Parkinson's disease (PD) and inflammatory bowel disease (IBD) are chronic diseases affecting the central nervous system and gastrointestinal tract, respectively. Recent research suggests a bidirectional relationship between neurodegeneration in PD and intestinal inflammation in IBD. PD patients may experience gastrointestinal dysfunction over a decade before motor symptom onset, and IBD may increase the risk of developing PD. Despite the "gut-brain axis" concept, the underlying pathophysiological mechanisms of this potential association remain unclear. This study aimed to investigate the biological mechanisms of differentially expressed genes in PD and IBD using bioinformatics tools, providing novel insights into the co-diagnosis and treatment of these diseases. We constructed a gene marker for disease diagnosis and identified five important genes (BTK, NCF2, CRH, FCGR3A and SERPINA3). Through nomogram and decision tree analyses, we found that both the IBD and PD required only the expression levels of BTK and NCF2 for accurate discrimination. Additionally, small molecule drugs RO-90-7501 and MST-312 may be useful for the treatment of both IBD and PD. These findings offer new perspectives on the co-diagnosis and treatment of PD and IBD, and suggest that targeting BTK may be a promising therapeutic strategy for both diseases.