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Objective: The aim of this study was to investigate (a) the potential of the Bruton's tyrosine kinase (BTK) inhibitors acalabrutinib and fenebrutinib to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) hemorrhagic shock (HS) rat models and (b) whether treatment with either acalabrutinib or fenebrutinib attenuates BTK, NF-κB and NLRP3 activation in HS. Background: The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. The protein BTK is known to play a role in the activation of the NLRP3 inflammasome, which is a key component of the innate inflammatory response. However, its role in trauma-hemorrhage is unknown. Methods: Acute HS rat models were performed to determine the influence of acalabrutinib or fenebrutinib on MODS. The activation of BTK, NF-κB and NLRP3 pathways were analyzed by western blot in the kidney. Results: We demonstrated that (a) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (b) treatment of HS-rats with either acalabrutinib or fenebrutinib attenuated the organ injury and dysfunction in acute HS models and (c) reduced the activation of BTK, NF- kB and NLRP3 pathways in the kidney. Conclusion: Our results point to a role of BTK in the pathophysiology of organ injury and dysfunction caused by trauma/hemorrhage and indicate that BTK inhibitors may be repurposed as a potential therapeutic approach for MODS after trauma and/or hemorrhage. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase (BTK) is a key protein in B cell antigen receptor (BCR) signaling pathway, and is a research hotspot in the clinical treatment of B cell tumors and B cell immune diseases. In this article, based on the structure of Ibrutinib, a series of novel irreversible BTK inhibitors with the scaffolding of 1H -pyrazolo [3, 4- d ] pyrimidin-4-amine were designed and synthesized. All the compounds showed a moderate to potent inhibitory activity against BTK. Among them, compound 6b showed the best BTK kinase inhibitory activity with the IC 50 value of 1.2 nM. The ADME/T properties performed by pkCSM demonstrated that compound 6b possesses a good druglikeness. Further druggability evaluation showed that 6b exhibited good water solubility and acceptable pharmacokinetic properties. Therefore, compound 6b provided a promising lead compound for developing novel irreversible BTK inhibitors. [ABSTRACT FROM AUTHOR]

Background: Periodontitis is not only one of the most prevalent inflammatory diseases among adults, but also commonly linked to numerous systemic conditions including cardiovascular diseases, stroke, and diabetes. Although osteoclasts are responsible for the alveolar bone resorption during periodontitis pathogenesis, the development of pharmacologic strategies targeting these cells has not been vastly fruitful.Methods: Bone marrow macrophages were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL) to examine the direct effect of acalabrutinib on osteoclastogenesis. Ca2+ oscillation and nuclear localization of NFATc1 in osteoclast precursors were examined to determine the precise molecular mechanism. LPS-induced alveolar bone loss model was employed for studying effect in in vivo bone resorption.Results: Acalabrutinib directly inhibited RANKL and LPS-induced in vitro osteoclast differentiation. In addition, acalabrutinib inhibited RANKL-induced phosphorylation of mitogen-activated protein kinases and reduced the expression of NF-κB. The inhibitory mechanism involved suppression of Ca2+ oscillation in osteoclast precursors resulting in the decreased NFATc1 expression and nuclear localization, which is a crucial prerequisite for osteoclastogenesis. The administration of acalabrutinib significantly reduced P. gingivalis lipopolysaccharide-induced alveolar bone erosion in mice.Conclusion: These data indicate that acalabrutinib is an effective inhibitor of osteoclastogenesis both in vitro and in vivo, with a potential for a novel strategy against bone destruction by periodontitis. [ABSTRACT FROM AUTHOR]

Most B-cell malignancies strictly depend on signals from the microenvironment for their survival and proliferation. This niche-dependency can be regarded as their Achilles' heel and provides an excellent target for therapy. Waldenström's macroglobulinemia (WM) is characterized by the accumulation of neoplastic post-germinal center B cells within the bone marrow (BM). Interestingly, one third of the patients carry activating mutations in the chemokine receptor CXCR4, a key mediator of B cell and plasma cell homing to the BM. We have previously shown that signals from the B-cell antigen receptor (BCR) and from chemokine receptors play a central role in controlling the interaction of normal and malignant B cells with their microenvironment by regulating the activity of integrin adhesion molecules. Apart from controlling the homing and retention of lymphocytes within their growth- and survival niches, integrins also emit signals that directly promote cell growth and survival. By analogy to the successful treatment with BTK inhibitors, we propose that targeting pathways controlling integrin-mediated retention of the WM cells in the BM, thereby inducing ‘homelessness’ (anoikis) by mobilization of the malignant cells from their protective niches, may be an efficient treatment strategy for WM. [ABSTRACT FROM AUTHOR]

We report a case of invasive pulmonary aspergillosis in a patient taking ibrutinib, a Bruton's tyrosine kinase inhibitor used to treat refractory chronic lymphocytic leukemia. We hypothesize that ibrutinib promoted this infection by suppressing innate immune responses against Aspergillus . Clinicians should be aware of potential Aspergillus infections in patients treated with this drug. [ABSTRACT FROM AUTHOR]

Abstract: Indolent lymphoma comprises a unique and challenging subset of non-Hodgkin lymphoma (NHL). While definitions of indolence will vary, the most common indolent NHL subtypes include follicular lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma. Patients with indolent NHL (iNHL) excluding those with rare localized presentations are often met with an incurable but highly treatable NHL. In the rituximab era, response rates are approaching 90% with rituximab plus chemotherapy and time to next treatment are beginning to be measured in years. As a result of a prolonged natural history, we are encountering a gridlock of novel regimens and agents that appropriately fill peer-reviewed journals. In this review, we tackle a spectrum of topics in the management of indolent lymphoma including the initial approach to the newly diagnosed patient, approaches to first cytotoxic chemotherapy, maintenance and consolidation techniques, as well as highlight promising treatments on the horizon in iNHL. Clinicians continue to face tough choices in the management of iNHL. Through well-thought out clinical trials and peer-reviewed vetting of data we will continue to determine how to best manage the clinical continuum that is iNHL. [Copyright &y& Elsevier]

Purpose: X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency disease caused by a mutation in the Bruton tyrosine kinase (BTK) gene resulting in defective B cell differentiation. Because it is a relatively rare disorder, it is difficult for clinicians to have a comprehensive understanding of XLA due to a lack of exposure to the disease. Clinical presentations of patients with XLA were analyzed and discussed to improve care plans. Materials and Methods: During a 20 year period, from January 1987 to June 2006, a total of 19 patients were diagnosed as XLA in the Department of Pediatrics at Severance Hospital, Seoul, Korea. A retrospective analysis of the clinical presentations of those patients was performed. Results: The mean age of the XLA patients included in the study was 4.89 years, with a range of 6 months to 13 years. Twelve patients were diagnosed before age 5, while the other 7 patients were diagnosed after age 5. Recurrent infections observed in the patients included pneumonia, acute otitis media, septic arthritis, skin infection, sepsis, sinusitis, acute gastroenteritis, cervical lymphadenitis, epididymitis, meningitis, osteomyelitis, urinary tract infection and encephalitis. Frequency of admissions was variable from 0 to 12 times, depending on the time at which immunoglobulin therapy was started. Six cases had family histories positive for XLA. BTK gene mutations were found in 8 cases. Conclusion: The overall prognosis of XLA is good as long as patients are diagnosed and treated early with regular intra venous gamma globulin therapy before the sequelae of recurrent infections appear. [ABSTRACT FROM AUTHOR]

Background: X-linked agammaglobulinemia (XLA) is characterized by impaired B-cell differentiation caused by mutations in the Bruton''s tyrosine kinase (Btk) gene. The natural disease model, the X-linked immunodeficiency mouse, shows a less severe phenotype, indicating a different requirement of Btk in human and mouse B cells. Btk is also expressed in the myeloid line and participates in LPS signaling. Deficient oxidative burst and myeloid differentiation have been reported in the X-linked immunodeficiency mouse, but the precise mechanism and relevance of Btk activity in human monocytes is poorly understood. Objective: The apparent absence in XLA of clinical manifestations of myeloid deficiency prompted us to explore the relevance of complete Btk absence in human myeloid cells. Methods: Seven patients with XLA with BTK mutations conditioning a null protein expression were included in the study. Monocyte LPS-induced mitogen-activated protein kinase activation, TNF-α and IL-6 production in monocytes, and oxidative burst in monocytes and granulocytes were analyzed by means of flow cytometry. Results: We show that in response to LPS, Btk-null monocytes from patients with XLA induce early mitogen-activated protein kinase activation and intracellular TNF-α and IL-6 production with the same intensity as cells from age- and sex-matched control subjects. In addition, the oxidative burst in response to LPS and other stimulants was completely normal in Btk-null monocytes and neutrophils. Conclusion: Our results indicate that Btk is not essential for early LPS signaling in human monocytes and that different Btk dependency might exist between human and mouse myeloid cells. Clinical implications: These findings provide a better understanding of XLA, and they show the differences between human XLA and murine Xid models. [Copyright &y& Elsevier]

Background: X-linked (Bruton''s) agammaglobulinemia (XLA) is a rare immunodeficiency caused by a block in B-cell development caused by mutations in the Bruton''s tyrosine kinase (BTK) gene. Many aspects of XLA and BTK function remain unresolved; atypical presentations have been reported, and no clear genotype-phenotype correlation has been established. Objectives: We sought to contribute to the understanding of XLA through the phenotypic and biochemical characterization of a large group of Spanish patients with agammaglobulinemia. We also sought to classify the mutations according to their severity to analyze a genotype-phenotype correlation. Methods: Clinical and analytic data were collected from the clinical records. We studied the BTK gene, protein expression, and function, and the findings were correlated with the phenotypic information. Results: Fifty-four patients were given diagnoses of XLA. We identified 38 different mutations in BTK, 26 not described in other patients, and several uncommon clinical phenotypes or analytic characteristics were found. The statistical analysis shows that less severe mutations or minimal detection of protein by means of flow cytometry are associated with decreased severity in clinical and analytic data, demonstrating a clear relation between the type of mutation and the disease expressivity. However, some exemptions to this rule were noted. Conclusions: XLA is a variable disease. Globally, a genotype-phenotype correlation is observed, but individual discrepancies between the severity of the mutation and the clinical and analytic phenotype suggest that other loci or ambient factors significantly influence the disease presentation and evolution. [Copyright &y& Elsevier]

Evobrutinib, a highly selective Bruton's tyrosine kinase (BTK) inhibitor, demonstrated a low annualized relapse rate (75mg twice-daily: 0.11, 95%CI 0.04–0.25) in a phase 2 randomized controlled trial in patients with relapsing multiple sclerosis (RMS; NCT02975349). This was maintained in an open-label extension (OLE) through 108 weeks (0.12, 95%CI 0.06–0.22; 75mg once-daily for ∼48 weeks, then 75mg twice-daily). Evobrutinib concentrations in the brain achieved high BTK occupancy in an experimental autoimmune encephalomyelitis model. We investigated evobrutinib distribution into cerebrospinal fluid (CSF) in patients with RMS. Plasma and CSF samples were collected 2–3 hours post-dose from phase 2 OLE patients (75mg twice-daily for >1 year, including ≥6 days uninterrupted dosing before sampling) and evobrutinib concentrations measured. Plasma protein binding was measured ex vivo in sub-study participant samples to determine free plasma evobrutinib concentrations. Nine patients from one center were enrolled: 89% female, median age 50.5 years and median disease duration 6.9 years (at phase 2 study baseline); all had stable RMS. In plasma, mean total evobrutinib concentration (95%CI) was 115.0 (71.8–184.3) ng/mL and free evobrutinib concentration was 5.5 ng/mL. Evobrutinib was quantifiable in the CSF of all patients; the geometric mean concentration in CSF was 3.21 (2.27–4.55) ng/mL; 58% of the free plasma concentration. Evobrutinib administered at an efficacious, steady-state dose was detected in the CSF of patients with RMS at concentrations consistent with free plasma concentrations. Therefore, evobrutinib may inhibit BTK-expressing cells, including B cells and microglia, in the central nervous system. [ABSTRACT FROM AUTHOR]