Experimental demonstration on 400†nm-scale bandwidth optical parametric chirped-pulse amplification based on mixed cascaded crystals.

We present an optical parametric chirped-pulse amplification (OPCPA) based on mixed cascaded crystals, taking advantage of the unique parametric phase-matching of lithium triborate (LiB3O5, LBO) and yttrium calcium oxyborate ((YCa4O(BO3)3, YCOB) crystals. The OPCPA properties of LBO at 880 nm and YCOB at 750 nm are studied respectively. After amplification by two LBO and two YCOB crystals, a total signal gain of 108 and spectral bandwidth close to 400 nm is obtained. After accurate dispersion compensation with a grating-pair compressor and chirped mirror compensator, a pulse duration of 9.4 fs is obtained by a SHG-frequency-resolved optical grating (FROG). This approach will be of great significance in high energy amplifier for high peak power few-cycle laser sources.

Myeloid-specific knockout of Notch-1 inhibits MyD88- and TRIF-mediated TLR signaling pathways by regulating oxidative stress-SHP2 axis, thus restraining aneurysm progression.

OBJECTIVE: Notch-1 is a signal regulatory protein with extensive effects in myeloid cells, but its role in aneurysms remains to be fully clarified. In this study, therefore, the aneurysm mouse model with myeloid-specific knockout of Notch-1 was established to observe the role of Notch-1 in aneurysm progression. METHODS AND RESULTS: The effect of Notch-1 was assessed by pathological staining and Western blotting. It was found that after myeloid-specific knockout of Notch-1 in the aneurysm mouse model, the area of aneurysms and the macrophage infiltration were significantly reduced, the damage to arterial elastic plates was significantly relieved, and the oxidative stress level significantly declined. The results of Western blotting showed that after myeloid-specific knockout of Notch-1, the levels of oxidative stress-related proteins p22 and p47 in aneurysm tissues significantly declined, accompanied by a significant increase in the protein level of Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2). In addition, the levels of phosphorylated myeloid differential protein-88 (MyD88), TIR domain-containing adaptor-inducing interferon-ß (TRIF) and nuclear factor-κB (NF-κB), and inflammatory cytokines interferon-γ (IFN-γ), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) also significantly decreased after myeloid-specific knockout of Notch-1. Following myeloid-specific knockout of Notch-1, the phagocytic capacity of macrophages was enhanced by promoting the SHP2 signaling pathway. CONCLUSION: Notch-1 in monocytes/macrophages can activate the Toll-like receptor (TLR)-mediated inflammatory and stress responses by activating oxidative stress and inhibiting the SHP2 protein expression, thus facilitating aneurysm progression.

Impact of diabetic versus non-diabetic patients undergoing coronary artery bypass graft surgery on postoperative wound complications: A meta-analysis.

The effect of diabetes mellitus (DM) on the incidence of postoperative wound complications in patients with coronary artery bypass grafting (CABG) is still unclear. Thus, we performed a meta-analysis of CABG in DM patients to evaluate existing data from both prospective and historical cohorts. The objective of this trial was to assess the relevance and extent of the effect of diabetes on the outcome of previous CABG procedures. Data sources like Embase and Pubmed were found throughout the research, and the language was limited to English through manual search. The searches were performed up to August 2023. The data were extracted from the study of the inclusion/exclusion criteria, the features of the population, the statistical approach and the clinical results. A qualitative evaluation of the qualifying studies has been carried out. Out of the 1874 studies identified, 21 cohort studies were chosen for analysis. Meta-analyses were performed in 258 454 patients (71 351 diabetic and 187 103 non-diabetic). Twenty-one studies on deep sternal wound infections in CABG patients showed a lower rate of deep sternal wound infections in non-diabetes group compared with those with diabetes (OR, 2.13; 95% CI: 1.97, 2.31, p < 0.00001). And 16 studies of superficial wound infections in patients undergoing CABG were found to be associated with a lower rate of superficial injury (OR, 1.93; 95% CI: 1.53, 2.43, p < 0.00001) compared with those with diabetes; In five trials, perfusion time during CABG (MD, 2.31; 95% CI: -0.16, 4.79, p = 0.07) was observed, and there were no significant differences between diabetes and non-diabetes. Currently, there is a higher risk for CABG in diabetes than in non-diabetes patients with sternal infections and superficial injuries. Future randomized trials will concentrate on the treatment of such perioperatively related complications, which will lower the risk of postoperative wound infection in diabetes.

Nutritional status efficacy of early nutritional support in gastrointestinal care: A systematic review and meta-analysis.

BACKGROUND: Gastrointestinal surgery is a complicated process used to treat many gastrointestinal diseases, and it is associated with a large trauma: Most patients often have different degrees of malnutrition and immune dysfunction before surgery and are prone to various infectious complications during postoperative recovery, thus affecting the efficacy of surgical treatment. Therefore, early postoperative nutritional support can provide essential nutritional supply, restore the intestinal barrier and reduce complication occurrence. However, different studies have shown different conclusions. AIM: To assess whether early postoperative nutritional support can improve the nutritional status of patients based on literature search and meta-analysis. METHODS: Articles comparing the effect of early nutritional support and delayed nutritional support were retrieved from PubMed, EMBASE, Springer Link, Ovid, China National Knowledge Infrastructure, China Biology Medicine databases. Notably, only randomized controlled trial articles were retrieved from the databases (from establishment date to October 2022). The risk of bias of the included articles was determined using Cochrane Risk of Bias V2.0. The outcome indicators, such as albumin, prealbumin, and total protein, after statistical intervention were combined. RESULTS: Fourteen literatures with 2145 adult patients undergoing gastrointestinal surgery (1138 patients (53.1%) receiving early postoperative nutritional support and 1007 patients (46.9%) receiving traditional nutritional support or delayed nutritional support) were included in this study. Seven of the 14 studies assessed early enteral nutrition while the other seven studies assessed early oral feeding. Furthermore, six literatures had "some risk of bias," and eight literatures had "low risk". The overall quality of the included studies was good. Meta-analysis showed that patients receiving early nutritional support had slightly higher serum albumin levels, than patients receiving delayed nutritional support [MD (mean difference) = 3.51, 95%CI: -0.05 to 7.07, Z = 1.93, P = 0.05]. Also, patients receiving early nutritional support had shorter hospital stay (MD = -2.29, 95%CI: -2.89 to -1.69), Z = -7.46, P < 0.0001) shorter first defecation time (MD = -1.00, 95%CI: -1.37 to -0.64), Z = -5.42, P < 0.0001), and fewer complications (Odd ratio = 0.61, 95%CI: 0.50 to 0.76, Z = -4.52, P < 0.0001) than patients receiving delayed nutritional support. CONCLUSION: Early enteral nutritional support can slightly shorten the defecation time and overall hospital stay, reduce complication incidence, and accelerate the rehabilitation process of patients undergoing gastrointestinal surgery.

A laser wakefield acceleration facility using SG-II petawatt laser system.

Laser wakefield acceleration (LWFA) using PW-class laser pulses generally requires cm-scale laser-plasma interaction Rayleigh length, which can be realized by focusing such pulses inside a long underdense plasma with a large f-number focusing optic. Here, we present a new PW-based LWFA instrument at the SG-II 5 PW laser facility, which employs f/23 focusing. The setup also adapted an online probing of the plasma density via Nomarski interferometry using a probe laser beam having 30 fs pulse duration. By focusing 1-PW, 30-fs laser pulses down to a focal spot of 230 µm, the peak laser intensity reached a mild-relativistic level of 2.6 × 1018 W/cm2, a level modest for standard LWFA experiments. Despite the large aspect ratio of >25:1 (transverse to longitudinal dimensions) of the laser pulse, electron beams were observed in our experiment only when the laser pulse experienced relativistic self-focusing at high gas-pressure thresholds, corresponding to plasma densities higher than 3 × 1018 cm-3.

Simple single-shot complete spatiotemporal intensity and phase measurement of an arbitrary ultrashort pulse using coherent modulation imaging.

We propose a simple single-shot spatiotemporal measurement technique called coherent modulation imaging for the spatio-spectrum (CMISS), which reconstructs the full three-dimensional high-resolution characteristics of ultrashort pulses based on frequency-space division and coherent modulation imaging. We demonstrated it experimentally by measuring the spatiotemporal amplitude and phase of a single pulse with a spatial resolution of 44 µm and a phase accuracy of 0.04 rad. CMISS has good potential for high-power ultrashort-pulse laser facilities and can measure even spatiotemporally complicated pulses with important applications.

Experimental demonstration of 1011 temporal contrast in pure nanosecond optical parametric chirped pulse amplifiers.

The temporal contrast of ultrashort and ultraintense laser pulses can significantly influence the laser-plasma interactions. As the optical parametric chirped pulse amplification (OPCPA) has been widely adopted in these laser facilities, the inherent optical parametric fluorescence, exhibiting a pedestal in the time window of the pump pulse, has become a significant problem. In this paper, we investigated experimentally its influence on the contrast of the compressed pulses at 808 nm using a multistage OPCPA amplifier. Compared to the highest value of 108 ever reported in the literature for such a type of regime, by adjusting the pump energy allocation between OPCPA stages and controlling the gain of small signal regime, we for the first time, to the best of our knowledge, realized a 1011 temporal contrast in a pure nanosecond OPCPA design at a gain exceeding 7×108, without adopting any other noise cleaning methods, such as picosecond OPCPA, cross-polarized wave generation, etc. This indicates that the OPCPA has a very significant potential for contrast improvement and to become a candidate for the future high-energy amplifiers in ultrashort high-power laser facilities.

Ultra-broadband high conversion efficiency optical parametric chirped-pulse amplification based on YCOB crystals.

We present a high efficiency and ultra-broadband optical parametric chirped-pulse amplification (OPCPA) system fully based on yttrium calcium oxyborate (YCOB) crystals. The OPCPA properties of YCOB at 808 nm are studied for both high gain and saturated amplification. The non-collinear angle is finely tuned to study the variation of gain spectrum at a certain phase-matching angle of YCOB crystals. After amplification by four YCOB crystals, a total signal gain of 0.9×109 is obtained and the FWHM spectral bandwidth is still over 100 nm. An amplified signal pulse of 182 mJ is achieved with pump energy of 440 mJ in the saturated amplification stage and the conversion efficiency is about 40%. After a four-grating compressor, a pulse duration of 20 fs is measured by a second-order autocorrelator.

Dynamic chromatic aberration pre-compensation scheme for ultrashort petawatt laser systems.

A novel chromatic aberration pre-compensation scheme for ultrashort petawatt laser systems was proposed. The pre-compensation scheme consists of a convex lens, group of concave lenses, and a spherical reflector combined with a conventional vacuum chamber. It provides a versatile method to accurately compensate the chromatic aberration of an entire laser system via controlling the amount of propagation time delay (PTD) induced by the compensator without changing the input and output beam size. A compensator, tailored based on the proposed scheme, was designed and experimentally evaluated for the Shen-Guang-II 5PW (SG-II 5PW) laser system at Shanghai Institute of Optics and Fine Mechanics (SIOM). The experimental results verified that chromatic aberration in the laser system was almost fully compensated: the size of laser beam focused by an f/2.42 off-axis parabolic mirror (OAP) was reduced tremendously from 32×18µm2to about 4×4µm2at full width at half maximum (FWHM). The proposed scheme provides the flexibility to accurately correct chromatic aberration in high-power laser systems within a wide dynamic range.

Cellular Uptake, Intracellular Trafficking, and Stability of Biocompatible Metal-Organic Framework (MOF) Particles in Kupffer Cells.

Rapid intracellular degradation of current drug-delivery nanocarriers presents a challenge for achieving ideal controlled drug-release kinetics. Recent in vivo studies have shown that porous hybrid metal-organic frameworks (MOFs), belonging to the Materials of Institute Lavoisier (MIL) family, display prolonged biodegradation behavior. In this study, we investigated stability of these materials in Kupffer cells, a relevant target for the treatment of several life-threatening immune-mediated liver diseases. For this aim, we selected fluorescently labeled microporous MOF particles of MIL88A and MIL88B-NH2, built from trimers of Fe(III) octahedra, as an inorganic component, and fumarate (MIL88A) or 2-amino terephthalate (MIL88B-NH2), as an organic linker. Cell uptake inhibition analysis of MOF particles by a Kupffer cell line (KUP5) has shown that phagocytosis is the major endocytic pathway involved in MIL88B-NH2 internalization. Investigation of MOF interaction with KUP5 cells by real-time microscopy indicated that the structure of MIL88B-NH2 MOFs stays intact up to 15 min after uptake, followed by MOF accumulation in acidic cell compartments and slow degradation, reaching a minimum of 10-15% decomposition over 24 h. MIL88A particles demonstrated similar degradation kinetics. Analysis of the mechanisms of MOF degradation has shown that inhibition of phagosome acidification as well as protease activity does not prevent decomposition of MIL88B-NH2 particles. Thus, our study demonstrates the relative stability of the MOF structure in the phagolysosomal environment of Kupffer cells, revealing potential use of these materials for controlled drug delivery in a case of immune-mediated liver diseases.

Metal Organic Framework (MOF) Particles as Potential Bacteria-Mimicking Delivery Systems for Infectious Diseases: Characterization and Cellular Internalization in Alveolar Macrophages.

PURPOSE: Intramacrophagic bacteria pose a great challenge for the treatment of infectious diseases despite many macrophage targeted drug delivery approaches explored. The use of biomimetic approaches for treating infectious diseases is promising, but not studied extensively. The study purpose is to evaluate iron-based metal-organic frameworks (MOF) as a potential bacteria-mimicking delivery system for infectious diseases. METHODS: Two types of carboxylated MOFs, MIL-88A(Fe) and MIL-100(Fe) were developed as "pathogen-like" particles by surface coating with mannose. MOF morphology, cellular uptake kinetics, and endocytic mechanisms in 3D4/21 alveolar macrophages were characterized. RESULTS: MIL-88A(Fe) is rod-shape (aspect ratio 1:5) with a long-axis size of 3628 ± 573 nm and MIL-100(Fe) is spherical with diameter of 103.9 ± 7.2 nm. Cellular uptake kinetics of MOFs showed that MIL-100(Fe) nanoparticles were internalized at a faster rate and higher extent compared to MIL-88A(Fe) microparticles. Mannosylation did not improve the uptake of MIL-100(Fe) particles, whereas it highly increased MIL-88A(Fe) cellular uptake and number of cells involved in internalization. Cell uptake inhibition studies indicated that macropinocytosis/phagocytosis was the main endocytic pathway for internalization of MOFs. Accumulation of MOF particles in acidic compartments was clearly observed. CONCLUSIONS: The successfully synthesized "pathogen-like" particles provide a novel application of MOF-based particles as biomimetic delivery system for intramacrophagic-based infections.

Broadband main OPCPA amplifier at 808 nm wavelength in high deuterated DKDP crystals.

The optical aperture of ultrashort extreme intensity laser facilities, which reach 10 PW, will be beyond several hundred millimeters. DKDP is by now the only nonlinear crystal that can be grown to such diameter and used in the main optical parametric chirped-pulse amplification (OPCPA) amplifier of such a laser system. Here, at the signal wavelength of 808 nm for the first time, we experimentally present a broadband OPCPA system that consists of a pre-amplifier in BBO crystals and a main OPCPA amplifier in two 95% deuterated DKDP crystals. The final amplified spectrum bandwidth exceeds 50 nm, and a compressed pulse duration of 27 fs has been measured. The conversion efficiency of the main OPCPA amplifier reached 24%, and a net signal gain of 13 was obtained. For the high energy OPCPA amplifier, the influence due to partial absorption on the idler pulses in DKDP crystal is theoretically analyzed. The results indicate the potential utilization of high deuterated DKDP for the main OPCPA amplifiers in a multi-petawatt laser system at 808 nm wavelength.

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma.

The BTK inhibitor ibrutinib has demonstrated a remarkable therapeutic effect in mantle cell lymphoma (MCL). However, approximately one-third of patients do not respond to the drug initially. To identify the mechanisms underlying primary ibrutinib resistance in MCL, we analyzed the transcriptome changes in ibrutinib-sensitive and ibrutinib-resistant cell lines on ibrutinib treatment. We found that MYC gene signature was suppressed by ibrutinib in sensitive but not resistant cell lines. We demonstrated that MYC gene was structurally abnormal and MYC protein was overexpressed in MCL cells. Further, MYC knockdown with RNA interference inhibited cell growth in ibrutinib-sensitive as well as ibrutinib-resistant cells. We explored the possibility of inhibiting MYC through HSP90 inhibition. The chaperon protein is overexpressed in both cell lines and primary MCL cells from the patients. We demonstrated that MYC is a bona fide client of HSP90 in the context of MCL by both immunoprecipitation and chemical precipitation. Furthermore, inhibition of HSP90 using PU-H71 induced apoptosis and caused cell cycle arrest. PU-H71 also demonstrates strong and relatively specific inhibition of the MYC transcriptional program compared with other oncogenic pathways. In a MCL patient-derived xenograft model, the HSP90 inhibitor retards tumor growth and prolongs survival. Last, we showed that PU-H71 induced apoptosis and downregulated MYC protein in MCL cells derived from patients who were clinically resistant to ibrutinib. In conclusion, MYC activity underlies intrinsic resistance to ibrutinib in MCL. As a client protein of HSP90, MYC can be inhibited via PU-H71 to overcome primary ibrutinib resistance.

Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment.

Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases. We demonstrated that cerdulatinib delivered potent tumor inhibition in 60 primary CLL patient samples, especially in those with poor prognostic indicators. Importantly, cerdulatinib, but not ibrutinib, is able to overcome the support of microenvironment and induces CLL cell death at clinically achievable concentrations. Notably, cerdulatinib blocked proliferation of ibrutinib-resistant primary CLL cells and of BTKC481S-transfected/ibrutinib-resistant lymphoma cells. These anti-tumor effects are well correlated with the inhibition of BCR and JAK-STAT signaling and downstream inhibition of the functions of AKT, ERK and NFκB. Collectively, our results show that simultaneous targeting of BCR and JAK-STAT pathways is a more effective strategy relative to single BTK inhibition.

Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL.

Ibrutinib has generated remarkable responses in patients with chronic lymphocytic leukemia (CLL), including those with an unfavorable cytogenetic profile. However, patients develop resistance, with poor outcomes and no established treatment options. Mutations in BTK and PLCG2 have emerged as main mechanisms of drug resistance, but not all patients carry these mutations. Further understanding of mechanisms of resistance is urgently needed and will support rational development of new therapeutic strategies. To that end, we characterized the genomic profiles of serial samples from 9 patients with ibrutinib-relapsed disease, including 6 who had Richter transformation. Mutations, indels, copy-number aberrations, and loss of heterozygosity were assessed using next-generation sequencing and single-nucleotide polymorphism array. We found that 18p deletion (del(18p)), together with del(17p)/TP53 mutations, was present in 5 of 9 patients before ibrutinib therapy. In addition to BTKC481 , we identified BTKT316A , a structurally novel mutation located in the SH2 domain of BTK. Minor BTK clones with low allele frequencies were captured in addition to major BTK clones. Although TP53 loss predisposes patients for relapse, clone size of TP53 loss may diminish during disease progression while mutant BTK clone expands. In patients who had Richter transformation, we found that the transformed cells were clonal descendants of circulating leukemia cells but continued to undergo evolution and drifts. Surprisingly, transformed lymphoma cells in tissue may acquire a different BTK mutation from that in the CLL leukemia cells. Collectively, these results provide insights into clonal evolution underlying ibrutinib relapse and prompt further investigation on genomic abnormalities that have clinical application potential.

Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL.

Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. Thus far, all described BTK mutations are located in its kinase domain and mutations outside this domain have never been described. Herein, we report a patient whose CLL progressed, was salvaged with ibrutinib and then relapsed. Serial analysis of samples throughout patient's clinical course identified a structurally novel mutation (BTKT316A) in the SH2 domain, but not kinase domain, of Bruton tyrosine kinase which was associated with disease relapse. Functionally, cells carrying BTKT316A show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTKC481S. Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.

Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib.

In chronic lymphocytic leukemia (CLL), patients with unmutated immunoglobulin heavy chain variable region gene (UM-CLL) have worse outcomes than mutated CLL (M-CLL) following chemotherapy or chemoimmunotherapy. However, in the era of BCR-targeted therapies, the adverse prognostic impact of unmutated IGHV seems to be diminishing, and there are clinical datasets showing unexpected improved responses in UM-CLL. We investigated the biological differences of BTK activity between these subgroups and further compared the impact of ibrutinib on molecular and cellular behaviors. Immunoblotting analysis revealed that phosphorylated active BTK is significantly higher in UM-CLL. Moreover, UM-CLL, compared to M-CLL, displayed a much higher proliferative capacity that was correlated with higher phospho-BTK and greater sensitivity to ibrutinib. In addition, BTK depletion with siRNA led to a more prominent reduction in the proliferation of UM-CLL, suggesting that elevated BTK activity is responsible for increased cell proliferation. Further, cell signaling activity by multiple measurements was consistently higher in UM-CLL accompanied by a higher sensitivity to ibrutinib. These studies link UM-CLL to elevated BCR signaling, heightened BTK-dependent cell proliferation and increased sensitivity to ibrutinib. The prognostic significance of IGHV mutation should be reevaluated in the era of new therapies targeting BCR signaling.

Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma.

B-cell receptor (BCR) and JAK/STAT pathways play critical roles in diffuse large B-cell lymphoma (DLBCL). Herein, we investigated the anti-lymphoma activity of cerdulatinib, a novel compound that dually targets SYK and JAK/STAT pathways. On a tissue microarray of 62 primary DLBCL tumors, 58% expressed either phosphorylated SYK or STAT3 or both. SYK and STAT3 are also phosphorylated in a panel of eleven DLBCL cell lines although ABC and GCB subtypes exhibited different JAK/STAT and BCR signaling profiles. In both ABC and GCB cell lines, cerdulatinib induced apoptosis that was associated with caspase-3 and PARP cleavage. The compound also blocked G1/S transition and caused cell cycle arrest, accompanied by inhibition of RB phosphorylation and down-regulation of cyclin E. Phosphorylation of BCR components and STAT3 was sensitive to cerdulatinib in both ABC and GCB cell lines under stimulated conditions. Importantly, JAK/STAT and BCR signaling can be blocked by cerdulatinib in primary GCB and non-GCB DLBCL tumor cells that were accompanied by cell death. Our work provides mechanistic insights into the actions of cerdulatinib, suggesting that the drug has a broad anti-tumor activity in both ABC and GCB DLBCL, at least in part by inhibiting SYK and JAK pathways.

Characterization of ibrutinib-sensitive and -resistant mantle lymphoma cells.

Ibrutinib inhibits Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated a remarkable response rate. However, approximately one-third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary MCL cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher BTK activity than normal B cells and MCL cells show differential sensitivity to BTK inhibition. Genetic knockdown of BTK inhibits the growth, survival and proliferation of ibrutinib-sensitive but not resistant MCL cell lines, suggesting that ibrutinib acts through BTK to produce its anti-tumour activities. Interestingly, inhibition of ERK1/2 and AKT, but not BTK phosphorylation per se, correlates well with cellular response to BTK inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to BTK inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach.