ORCID Profile
0000-0002-6238-4092
Current Organisations
Walter and Eliza Hall Institute of Medical Research
,
University of Melbourne
,
Royal Australasian College of Physicians
,
Peter MacCallum Cancer Institute
,
Royal Melbourne Hospital
,
Royal College of Pathologists of Australasia
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Publications
Proapoptotic Bak and Bax guard against fatal systemic and organ-specific autoimmune disease
Publisher: Proceedings of the National Academy of Sciences
Date: 24-01-2013
Abstract: Dysregulation of the “intrinsic” apoptotic pathway is associated with the development of cancer and autoimmune disease. Bak and Bax are two proapoptotic members of the Bcl-2 protein family with overlapping, essential roles in the intrinsic apoptotic pathway. Their activity is critical for the control of cell survival during lymphocyte development and homeostasis, best demonstrated by defects in thymic T-cell differentiation and peripheral lymphoid homeostasis caused by their combined loss. Because most bak −/− bax −/− mice die perinatally, the roles of Bax and Bak in immunological tolerance and prevention of autoimmune disease remain unclear. We show that mice reconstituted with a Bak/Bax doubly deficient hematopoietic compartment develop a fatal systemic lupus erythematosus-like autoimmune disease characterized by hypergammaglobulinemia, autoantibodies, lymphadenopathy, glomerulonephritis, and vasculitis. Importantly, these mice also develop a multiorgan autoimmune disease with autoantibodies against most solid glandular structures and evidence of glandular atrophy and necrotizing vasculitis. Interestingly, similar albeit less severe pathology was observed in mice containing a hematopoietic compartment deficient for only Bak, a phenotype reminiscent of the disease seen in patients with point mutations in BAK . These studies demonstrate a critical role for Bak and an ancillary role for Bax in safeguarding immunological tolerance and prevention of autoimmune disease. This suggests that direct activators of the intrinsic apoptotic pathway, such as BH3 mimetics, may be useful for treatment of erse autoimmune diseases.
Go with the flow for monitoring response in myeloma with minimal residual disease
Publisher: Informa UK Limited
Date: 2008
Feasibility of Enhancing Parenting in Cancer, a psychoeducational intervention for communicating with children about parental cancer
Publisher: Wiley
Date: 06-03-2021
DOI: 10.1002/PON.5655
Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis
Publisher: Springer Science and Business Media LLC
Date: 24-02-2016
DOI: 10.1038/NMICROBIOL.2015.34
Abstract: Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease(1). Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1. Consequently, a single dose of a BCL-XL-targeted BH3-mimetic therapy, or myeloid cell-restricted deletion of BCL-XL, limits Legionella replication and prevents lethal lung infections in mice. These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires' and other diseases caused by intracellular microbes.
Altered B-lymphopoiesis in mice with deregulated thrombopoietin signaling
Publisher: Springer Science and Business Media LLC
Date: 02-11-2017
DOI: 10.1038/S41598-017-15023-2
Abstract: Thrombopoietin (TPO) is the master cytokine regulator of megakaryopoiesis. In addition to regulation of megakaryocyte and platelet number, TPO is important for maintaining proper hematopoietic stem cell (HSC) function. It was previously shown that a number of lymphoid genes were upregulated in HSCs from Tpo −/− mice. We investigated if absent or enhanced TPO signaling would influence normal B-lymphopoiesis. Absent TPO signaling in Mpl −/− mice led to enrichment of a common lymphoid progenitor (CLP) signature in multipotential lineage-negative Sca-1 + c-Kit + (LSK) cells and an increase in CLP formation. Moreover, Mpl −/− mice exhibited increased numbers of PreB2 and immature B-cells in bone marrow and spleen, with an increased proportion of B-lymphoid cells in the G1 phase of the cell cycle. Conversely, elevated TPO signaling in Tpo Tg mice was associated with reduced B-lymphopoiesis. Although at steady state, peripheral blood lymphocyte counts were normal in both models, Mpl −/− Eµ- myc mice showed an enhanced preneoplastic phase with increased numbers of splenic PreB2 and immature B-cells, a reduced quiescent fraction, and augmented blood lymphocyte counts. Thus, although Mpl is not expressed on lymphoid cells, TPO signaling may indirectly influence B-lymphopoiesis and the preneoplastic state in Myc -driven B-cell lymphomagenesis by lineage priming in multipotential progenitor cells.
Maternal breast cancer and communicating with children: A qualitative exploration of what resources mothers want and what health professionals provide
Publisher: Hindawi Limited
Date: 11-2019
DOI: 10.1111/ECC.13153
Abstract: To explore the communication and resource needs of mothers diagnosed with breast cancer treated with curative intent in communicating with their young children and to identify gaps in the resources and support provided to these women. Data were collected via semi-structured telephone interviews from 13 mothers who were diagnosed with breast cancer while parenting a young child (age 3-12 years), and 10 health professionals in Victoria, Australia. Data were analysed qualitatively using the Framework Method. Mothers and health professionals prioritised communication with children about the cancer diagnosis however, health professionals and mothers differed in their views of parents' communication needs both in terms of the nature of the support/information needed and the delivery of this support/information. Mothers wanted easily accessible resources that were both instructive and practical. Mothers also emphasised quality over quantity of support. Health professionals were mostly aware of mothers' needs, however, emphasised less instructive support and information. This study highlights the need for improved coordination and tailoring of psychosocial resources and supports for these parents and families communicating about a cancer diagnosis with their young children.
Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function
Publisher: American Society of Hematology
Date: 16-07-2009
DOI: 10.1182/BLOOD-2009-01-200345
Abstract: Procoagulant platelets exhibit hallmark features of apoptotic cells, including membrane blebbing, microvesiculation, and phosphatidylserine (PS) exposure. Although platelets possess many well-known apoptotic regulators, their role in regulating the procoagulant function of platelets is unclear. To clarify this, we investigated the consequence of removing the essential mediators of apoptosis, Bak and Bax, or directly inducing apoptosis with the BH3 mimetic compound ABT-737. Treatment of platelets with ABT-737 triggered PS exposure and a marked increase in thrombin generation in vitro. This increase in procoagulant function was Bak/Bax- and caspase-dependent, but it was unaffected by inhibitors of platelet activation or by chelating extracellular calcium. In contrast, agonist-induced platelet procoagulant function was unchanged in Bak−/−Bax−/− or caspase inhibitor–treated platelets, but it was completely eliminated by extracellular calcium chelators or inhibitors of platelet activation. These studies show the existence of 2 distinct pathways regulating the procoagulant function of platelets.
No Benefit of Rituximab in Primary Central Nervous System Lymphoma Patients: Results of the Randomised Phase III HOVON 105 / ALLG NHL 24 Intergroup Study
Publisher: Elsevier BV
Date: 2018
DOI: 10.2139/SSRN.3223133
Breaking Good—Improving Access to Primary Care Based Long Term Follow Up for Allograft Survivors
Publisher: Elsevier BV
Date: 03-2018
Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor-mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of type 1 diabetes
Publisher: Springer Science and Business Media LLC
Date: 10-10-2014
DOI: 10.1007/S00125-014-3407-5
Abstract: Type 1 diabetes results from T cell-mediated destruction of pancreatic beta cells. The mechanisms of beta cell destruction in vivo, however, remain unclear. We aimed to test the relative roles of the main cell death pathways: apoptosis, necrosis and necroptosis, in beta cell death in the development of CD4(+) T cell-mediated autoimmune diabetes. We altered expression levels of critical cell death proteins in mouse islets and tested their ability to survive CD4(+) T cell-mediated attack using an in vivo graft model. Loss of the B cell leukaemia/lymphoma 2 (BCL-2) homology domain 3-only proteins BIM, PUMA or BID did not protect beta cells from this death. Overexpression of the anti-apoptotic protein BCL-2 or combined deficiency of the pro-apoptotic multi-BCL2 homology domain proteins BAX and BAK also failed to prevent beta cell destruction. Furthermore, loss of function of the death receptor Fas or its essential downstream signalling molecule Fas-associated death domain (FADD) in islets was also not protective. Using electron microscopy we observed that dying beta cells showed features of necrosis. However, islets deficient in receptor-interacting serine/threonine protein kinase 3 (RIPK3), a critical initiator of necroptosis, were still normally susceptible to CD4(+) T cell-mediated destruction. Remarkably, simultaneous inhibition of apoptosis and necroptosis by combining loss of RIPK3 and overexpression of BCL-2 in islets did not protect them against immune attack either. Collectively, our data indicate that beta cells die by necrosis in autoimmune diabetes and that the programmed cell death pathways apoptosis and necroptosis are both dispensable for this process.
Diagnosis within a Diagnosis
Publisher: Science and Education Publishing Co., Ltd.
Date: 28-08-2017
DOI: 10.12691/NOVN-2-1-1
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
Publisher: Springer Science and Business Media LLC
Date: 06-01-2013
DOI: 10.1038/NM.3048
Abstract: Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.
Spontaneous rupture of the spleen as the presenting feature of the blastoid variant of mantle cell lymphoma
Publisher: Wiley
Date: 23-07-2003
DOI: 10.1046/J.1365-2257.2003.00522.X
Abstract: Spontaneous splenic rupture is rare, and particularly so as the initial presentation of a lymphoproliferative disorder. Although rare cases of splenic rupture have been reported in mantle cell lymphoma there has not been a report of the blastoid variant presenting in this manner. We report such a case in a 64-year-old man.
Strongyloides hyperinfection: a preventable complication of immunosuppression
Publisher: Wiley
Date: 26-05-2022
DOI: 10.5694/MJA2.51561
Proinflammatory microenvironment promotes lymphoma progression in mice with high megakaryocyte and TPO levels
Publisher: American Society of Hematology
Date: 14-04-2023
DOI: 10.1182/BLOODADVANCES.2022007849
Abstract: Platelets have been shown to enhance the survival of lymphoma cell lines, but it is unclear if they play a role in lymphoma. Here we investigate a potential role for platelets and/or megakaryocytes in Eµ-myc lymphoma progression. Eµ-myc tumour cells were transplanted into recipient wild-type control mice, Mpl-/-, or TpoTg mice, which exhibit normal, low and high platelet and megakaryocyte counts, respectively. Transplanted TpoTg mice exhibited enhanced lymphoma progression with increased WBC counts, spleen and lymph node weights and enhanced liver infiltration when compared to wild-type. Conversely, tumour bearing Mpl-/- mice presented with reduced WBC counts, lymph node weights and less liver infiltration when compared to wild-type. Utilizing a Mpl-deficient thrombocytopenic immunocompromised mouse model, our results were confirmed with the human NHL GRANTA cell line. While we found that platelets and platelet released molecules supported Eµ-myc tumour cell survival in vitro, pharmacological inhibition of platelet function or anticoagulation in Eµ-myc transplanted wild-type mice did not improve disease outcome. Furthermore, transient platelet depletion or sustained Bcl-xL dependent thrombocytopenia did not alter lymphoma progression. Cytokine analysis of the bone marrow fluid microenvironment revealed increased levels of the proinflammatory molecule interleukin (IL)-1 in TpoTg mice, whereas levels were lowered in Mpl-/- mice. Moreover, RNA sequencing of blood-resident Eµ-myclymphoma cells from TpoTgand wild-type mice after tumour transplant revealed upregulation of hallmark gene sets associated with inflammatory response in TpoTg mice. We propose that a pro-inflammatory microenvironment in TpoTgmice promoted lymphoma progression.
Favourable outcomes with an initial active surveillance strategy for asymptomatic radiation-induced meningiomas in long-term survivors of paediatric and young adult malignancies
Publisher: Elsevier BV
Date: 12-2023
Evaluation of the Impact of Magnetic Resonance Imaging with Susceptibility-weighted Imaging for Screening and Surveillance of Radiation-induced Cavernomas in Long-term Survivors of Malignancy
Publisher: Elsevier BV
Date: 10-2021
The immunophenotype of acute myeloid leukemia: Is there a relationship with prognosis?
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.BLRE.2005.08.002
Abstract: Immunophenotyping of acute myeloid leukemia has controversial implications with regards to prognosis. Many associations have been described between in idual antigen expression on myeloid blasts and prognosis, however few are consistent. Markers with a consistent prognostic association that have been demonstrated in more than one study have been CD13, CD14, and CD15. The association of the expression of CD11b with poor prognosis appears definite, as does CD7 expression. When compared with the expression of a single antigen, a pattern of antigen expression is likely to have a more significant relationship to prognosis. This is exemplified by the panmyeloid phenotype (expression of 5 myeloid antigens) which appears to be associated with a good prognosis and may differentiate a subgroup within an otherwise intermediate prognosis group of patients. Further analysis with the inclusion of novel antibodies and the combination of multiple antibodies to create further subgroups such as the panmyeloid phenotype will continue to enhance knowledge in this area.
The Australia and New Zealand Cardio-Oncology Registry: evaluation of chemotherapy-related cardiotoxicity in a national cohort of paediatric cancer patients
Publisher: Wiley
Date: 02-2021
DOI: 10.1111/IMJ.14719
Abstract: Cancer therapy related cardiac dysfunction (CTRCD) is an area of increasing focus, particularly during the survivorship period, for paediatric, adolescent and adult cancer survivors. With the advent of immunotherapy and targeted therapy, there is a new set of mechanisms from which paediatric and young adult patients with cancer may suffer cardiovascular injury. Furthermore, cardiovascular disease is the leading cause of morbidity and mortality in the survivorship period. The recently established Australian Cardio-Oncology Registry is the largest and only population-based cardiotoxicity database of paediatric and adolescent and young adult oncology patients in the world, and the first paediatric registry that will document cardiotoxicity caused by chemotherapy and novel targeted therapies using a prospective approach. The database is designed for comprehensive data collection and evaluation of the Australian practice in terms of diagnosis and management of CTRCD. Using the Australian Cardio-Oncology Registry critical clinical information will be collected regarding predisposing factors for the development of CTRCD, the rate of subclinical left ventricular dysfunction and transition to overt heart failure, further research into protectant molecules against cardiac dysfunction and aid in the discovery of which genetic variants predispose to CTRCD. A health economic arm of the study will assess the cost/benefit of both the registry and cardio-oncology clinical implementation. Finally, an imaging arm will establish if exercise cardiac magnetic resonance imaging and VO
Bcl-xL–inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets
Publisher: American Society of Hematology
Date: 11-08-2011
DOI: 10.1182/BLOOD-2011-04-347849
Abstract: BH3 mimetics are a new class of proapo-ptotic anticancer agents that have shown considerable promise in preclinical animal models and early-stage human trials. These agents act by inhibiting the pro-survival function of one or more Bcl-2–related proteins. Agents that inhibit Bcl-xL induce rapid platelet death that leads to thrombocytopenia however, their impact on the function of residual circulating platelets remains unclear. In this study, we demonstrate that the BH3 mimetics, ABT-737 or ABT-263, induce a time- and dose-dependent decrease in platelet adhesive function that correlates with ectodomain shedding of the major platelet adhesion receptors, glycoprotein Ibα and glycoprotein VI, and functional down-regulation of integrin αIIbβ3. Analysis of platelets from mice treated with higher doses of BH3 mimetics revealed the presence of a subpopulation of circulating platelets undergoing cell death that have impaired activation responses to soluble agonists. Functional analysis of platelets by intravital microscopy revealed a time-dependent defect in platelet aggregation at sites of vascular injury that correlated with an increase in tail bleeding time. Overall, these studies demonstrate that Bcl-xL–inhibitory BH3 mimetics not only induce thrombocytopenia but also a transient thrombocytopathy that can undermine the hemostatic function of platelets.
Comparison of gene expression and flow cytometry for immune profiling in chronic lymphocytic leukaemia
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.JIM.2018.09.013
Abstract: Understanding how cancer and cancer therapies affect the immune system is integral to the rational application of immunotherapies. Flow cytometry is the gold standard method of peripheral blood immune cell profiling. However, the requirement for viable cells can limit its applicability, especially in studies of retrospective clinical cohorts. We aimed to determine if gene expression, analysed using the NanoString platform, could be used to quantify the immune populations present in cryopreserved peripheral blood mononuclear cell (PBMC) s les from patients with chronic lymphocytic leukaemia. Cell abundance scores derived from gene expression analysis were significantly correlated with the population frequency quantified by flow cytometry for all subsets analysed, including T cells, NK cells and Monocytes. This study demonstrates that gene expression analysis can be applied to cryopreserved PBMC and provides a concordant and complementary understanding of the immune profile to flow cytometry.
Disseminated toxoplasmosis after allogeneic stem cell transplantation in a seronegative recipient
Publisher: Wiley
Date: 20-12-2013
DOI: 10.1111/TID.12043
Abstract: Toxoplasmosis is increasingly diagnosed after hematopoietic stem cell transplantation (HSCT) and is associated with considerable morbidity and mortality. In the majority of cases, reactivation of latent disease secondary to impaired cellular and humoral immunity after HSCT is believed to be the main pathogenetic mechanism. Hence, primary toxoplasmosis is rarely considered in the differential diagnosis of infections after HSCT in a recipient who is seronegative for Toxoplasma gondii pre-transplant. We herein report a seronegative patient with acute T-cell lymphoblastic leukemia, who developed primary disseminated toxoplasmosis 5 months after HSCT from a seronegative unrelated donor. A review of all reported cases of primary toxoplasmosis after HSCT revealed significantly increased morbidity and mortality. Patients with negative pre-transplant Toxoplasma serology should therefore be considered at risk for toxoplasmosis after allogeneic HSCT. Possible prevention and monitoring strategies for seronegative recipients are reviewed and discussed in detail.
Capturing the lived experiences of women with lymphoma in pregnancy: a qualitative study
Publisher: Informa UK Limited
Date: 24-11-2022
DOI: 10.1080/10428194.2022.2148376
Abstract: Lymphoma in pregnancy is a rare and challenging diagnosis that complicates ∼1:6000 pregnancies posing a series of unique therapeutic, social, and ethical challenges to the patient, her family, and the medical professionals involved. These difficulties are compounded by the paucity of real-world data on the management of LIP, and a lack of relevant support systems for women in this setting. We conducted a retrospective multicenter qualitative study, interviewing women aged ≥18 years of age diagnosed with Hodgkin (HL) or non-Hodgkin lymphoma (NHL) during pregnancy or within 12 months postpartum, between 1 January 2009 and 31 December 2020 from 13 Australasian sites. Semi-structured telephone interviews were conducted, recorded, and analyzed using QSR Int NVivo 12 Pro (March 2020, USA) to quantify salient themes. Of the 32 women interviewed, 20 (63%) were diagnosed during pregnancy (16, 34, and 13% in the 1st, 2nd, and 3rd trimesters, respectively), while 12 (37%) were diagnosed post-partum. Women recalled that their chief concerns at diagnosis were the welfare of their child (
Why did we fail? Challenges recruiting parents with cancer into a psycho‐educational support program
Publisher: Wiley
Date: 31-10-2019
DOI: 10.1002/PON.5226
Marked eosinophilia with abnormal basophilic granules in acute graft-versus-host disease post-allogeneic haemopoietic stem cell transplant for acute myeloid leukaemia without CBFB-MYH11 mutation
Publisher: Wiley
Date: 19-12-2013
DOI: 10.1111/EJH.12032
BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs.
Publisher: Proceedings of the National Academy of Sciences
Date: 06-2010
Abstract: Death by apoptosis shapes tissue homeostasis. Apoptotic mechanisms are so universal that harnessing them for tailored immune intervention would seem challenging however, the range and different expression levels of pro- and anti-apoptotic molecules among tissues offer hope that targeting only a subset of such molecules may be therapeutically useful. We examined the effects of the drug ABT-737, a mimetic of the killer BH3 domain of the Bcl-2 family of proteins that induces apoptosis by antagonizing Bcl-2, Bcl-X L , and Bcl-W (but not Mcl-1 and A1), on the mouse immune system. Treatment with ABT-737 reduced the numbers of selected lymphocyte and dendritic cell subpopulations, most markedly in lymph nodes. It inhibited the persistence of memory B cells, the establishment of newly arising bone marrow plasma cells, and the induction of a cytotoxic T cell response. Preexisting plasma cells and germinal centers were unaffected. Notably, ABT-737 was sufficiently immunomodulatory to allow long-term survival of pancreatic allografts, reversing established diabetes in this model. These results provide an insight into the selective mechanisms of immune cell survival and how this selectivity avails a different strategy for immune modulation.
Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial
Publisher: American Society of Hematology
Date: 02-05-2019
DOI: 10.1182/BLOOD-2018-11-880526
Abstract: Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations) complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5% n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8 higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.
Open-Label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma
Publisher: Informa UK Limited
Date: 16-06-2020
Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets
Publisher: Rockefeller University Press
Date: 12-09-2011
DOI: 10.1084/JEM.20110750
Abstract: It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic- or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax. We found that platelet production was unperturbed. In stark contrast, deletion of the prosurvival protein Bcl-xL resulted in megakaryocyte apoptosis and a failure of platelet shedding. This could be rescued by deletion of Bak and Bax. We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak−/− Bax−/− hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.
Low adhesion receptor levels on circulating platelets in patients with lymphoproliferative diseases before receiving Navitoclax (ABT-263)
Publisher: American Society of Hematology
Date: 21-02-2013
Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients: results from a randomised phase III study
Publisher: Elsevier BV
Date: 08-2020
In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas
Publisher: Proceedings of the National Academy of Sciences
Date: 18-11-2008
Abstract: Deregulated Myc expression drives many human cancers, including Burkitt's lymphoma and a highly aggressive subset of diffuse large cell lymphomas. Myc-driven tumors often display resistance to chemotherapeutics because of acquisition of mutations that impair the apoptosis pathway regulated by the Bcl-2 protein family. Given the need to identify new therapies for such lymphomas, we have evaluated the efficacy of ABT-737, a small molecule that mimics the action of the BH3-only proteins, natural antagonists of the prosurvival Bcl-2 proteins. ABT-737 selectively targets certain prosurvival proteins (Bcl-2, Bcl-x L , and Bcl-w) but not others (Mcl-1 and A1). We treated mice transplanted with lymphomas derived either from Eμ- myc transgenic mice or Eμ- myc mice that also expressed an Eμ- bcl -2 transgene. As a single agent, ABT-737 significantly prolonged the survival of mice transplanted with the myc / bcl -2 lymphomas but was ineffective for the myc lymphomas, probably because of the relatively higher Mcl-1 levels found in the latter. Strikingly, when combined with low-dose cyclophosphamide, ABT-737 produced sustained disease-free survival of all animals transplanted with two of three myc / bcl -2 lymphomas tested. The combination therapy was also more effective against some myc lymphomas than treatment with either agent alone. Our data suggest that antagonism of Bcl-2 with small organic compounds is an attractive approach to enhance the efficacy of conventional therapy for the treatment of Myc-driven lymphomas that over-express this prosurvival molecule.
The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia
Publisher: Springer Science and Business Media LLC
Date: 30-07-2009
DOI: 10.1038/LEU.2009.151
Abstract: As chronic lymphocytic leukemia (CLL) is characterized by overexpression of pro-survival BCL2, compounds that mimic its physiological antagonists, the BH3-only proteins, may have a role in treatment of this disease. ABT-737 is a BH3 mimetic compound that selectively targets BCL2 and BCLX(L). In the present work, we report that ABT-737 is highly effective (LC(50)<50 nM) as a single agent against most (21/30) primary CLL s les, but that a sizable minority is relatively insensitive. In vitro sensitivity to ABT-737 could not be simply predicted by the patients' clinical features, including response to prior therapy or known prognostic markers (CD38 expression, 17p deletion), or the relative expression of BCL2 family proteins (BCL2, MCL1, BAX, BIM). Strikingly, co-incubation with cytotoxic agents (dexamethasone, etoposide, fludarabine, doxorubicin) sensitized most CLL s les to ABT-737, but this could not be predicted by responses to either ABT-737 or the cytotoxic agent alone. Of 17 s les least sensitive to ABT-737, 13 were sensitized by co-treatment with at least one cytotoxic agent. These data indicate that combination of ABT-737 with a second anti-leukemic agent would improve response rates and suggest a potential role for combination therapies that include BH3 mimetics for the treatment of this disease.
Study protocol for Enhancing Parenting In Cancer (EPIC): development and evaluation of a brief psycho-educational intervention to support parents with cancer who have young children
Publisher: Springer Science and Business Media LLC
Date: 12-2017
Nephrotic syndrome as a complication of chronic graft-versus-host disease after allogeneic haemopoietic stem cell transplantation
Publisher: Wiley
Date: 06-2016
DOI: 10.1111/IMJ.13098
Abstract: Nephrotic syndrome (NS) is a rare complication following allogeneic haemopoietic stem cell transplantation (allo-HSCT), with limited current understanding of its pathogenesis. Here, we describe four cases of NS following allo-HSCT diagnosed at our institutions to identify key clinical and pathological features. In addition, a PubMed search was performed to identify existing reports that were pooled together with our cases for analysis. NS occurred as a late complication following allo-HSCT, with median onset 19.5 months after transplant (range: 3.9-84 months). The most common histopathology observed was membranous nephropathy however, cases of minimal change disease have also been reported. There is a high incidence of prior extra-renal graft-versus-host disease (GvHD), with all four of our cases and 82% of published cases having prior GvHD. Glucocorticosteroids are the most common treatment, with variable degrees of response. Responses to immunosuppression with calcineurin inhibitors and rituximab have been described in steroid-refractory cases.
Cancer during pregnancy
Publisher: Hindawi Limited
Date: 10-02-2021
DOI: 10.1111/ECC.13425
Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence
Publisher: Springer Science and Business Media LLC
Date: 22-11-2021
DOI: 10.1186/S12967-021-03136-2
Abstract: The development of Bruton’s tyrosine kinase inhibitors (BTKi) for the treatment of chronic lymphocytic leukaemia (CLL) has provided a highly effective and relatively non-toxic alternative to conventional chemotherapy. Some studies have shown that BTKi can also lead to improvements in T cell immunity in patients despite in vitro analyses suggesting an immunosuppressive effect of BTKi on T cell function. In this study, we examined both the in vitro effect and long-term in vivo effect of two clinically available BTKi, ibrutinib and zanubrutinib. Additional in vitro assessments were undertaken for a third BTKi, acalabrutinib. Immune subset phenotyping, cytokine secretion, T cell degranulation and proliferation assays were performed on peripheral blood mononuclear cells isolated from untreated CLL patients, and CLL patients on long-term ( 12 months) BTKi treatment. Similar to prior studies we observed that long-term BTKi treatment normalises lymphocyte subset frequency and reduces PD-1 expression on T cells. We also observed that T cells from patients taken prior to BTKi therapy showed an abnormal hyper-proliferation pattern typical of senescent T cells, which was normalised by long-term BTKi treatment. Furthermore, BTKi therapy resulted in reduced expression of the T cell exhaustion markers PD-1, TIM3 and LAG3 in late generations of T cells undergoing proliferation. Collectively, these findings indicate that there are critical differences between the in vitro effects of BTKi on T cell function and the effects derived from long-term BTKi exposure in vivo. Overall long-term exposure to BTKi, and particularly ibrutinib, resulted in improved T cell fitness in part due to suppressing the abnormal hyper-proliferation of CLL T cells and the associated development of T cell senescence.
Older recipient age is paradoxically associated with a lower incidence of chronic GVHD in Thymoglobulin recipients: a retrospective study exploring risk factors for GVHD in allogeneic transplantation
Publisher: Springer Science and Business Media LLC
Date: 02-02-2015
DOI: 10.1038/BMT.2014.313
Abstract: Thymoglobulin (TG) given with conditioning for allogeneic haematopoietic SCT (alloHSCT) is effective in reducing the risk of acute and chronic GVHD (cGVHD). Whether conventional risk factors for GVHD apply to TG-conditioned alloHSCT is unknown. We retrospectively studied 356 adults from three centres who received TG 4.5 mg/kg prior to alloHSCT for haematologic malignancy. Donors were unrelated in 64%. At 3 years, OS was 61% (95% confidence interval (CI) 55-67%), cumulative incidence of relapse was 28% (95% CI 23-33%) and non-relapse mortality was 19% (14-24%). The cumulative incidences of grade 2-4, and grade 3-4 acute GVHD were 23% (95% CI 19-28%) and 10% (95% CI 6-13%), respectively. The cumulative incidence of cGVHD requiring systemic immunosuppression (cGVHD-IS) at 3 years was 32% (95% CI 27-37%). On multivariate analysis, counterintuitively, recipient age over 40 was associated with a significantly decreased risk of cGVHD-IS (P=0.001). We report for the first time a paradoxical association of older age with reduced cGVHD in TG recipients, and conclude that traditional risk factors for GVHD may behave differently in the context of pre-transplant TG.
Mitochondrial apoptosis is dispensable for NLRP 3 inflammasome activation but non‐apoptotic caspase‐8 is required for inflammasome priming
Publisher: EMBO
Date: 02-07-2014
Abstract: A current paradigm proposes that mitochondrial damage is a critical determinant of NLRP 3 inflammasome activation. Here, we genetically assess whether mitochondrial signalling represents a unified mechanism to explain how NLRP 3 is activated by ergent stimuli. Neither co‐deletion of the essential executioners of mitochondrial apoptosis BAK and BAX , nor removal of the mitochondrial permeability transition pore component cyclophilin D, nor loss of the mitophagy regulator Parkin, nor deficiency in MAVS affects NLRP 3 inflammasome function. In contrast, caspase‐8, a caspase essential for death‐receptor‐mediated apoptosis, is required for efficient Toll‐like‐receptor‐induced inflammasome priming and cytokine production. Collectively, these results demonstrate that mitochondrial apoptosis is not required for NLRP 3 activation, and highlight an important non‐apoptotic role for caspase‐8 in regulating inflammasome activation and pro‐inflammatory cytokine levels.
The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized
Publisher: Elsevier BV
Date: 11-2006
Programmed Anuclear Cell Death Delimits Platelet Life Span
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.CELL.2007.01.037
Abstract: Platelets are anuclear cytoplasmic fragments essential for blood clotting and wound healing. Despite much speculation, the factors determining their life span in the circulation are unknown. We show here that an intrinsic program for apoptosis controls platelet survival and dictates their life span. Pro-survival Bcl-x(L) constrains the pro-apoptotic activity of Bak to maintain platelet survival, but as Bcl-x(L) degrades, aged platelets are primed for cell death. Genetic ablation or pharmacological inactivation of Bcl-x(L) reduces platelet half-life and causes thrombocytopenia in a dose-dependent manner. Deletion of Bak corrects these defects, and platelets from Bak-deficient mice live longer than normal. Thus, platelets are, by default, genetically programmed to die by apoptosis. The antagonistic balance between Bcl-x(L) and Bak constitutes a molecular clock that determines platelet life span: this represents an important paradigm for cellular homeostasis, and has profound implications for the diagnosis and treatment of disorders that affect platelet number and function.
Pharmacological blockade of Bcl-2, Bcl-x(L) and Bcl-w by the BH3 mimetic ABT-737 has only minor impact on tumour development in p53-deficient mice.
Publisher: Springer Science and Business Media LLC
Date: 14-10-2012
DOI: 10.1038/CDD.2011.133
Inhibitor of Apoptosis Proteins Limit RIP3 Kinase-Dependent Interleukin-1 Activation
Publisher: Elsevier BV
Date: 02-2012
Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study
Publisher: Elsevier BV
Date: 02-2019
Related Organisations
Walter And Eliza Hall Institute Of Medical Research
Location: Australia
Related Funding Activities
No related grants have been discovered for Kylie Mason.