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"Smith, Victoria"
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Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker
A wide range of diseases have been shown to be influenced by the accumulation of senescent cells, from fibrosis to diabetes, cancer, Alzheimer’s and other age-related pathologies. Consistent with this, clearance of senescent cells can prolong healthspan and lifespan in in vivo models. This provided a rationale for developing a new class of drugs, called senolytics, designed to selectively eliminate senescent cells in human tissues. The senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant. Here, we propose to use an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells. We show that an antibody–drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.
Journal Article
The tailoring book : a step-by-step guide to creating bespoke garments
With step-by-step techniques on measuring, cutting, altering and finishing, this is the only book you will need to create and alter a tailored garment. Alison Smith, one of the world's leading tailoring experts, reveals trade secrets and all the practical know-how necessary to master this heritage craft.
BOOK
Exosomes function in antigen presentation during an in vivo Mycobacterium tuberculosis infection
Mycobacterium tuberculosis
-infected macrophages and dendritic cells are limited in their ability to present antigen to CD4+ T cells suggesting that other mechanism of antigen presentation are driving the robust T cell response observed during an
M. tuberculosis
infection. These mechanisms could include antigens present in apoptotic bodies, necrotic debris, exosomes or even release of non-vesicular antigen from infected cells. However, there is limited data to support any of these mechanisms as important in driving T cell activation
in vivo
. In the present study we use Rab27a-deficient mice which show diminished trafficking of mycobacterial components to exosomes as well as
M. tuberculosis
strains that express recombinant proteins which traffic or fail to traffic to exosomes. We observed that exosomes released during a mouse
M. tuberculosis
infection contribute significantly to its T cell response. These finding imply that exosomes function to promote T cell immunity during a bacterial infection and are an important source of extracellular antigen.
Journal Article
A laboratory of her own : women and science in Spanish culture
\"The eclectic intersection of women, science, and culture in Spain during the nineteenth, twentieth, and twenty-first centuries\"-- Provided by publisher.
BOOK
Late-stage volatile saturation as a potential trigger for explosive volcanic eruptions
Magma reservoirs are thought to grow relatively slowly, assembling incrementally under volatile-saturated conditions. Eruptions may be triggered by injections of volatile-rich melt, or generation of over-pressure due to protracted crystallization. Here, we analyse fluorine, chlorine and water in apatite crystals trapped at different stages of magma evolution, and in melt inclusions from clinopyroxene and biotite crystals expelled during an explosive eruption of the Campi Flegrei caldera, Italy, about 4,000 years ago. We combine our geochemical analyses with thermodynamic modelling to reconstruct the evolution of magmatic volatile contents leading up to the explosive eruption. We find that the magma reservoir remained persistently water-undersaturated throughout most of its lifetime. Even crystals in contact with the melt shortly before eruption show that the magma was volatile-undersaturated. Our models suggest that the melt reached volatile saturation at low temperatures, just before eruption. We suggest that late-stage volatile saturation probably triggered the eruption, and conclude that ‘priming’ of the magma system for eruption may occur on timescales much shorter than the decadal to centennial timescales thought typical for magma reservoir assembly. Thus, surface deformation pulses that record magma assembly at depth beneath Campi Flegrei and other similar magmatic systems may not be immediately followed by an eruption; and explosive eruptions may begin with little warning.
Magma reservoirs typically accumulate over hundreds to thousands of years. Yet, geochemical analyses of volcanic rocks from Campi Flegrei suggest activity there was triggered by injections of volatile-rich magma only days before the eruption.
Journal Article
The magnitude and impact of the 431 CE Tierra Blanca Joven eruption of Ilopango, El Salvador
The Tierra Blanca Joven (TBJ) eruption from Ilopango volcano deposited thick ash over much of El Salvador when it was inhabited by the Maya, and rendered all areas within at least 80 km of the volcano uninhabitable for years to decades after the eruption. Nonetheless, the more widespread environmental and climatic impacts of this large eruption are not well known because the eruption magnitude and date are not well constrained. In this multifaceted study we have resolved the date of the eruption to 431 ± 2 CE by identifying the ash layer in a well-dated, high-resolution Greenland ice-core record that is >7,000 km from Ilopango; and calculated that between 37 and 82 km³ of magma was dispersed from an eruption coignimbrite column that rose to ∼45 km by modeling the deposit thickness using state-of-the-art tephra dispersal methods. Sulfate records from an array of ice cores suggest stratospheric injection of 14 ± 2 Tg S associated with the TBJ eruption, exceeding those of the historic eruption of Pinatubo in 1991. Based on these estimates it is likely that the TBJ eruption produced a cooling of around 0.5 °C for a few years after the eruption. The modeled dispersal and higher sulfate concentrations recorded in Antarctic ice cores imply that the cooling would have been more pronounced in the Southern Hemisphere. The new date confirms the eruption occurred within the Early Classic phase when Maya expanded across Central America.
Journal Article
The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy
The B cell lymphoma 2 (BCL2) protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria. In this cutting-edge review, we summarize the basic biology regulating the BCL2 family including canonical and non-canonical functions, and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions. We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) and tools targeting the BH4 domain of BCL2. The first BCL2-selective BH3-mimetic, venetoclax, showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies. Following its success, several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation, alone and in combination. Genetic analysis highlights the importance of BCL-X
L
and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins. However, the development of BH3-mimetics targeting BCL-X
L
or MCL1 has been more challenging, with on-target toxicities including thrombocytopenia for BCL-X
L
and cardiac toxicities for MCL1 inhibitors precluding clinical development. Tumor-specific BCL-X
L
or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy. Taken together, we envision that the targeting of BCL2 proteins, while already a success story of translational research, may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.
Journal Article
Survival in a consecutive series of 467 glioblastoma patients: Association with prognostic factors and treatment at recurrence at two independent institutions
Therapy of recurrent glioblastoma (GBM) is challenging due to lack of standard treatment. We investigated physicians’ treatment choice at recurrence and prognostic and predictive factors for survival in GBM patients from Norway’s two largest regional hospitals. Clinicopathological data from n = 467 patients treated at Haukeland and Oslo university hospitals from January 2015 to December 2017 was collected. Data included tumour location, promoter methylation of O
6
methylguanine-DNA methyltransferase (
MGMT
) and mutation of isocitrate dehydrogenase (
IDH
), patient age, sex, extent of resection at primary diagnosis and treatment at successive tumour recurrences. Cox-proportional hazards regression adjusting for multiple risk factors was used. Median overall survival (OS) was 12.1 months and 21.4% and 6.8% of patients were alive at 2 and 5 years, respectively. Median progression-free survival was 8.1 months. Treatment at recurrence varied but was not associated with difference in overall survival (OS) (
p
= 0.201). Age,
MGMT
hypermethylation, tumour location and extent of resection were independent prognostic factors. Patients who received 60 Gray radiotherapy with concomitant and adjuvant temozolomide at primary diagnosis had 16.1 months median OS and 9.3% were alive at 5 years. Patients eligible for gamma knife/stereotactic radiosurgery alone or combined with chemotherapy at first recurrence had superior survival compared to chemotherapy alone (
p
<0.001). At second recurrence, combination chemotherapy with or without bevacizumab were both superior to no treatment. Treatment at recurrence differed between the institutions but there was no difference in median OS, indicating that it is the disease biology that dictates patient outcome.
Journal Article
Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer
The phosphoinositide 3-kinase (PI3K) signalling pathway is highly dysregulated in cancer, leading to elevated PI3K signalling and altered cellular processes that contribute to tumour development. The pathway is normally orchestrated by class I PI3K enzymes and negatively regulated by the phosphatase and tensin homologue, PTEN. Endometrial carcinomas harbour frequent alterations in components of the pathway, including changes in gene copy number and mutations, in particular in the oncogene PIK3CA, the gene encoding the PI3K catalytic subunit p110α, and the tumour suppressor PTEN. PIK3CB, encoding the other ubiquitously expressed class I isoform p110β, is less frequently altered but the few mutations identified to date are oncogenic. This isoform has received more research interest in recent years, particularly since PTEN-deficient tumours were found to be reliant on p110β activity to sustain transformation. In this review, we describe the current understanding of the common and distinct biochemical properties of the p110α and p110β isoforms, summarise their mutations and highlight how they are targeted in clinical trials in endometrial cancer.
Journal Article