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"CULLEN, Michael"
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Polyamines in cancer: integrating organismal metabolism and antitumour immunity
The natural mammalian polyamines putrescine, spermidine and spermine are essential for both normal and neoplastic cell function and replication. Dysregulation of metabolism of polyamines and their requirements is common in many cancers. Both clinical and experimental depletion of polyamines have demonstrated their metabolism to be a rational target for therapy; however, the mechanisms through which polyamines can establish a tumour-permissive microenvironment are only now emerging. Recent data indicate that polyamines can play a major role in regulating the antitumour immune response, thus likely contributing to the existence of immunologically ‘cold’ tumours that do not respond to immune checkpoint blockade. Additionally, the interplay between the microbiota and associated tissues creates a tumour microenvironment in which polyamine metabolism, content and function can all be dramatically altered on the basis of microbiota composition, dietary polyamine availability and tissue response to its surrounding microenvironment. The goal of this Perspective is to introduce the reader to the many ways in which polyamines, polyamine metabolism, the microbiota and the diet interconnect to establish a tumour microenvironment that facilitates the initiation and progression of cancer. It also details ways in which polyamine metabolism and function can be successfully targeted for therapeutic benefit, including specifically enhancing the antitumour immune response.This Perspective discusses how polyamines, polyamine metabolism, the microbiota and the diet interconnect to establish a tumour microenvironment that facilitates the initiation and progression of cancer. It also details ways in which polyamine metabolism and function can be targeted for therapeutic benefit, including specifically enhancing the antitumour immune response.
Journal Article
mathematical theory of large-scale atmosphere/ocean flow
This book counteracts the current fashion for theories of \"chaos\" and unpredictability by describing a theory that underpins the surprising accuracy of current deterministic weather forecasts, and it suggests that further improvements are possible. The book does this by making a unique link between an exciting new branch of mathematics called \"optimal transportation\" and existing classical theories of the large-scale atmosphere and ocean circulation. It is then possible to solve a set of simple equations proposed many years ago by Hoskins which are asymptotically valid on large scales, and use them to derive quantitative predictions about many large-scale atmospheric and oceanic phenomena. A particular feature is that the simple equations used have highly predictable solutions, thus suggesting that the limits of deterministic predictability of the weather may not yet have been reached. It is also possible to make rigorous statements about the large-scale behaviour of the atmosphere and ocean by proving results using these simple equations and applying them to the real system allowing for the errors in the approximation. There are a number of other titles in this field, but they do not treat this large-scale regime.
eBook
A Simple Model of a Balanced Boundary Layer Coupled to a Large-Scale Convective Circulation
Many simple models of large-scale tropical circulations do not include a frictional boundary layer. A simple model is presented where the convective circulation is coupled to the boundary layer convergence. In the free troposphere, convection and boundary layer heating try to relax to a moist adiabat from the local sea surface temperature with a time scale τc, but other processes act to maintain a weak temperature gradient. There is a mass balance between radiatively driven subsidence and the large-scale convective mass flux. For a prescribed Gaussian surface temperature, the model predicts a mass flux that varies as and a convective width proportional to its reciprocal. In the boundary layer, there can be significant horizontal temperature gradients and a balance between the pressure gradient and drag is assumed. Coupling between the two layers is mediated by the vertical velocity at the top of the boundary layer. The boundary layer constrains the circulation in three ways. First, it may lengthen the relaxation time scale compared to deep convection. Second, the evaporation in the nonconvecting region constrains the horizontal moisture advection. Third, it maintains a convective boundary layer where there is a convective mass flux; this condition cannot be satisfied if τc is too small or if the drag is too large, thus showing that such values are physically impossible. These results provide testable hypotheses concerning the physics and large-scale dynamics in weather and climate models.
Journal Article
Fragmented identity
Swiss artist Andy Denzler (born 1965) creates work that responds to traditional portrait and interior painting through an expressive and multilayered application of paint and the subsequent removal thereof, shifting the image into something surreal and seemingly transient. Fragmented Identity examines Denzler's works from the past seven years.
Book
Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma
Maria Teresa Landi and colleagues identify a rare missense variant in
POT1
shared by five melanoma-prone families from Italy and associated with increased telomere length and telomere fragility. They also identify additional familial melanoma cases with rare missense variants in
POT1
and find a significant excess of rare exonic
POT1
variants in melanoma cases compared to controls, implicating
POT1
variants in melanoma susceptibility.
Although
CDKN2A
is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene
POT1
(chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare
POT1
variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for
POT1
variants comparable to that for
CDKN2A
mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent
POT1
variants in US and French familial melanoma cases. Our findings suggest that
POT1
is a major susceptibility gene for familial melanoma in several populations.
Journal Article
Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance
HPV16 causes half of cervical cancers worldwide; for unknown reasons, most infections resolve within two years. Here, we analyze the viral genomes of 5,328 HPV16-positive case-control samples to investigate mutational signatures and the role of human APOBEC3-induced mutations in viral clearance and cervical carcinogenesis. We identify four de novo mutational signatures, one of which matches the COSMIC APOBEC-associated signature 2. The viral genomes of the precancer/cancer cases are less likely to contain within-host somatic HPV16 APOBEC3-induced mutations (Fisher’s exact test,
P
= 6.2 x 10
−14
), and have a 30% lower nonsynonymous APOBEC3 mutation burden compared to controls. We replicate the low prevalence of HPV16 APOBEC3-induced mutations in 1,749 additional cases. APOBEC3 mutations also historically contribute to the evolution of HPV16 lineages. We demonstrate that cervical infections with a greater burden of somatic HPV16 APOBEC3-induced mutations are more likely to be benign or subsequently clear, suggesting they may reduce persistence, and thus progression, within the host.
The APOBEC mutational signature is prevalent in different tumour types. Here, using HPV16- positive cervical samples, the authors show that the signature is more prevalent in the viral genome of benign or clearing HPV16 infections compared to the viral genomes of the more advanced precancerous lesions or cervical cancer.
Journal Article
Understanding characteristics of internal medicine residents matching into pulmonary critical care medicine fellowships
Background
Internal medicine (IM) residents face significant challenges when pursing subspecialty fellowships. This study determined the factors that differentiate IM residents entering pulmonary and critical care medicine (PCCM) fellowships from those pursuing other careers.
Methods
We completed a retrospective study of 12 classes of IM residents at a single institution completing residency between 2010 and 2021. Data included pre-residency characteristics, global residency performance, and PCCM-specific experiences. Logistic regression models examined associations between these variables and the primary outcome of matching into a PCCM fellowship within one year of completing IM residency.
Results
Among 522 residents, 10.3% matched into PCCM. Completing a pulmonary elective significantly increased the odds of matching into PCCM (OR 7.78, 99% CI 3.10–19.53,
p
< 0.0001). Residents who match into PCCM were more likely to have < 3 publications than 3 + (OR 3.51 (1.20–10.25),
p
= 0.003).” A stated intent to enter PCCM was positively associated with matching into PCCM in the univariable, but not the multivariable, model.
Conclusions
Matriculating into PCCM fellowship was significantly associated with completing a pulmonary elective during residency. PCCM-bound residents were less likely to achieve high numbers of publications, suggesting these residents’ preferences for clinical learning and practice over scholarship. This study provides insights into characteristics of residents who match into PCCM and guides mentors as they counsel residents considering PCCM.
Journal Article