50 research outputs found
Clonal Interactions in Barrett’s Carcinogenesis.
PhDIntroduction:
Barrett’s
oesophagus
(BO)
is
a
metaplastic
premalignant
disease
which
can
undergo
a
metaplasia-‐dysplasia-‐adenocarcinoma
pathway.
It
represents
an
example
of
field
cancerization
by
which
an
area
occupied
by
BO
can
undergo
molecular
and
genetic
changes
associated
with
carcinogenesis
without
being
phenotypically
cancerous.
Previous
work
suggested
that
non-‐cancerous
BO
contains
a
monoclonal
population.
More
recent
work
demonstrated
that
premalignant
Barrett’s
fields
are
polyclonal
suggesting
that
clonal
interactions
may
be
important
in
carcinogenesis.
It
is
the
aim
of
this
thesis
to
further
investigate
clonal
interactions
in
BO
by
understanding
the
effects
of
therapy
in
altering
the
relationships
of
clonal
populations
in
BO,
by
assessing
the
relationship
of
clonal
populations
in
dysplasia
as
compared
with
the
associated
cancer,
and
by
attempting
to
elucidate
a
potential
molecular
mechanism
of
clonal
interactions.
Results:
The
overall
results
can
be
summarised
as
follows:
1.Premalignant
clonal
populations
are
well
mixed
allowing
for
clonal
interactions.
However,
the
adenocarcinoma
associated
with
high
grade
dysplasia
is
monoclonal
and
derived
from
clonal
populations
found
in
the
dysplasia,
indicating
possible
clonal
interactions
during
carcinogenesis.
2.
Patients
with
persistent
disease
after
endoscopy
retain
the
same
clonal
populations.
However,
the
clonal
populations
of
recurrent
disease
changes
such
that
new
clonal
populations
arise
or
may
benefit
from
the
extinction
of
others.
3.
These
clonal
populations
may
be
derived
from
deep
submucosal
glands
or
may
be
found
in
phenotypically
normal
squamous
epithelium
indicating
a
common
stem
cell
origin.
4.
A
possible
mechanism
of
clonal
interaction
may
be
the
senescence
associated
secretory
phenotype:
senescence
is
abundant
in
BO
and
can
cause
proliferation
in
neighbouring
cells
in
vitro.
Conclusion:
This
thesis
has
investigated
the
implications
of
clonal
interactions
in
BO.
The
demonstration
of
temporal
clonal
heterogeneity
as
a
result
of
endoscopic
therapy,
as
well
as
spatial
clonal
heterogeneity
possibly
resulting
in
carcinogenesis,
asks
for
a
mechanistic
explanation
of
clonal
interactions.
The
consequences
of
senescence
may
well
provide
one
such
mechanism.Derek Butler Trust; CORE
Digestive
Diseases
Charity,
Grant
Number:
TBYG1J3R
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Racial discrimination in medical care settings and opioid pain reliever misuse in a U.S. cohort: 1992 to 2015
BACKGROUND: In the United States whites are more likely to misuse opioid pain relievers (OPRs) than blacks, and blacks are less likely to be prescribed OPRs than whites. Our objective is to determine whether racial discrimination in medical settings is protective for blacks against OPR misuse, thus mediating the black-white disparities in OPR misuse.
METHODS: We used data from 3528 black and white adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study, an ongoing multi-site cohort. We employ causal mediation methods, with race (black vs white) as the exposure, lifetime discrimination in medical settings prior to year 2000 as the mediator, and OPR misuse after 2000 as the outcome.
RESULTS: We found black participants were more likely to report discrimination in a medical setting (20.3% vs 0.9%) and less likely to report OPR misuse (5.8% vs 8.0%, OR = 0.71, 95% CI = 0.55, 0.93, adjusted for covariates). Our mediation models suggest that when everyone is not discriminated against, the disparity is wider with black persons having even lower odds of reporting OPR misuse (OR = 0.63, 95% CI = 0.45, 0.89) compared to their white counterparts, suggesting racial discrimination in medical settings is a risk factor for OPR misuse rather than protective.
CONCLUSIONS: These results suggest that racial discrimination in a medical setting is a risk factor for OPR misuse rather than being protective, and thus could not explain the seen black-white disparity in OPR misuse
The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands
Objective: Barrett's oesophagus shows appearances described as ‘intestinal metaplasia’, in structures called ‘crypts’ but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands.
Methods: Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and LGR5 mRNA was determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry.
Results: Proliferation predominantly occurs in the middle of Barrett's glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett's mirrors pyloric glands and is preserved in Barrett's dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett's glands, and TFF3 is concentrated in the same region. LGR5 mRNA is detected in the middle of Barrett's glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett's glands are clonal, indicating derivation from a single stem cell.
Conclusions: Barrett's shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett's oesophagus
Processing emotion from abstract art in frontotemporal lobar degeneration
Abstract art may signal emotions independently of a biological or social carrier: it might therefore constitute a test case for defining brain mechanisms of generic emotion decoding and the impact of disease states on those mechanisms. This is potentially of particular relevance to diseases in the frontotemporal lobar degeneration (FTLD) spectrum. These diseases are often led by emotional impairment despite retained or enhanced artistic interest in at least some patients. However, the processing of emotion from art has not been studied systematically in FTLD. Here we addressed this issue using a novel emotional valence matching task on abstract paintings in patients representing major syndromes of FTLD (behavioural variant frontotemporal dementia, n=11; sematic variant primary progressive aphasia (svPPA), n=7; nonfluent variant primary progressive aphasia (nfvPPA), n=6) relative to healthy older individuals (n=39). Performance on art emotion valence matching was compared between groups taking account of perceptual matching performance and assessed in relation to facial emotion matching using customised control tasks. Neuroanatomical correlates of art emotion processing were assessed using voxel-based morphometry of patients' brain MR images. All patient groups had a deficit of art emotion processing relative to healthy controls; there were no significant interactions between syndromic group and emotion modality. Poorer art emotion valence matching performance was associated with reduced grey matter volume in right lateral occopitotemporal cortex in proximity to regions previously implicated in the processing of dynamic visual signals. Our findings suggest that abstract art may be a useful model system for investigating mechanisms of generic emotion decoding and aesthetic processing in neurodegenerative diseases
A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy
The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.This study was partly funded by a project grant from Cancer Research UK. R.C.F. is funded by an NIHR Professorship and receives core funding from the Medical Research Council and infrastructure support from the Biomedical Research Centre and the Experimental Cancer Medicine Centre. We acknowledge the support of The University of Cambridge, Cancer Research UK (C14303/A17197) and Hutchison Whampoa Limited
An obstructing mass in a young ulcerative colitis patient
We present a case of a 19-year-old female who developed subacute obstruction due to giant inflammatory polyps, having undergone treatment for left-sided ulcerative colitis. This is followed by a review of the literature