Pathways of Colorectal Carcinogenesis Nguyen, Long H.; Goel, Ajay; Chung, Daniel C.
Gastroenterology (New York, N.Y. 1943),
01/2020, Letnik:
158, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic changes associated with the ...development of precancerous colorectal adenomas and their progression to tumors, as well as the effects of defective DNA repair, chromosome instability, microsatellite instability, and alterations in the serrated pathway and DNA methylation. We provide insights into the different molecular subgroups of colorectal tumors that develop via each of these different mechanisms and their associations with patient outcomes.
The acquisition of genomic instability is a crucial feature in tumor development and there are at least 3 distinct pathways in colorectal cancer pathogenesis: the chromosomal instability (CIN), ...microsatellite instability, and CpG island methylator phenotype pathways. Most cases of colorectal cancer arise through the CIN pathway, which is characterized by widespread imbalances in chromosome number (aneuploidy) and loss of heterozygosity. It can result from defects in chromosomal segregation, telomere stability, and the DNA damage response, although the full complement of genes underlying CIN remains incompletely described. Coupled with the karyotypic abnormalities observed in CIN tumors are the accumulation of a characteristic set of mutations in specific tumor suppressor genes and oncogenes that activate pathways critical for colorectal cancer initiation and progression. Whether CIN creates the appropriate milieu for the accumulation of these mutations or vice versa remains a provocative and unanswered question. The goal of this review is to provide an updated perspective on the mechanisms that lead to CIN and the key mutations that are acquired in this pathway.
A
bstract
Through a mechanism similar to perturbative particle scattering, particles of mass
m
χ
larger than the Hubble expansion rate
H
inf
during inflation can be gravitationally produced at the ...end of inflation without the exponential suppression powers of exp(−
m
χ
/H
inf
). Here we develop an analytic formalism for computing particle production for such massive particles. We apply our formalism to specific models that have been previously been studied only numerically, and we find that our analytical approximations reproduce those numerical estimates well.
A
bstract
Analytic and numerical techniques are presented for computing gravitational production of scalar particles in the limit that the inflaton mass is much larger than the Hubble expansion rate ...at the end of inflation. These techniques rely upon adiabatic invariants and time modeling of a typical inflaton field which has slow and fast time variation components. A faster computation time for numerical integration is achieved via subtraction of slowly varying components that are ultimately exponentially suppressed. The fast oscillatory remnant results in production of scalar particles with a mass larger than the inflationary Hubble expansion rate through a mechanism analogous to perturbative particle scattering. An improved effective Boltzmann collision equation description of this particle production mechanism is developed. This model allows computation of the spectrum using only adiabatic invariants, avoiding the need to explicitly solve the inflaton equations of motion.
It is known that if the Peccei-Quinn symmetry-breaking field is displaced from its minimum during inflation, the axion isocurvature spectrum is generically strongly blue tilted with a break ...transition to a flat spectrum. We fit this spectrum (incorporated into the “vanilla” Λ−CDM cosmological model) to the Planck and BOSS DR11 data to assess how much the existing data can accommodate the presence of axionic blue-tilted isocurvature perturbations. We find that the preferred parameter region is consistent with all of the dark matter being composed of QCD axions in the context of inflationary cosmology with an expansion rate of order 108 GeV, the axion decay constant of order 1013 GeV, and the initial misalignment angle of order unity. The data are consistent with there being no isocurvature perturbations at the level of just above one sigma. Intriguingly, isocurvature with a spectral break may at least partially explain the low-ℓ vs high-ℓ anomalies seen in the CMB data.
Predicting the Drag of Rough Surfaces Chung, Daniel; Hutchins, Nicholas; Schultz, Michael P ...
Annual review of fluid mechanics,
01/2021, Letnik:
53, Številka:
1
Journal Article
Recenzirano
Reliable full-scale prediction of drag due to rough wall-bounded turbulent fluid flow remains a challenge. Currently, the uncertainty is at least 10%, with consequences, for example, on energy and ...transport applications exceeding billions of dollars per year. The crux of the difficulty is the large number of relevant roughness topographies and the high cost of testing each topography, but computational and experimental advances in the last decade or so have been lowering these barriers. In light of these advances, here we review the underpinnings and limits of relationships between roughness topography and drag behavior, focusing on canonical and fully turbulent incompressible flow over rigid roughness. These advances are beginning to spill over into multiphysical areas of roughness, such as heat transfer, and promise broad increases in predictive reliability.
Stimulants are considered the first-line treatment for Attention Deficit Hyperactivity Disorder (ADHD) in the US and they are used in other indications. Stimulants are also diverted for non-medical ...purposes. Ethnic and regional differences in ADHD diagnosis and in stimulant use have been identified in earlier research. The objectives of this report were to examine the pharmacoepidemiological pattern of these controlled substances over the past decade and to conduct a regional analysis.
Data (drug weights) reported to the US Drug Enforcement Administration's Automation of Reports and Consolidated Orders System for four stimulants (amphetamine, methylphenidate, lisdexamfetamine, and methamphetamine) were obtained from 2006 to 2016 for Unites States/Territories. Correlations between state level use (mg/person) and Hispanic population were completed.
Amphetamine use increased 2.5 fold from 2006 to 2016 (7.9 to 20.0 tons). Methylphenidate use, at 16.5 tons in 2006, peaked in 2012 (19.4 tons) and subsequently showed a modest decline (18.6 tons in 2016). The consumption per municipality significantly increased 7.6% for amphetamine and 5.5% for lisdexamfetamine but decreased 2.7% for methylphenidate (all p < .0005) from 2015 to 2016. Pronounced regional differences were also observed. Lisdexamfetamine use in 2016 was over thirty-fold higher in the Southern US (43.8 mg/person) versus the Territories (1.4 mg/person). Amphetamine use was about one-third lower in the West (48.1 mg/person) relative to the Northeastern (75.4 mg/person, p < .05) or the Midwestern (69.9 mg/person, p ≤ .005) states. States with larger Hispanic populations had significantly lower methylphenidate (r(49) = -0.63), lisdexamfetamine (B, r(49) = -0.49), and amphetamine (r(49) = -0.43) use.
Total stimulant usage doubled in the last decade. There were dynamic changes but also regional disparities in the use of stimulant medications. Future research is needed to better understand the reasons for the sizable regional and ethnic variations in use of these controlled substances.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Previous preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased ...intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound.
We did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged ≥18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment.
Between March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3·7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2·34 μg/g (SD 0·93) immediately after drug infusion to 8·56 μg/g (5·69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3–4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred.
The combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy.
Oxford Biomedical Research Centre, National Institute for Health Research.
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