Cancer epigenetics in solid organ tumours: A primer for surgical oncologists

Cancer is initiated through both genetic and epigenetic alterations. The end-effect of such changes to the DNA machinery is a set of uncontrolled mechanisms of cell division, invasion and, eventually, metastasis. Epigenetic changes are now increasingly appreciated as an essential driver to the cancer phenotype. The epigenetic regulation of cancer is complex and not yet fully understood, but application of epigenetics to clinical practice and in cancer research has the potential to improve cancer care. Epigenetics changes do not cause changes in the DNA base-pairs (and, hence, does not alter the genetic code per se) but rather occur through methylation of DNA, by histone modifications, and, through changes to chromatin structure to alter genetic expression. Epigenetic regulators are characterized as writers, readers or erasers by their mechanisms of action. The human epigenome is influenced from cradle to grave, with internal and external life-time exposure influencing the epigenetic marks that may act as modifiers or drivers of carcinogenesis. Preventive and public health strategies may follow from better understanding of the life-time influence of the epigenome. Epigenetics may be used to define risk, to investigate mechanisms of carcinogenesis, to identify biomarkers, and to identify novel therapeutic options. Epigenetic alterations are found across many solid cancers and are increasingly making clinical impact to cancer management. Novel epigenetic drugs may be used for a more tailored and specific response to treatment of cancers. We present a primer on epigenetics for surgical oncologists with examples from colorectal cancer, breast cancer, pancreatic cancer and hepatocellular carcinoma.publishedVersio

Portable X-Ray Fluorescence Spectroscopy for Rapid and Cost-Effective Determination of Elemental Composition of Ground Forage

The recent development of portable X-ray fluorescence spectrometers (PXRF) has created new avenues for rapid plant elemental concentration determination at reduced cost while avoiding hazardous chemicals. A few studies have indicated the potential use of PXRF for homogenous plant tissue analysis. However, there is a lack of information for analysis of heterogeneous plant samples like livestock forage, which consists of a mixture of several species and plant parts, each varying in elemental concentration. Our objective was to evaluate PXRF for forage analysis, specifically the effect of forage particle size and scan time on important elements including P, K, Ca, and Fe determination. Hay samples (n = 42) were oven dried (60◦C for 3 days) and ground into three particle sizes (≤0.5 mm, 0.25–0.5 mm and 1–2 mm). Prepared samples were scanned by PXRF using a vacuum (\u3c10 torr) without a filter. Samples were placed in cups over thin prolene X-ray film and scanned for 180 s. A subset (n = 29) were also scanned for 60 and 120 s. PXRF counts for P, K, Ca, and Fe were compared with laboratory Inductively Coupled Plasma Optical Emission Spectroscopy (ICP) determinations, using regression models. Results indicated that these elements could potentially be determined with PXRF (r 2 ≥ 0.70) in heterogeneous forage samples. Relationship strength increased with decreasing particle size, however, the relationship was still strong (r 2 ≥ 0.57) at the largest particle size. Scanning time did not affect the relationship with ICP concentration for any of the particle sizes evaluated. This work demonstrated that with the right sample preparation PXRF can obtain results comparable to acid digestion and ICP regardless of sample composition, and suggests the potential for in situ determination

Deeper Chandra Follow-up of Cygnus TeV Source Perpetuates Mystery

A 50 ksec Chandra observation of the unidentified TeV source in Cygnus reported by the HEGRA collaboration reveals no obvious diffuse X-ray counterpart. However, 240 Pointlike X-ray sources are detected within or nearby the extended TeV J2032+4130 source region, of which at least 36 are massive stars and 2 may be radio emitters. That the HEGRA source is a composite, having as counterpart the multiple point-like X-ray sources we observe, cannot be ruled out. Indeed, the distribution of point-like X-ray sources appears non-uniform and concentrated broadly within the extent of the TeV source region. We offer a hypothesis for the origin of the very high energy gamma-ray emission in Cyg OB2 based on the local acceleration of TeV range cosmic rays and the differential distribution of OB vs. less massive stars in this association.Comment: Substantially revised version; incorporates referee suggestions & expanded discussio

Length polymorphism in the Period 3 gene is associated with sleepiness and maladaptive circadian phase in night‐shift workers

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111752/1/jsr12264.pd

High-throughput, fluorescent-aptamer-based measurements of steady-state transcription rates for the Mycobacterium tuberculosis RNA polymerase

The first step in gene expression is the transcription of DNA sequences into RNA. Regulation at the level of transcription leads to changes in steady-state concentrations of RNA transcripts, affecting the flux of downstream functions and ultimately cellular phenotypes. Changes in transcript levels are routinely followed in cellular contexts via genome-wide sequencing techniques. However, in vitro mechanistic studies of transcription have lagged with respect to throughput. Here, we describe the use of a real-time, fluorescent-aptamer-based method to quantitate steady-state transcription rates of the Mycobacterium tuberculosis RNA polymerase. We present clear controls to show that the assay specifically reports on promoter-dependent, full-length RNA transcription rates that are in good agreement with the kinetics determined by gel-resolved, α-32P NTP incorporation experiments. We illustrate how the time-dependent changes in fluorescence can be used to measure regulatory effects of nucleotide concentrations and identity, RNAP and DNA concentrations, transcription factors, and antibiotics. Our data showcase the ability to easily perform hundreds of parallel steady-state measurements across varying conditions with high precision and reproducibility to facilitate the study of the molecular mechanisms of bacterial transcription

Solar Magnetic Field Studies Using the 12-Micron Emission Lines. IV. Observations of a Delta-Region Solar Flare

We have recently developed the capability to make solar vector (Stokes IQUV) magnetograms using the infrared line of MgI at 12.32 microns. On 24 April 2001, we obtained a vector magnetic map of solar active region NOAA 9433, fortuitously just prior to the occurrence of an M2 flare. Examination of a sequence of SOHO/MDI magnetograms, and comparison with ground-based H-alpha images, shows that the flare was produced by the cancellation of newly emergent magnetic flux outside of the main sunspot. The very high Zeeman-sensitivity of the 12-micron data allowed us to measure field strengths on a spatial scale which was not directly resolvable. At the flare trigger site, opposite polarity fields of 2700 and 1000 Gauss occurred within a single 2 arc-sec resolution element, as revealed by two resolved Zeeman splittings in a single spectrum. Our results imply an extremely high horizontal field strength gradient (5 G/km) prior to the flare, significantly greater than seen in previous studies. We also find that the magnetic energy of the cancelling fields was more than sufficient to account for the flare's X-ray luminosity.Comment: 14 pages, 5 figures, accepted for Ap.

Changes in hospital mortality in patients with cancer during the COVID-19 pandemic (ISARIC-CCP-UK):a prospective, multicentre cohort study

BACKGROUND: Patients with cancer are at greater risk of dying from COVID-19 than many other patient groups. However, how this risk evolved during the pandemic remains unclear. We aimed to determine, on the basis of the UK national pandemic protocol, how factors influencing hospital mortality from COVID-19 could differentially affect patients undergoing cancer treatment. We also examined changes in hospital mortality and escalation of care in patients on cancer treatment during the first 2 years of the COVID-19 pandemic in the UK.METHODS: We conducted a prospective cohort study of patients aged older than 19 years and admitted to 306 health-care facilities in the UK with confirmed SARS-CoV-2 infection, who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol (CCP) across the UK from April 23, 2020, to Feb 28, 2022; this analysis included all patients in the complete dataset when the study closed. The primary outcome was 30-day in-hospital mortality, comparing patients on cancer treatment and those without cancer. The study was approved by the South Central-Oxford C Research Ethics Committee in England (Ref: 13/SC/0149) and the Scotland A Research Ethics Committee (Ref 20/SS/0028), and is registered on the ISRCTN Registry (ISRCTN66726260).FINDINGS: 177 871 eligible adult patients either with no history of cancer (n=171 303) or on cancer treatment (n=6568) were enrolled; 93 205 (52·4%) were male, 84 418 (47·5%) were female, and in 248 (13·9%) sex or gender details were not specified or data were missing. Patients were followed up for a median of 13 (IQR 6-21) days. Of the 6568 patients receiving cancer treatment, 2080 (31·7%) died at 30 days, compared with 30 901 (18·0%) of 171 303 patients without cancer. Patients aged younger than 50 years on cancer treatment had the highest age-adjusted relative risk (hazard ratio [HR] 5·2 [95% CI 4·0-6·6], p&lt;0·0001; vs 50-69 years 2·4 [2·2-2·6], p&lt;0·0001; 70-79 years 1·8 [1·6-2·0], p&lt;0·0001; and &gt;80 years 1·5 [1·3-1·6], p&lt;0·0001) but a lower absolute risk (51 [6·7%] of 763 patients &lt;50 years died compared with 459 [30·2%] of 1522 patients aged &gt;80 years). In-hospital mortality decreased for all patients during the pandemic but was higher for patients on cancer treatment than for those without cancer throughout the study period.INTERPRETATION: People with cancer have a higher risk of mortality from COVID-19 than those without cancer. Patients younger than 50 years with cancer treatment have the highest relative risk of death. Continued action is needed to mitigate the poor outcomes in patients with cancer, such as through optimising vaccination, long-acting passive immunisation, and early access to therapeutics. These findings underscore the importance of the ISARIC-WHO pandemic preparedness initiative.FUNDING: National Institute for Health Research and the Medical Research Council.</p