Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis

Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer

Deoxycholate, an Endogenous Cytotoxin/Genotoxin, Induces the Autophagic Stress-Survival Pathway: Implications for Colon Carcinogenesis

We report that deoxycholate (DOC), a hydrophobic bile acid associated with a high-fat diet, activates the autophagic pathway in non-cancer colon epithelial cells (NCM-460), and that this activation contributes to cell survival. The DOC-induced increase in autophagy was documented by an increase in autophagic vacuoles (detected using transmission electron microscopy, increased levels of LC3-I and LC3-II (western blotting), an increase in acidic vesicles (fluorescence spectroscopy of monodansycadaverine and lysotracker red probes), and increased expression of the autophagic protein, beclin-1 (immunohistochemistry/western blotting). The DOC-induced increase in beclin-1 expression was ROS-dependent. Rapamycin (activator of autophagy) pre-treatment of NCM-460 cells significantly (P < .05) decreased, and 3-MA (inhibitor of autophagy) significantly (P < .05) increased the cell loss caused by DOC treatment, alone. Rapamycin pre-treatment of the apoptosis-resistant colon cancer cell line, HCT-116RC (developed in our laboratory), resulted in a significant decrease in DOC-induced cell death. Bafilomycin A1 and hydroxychloroquine (inhibitors of the autophagic process) increased the DOC-induced percentage of apoptotic cells in HCT-116RC cells. It was concluded that the activation of autophagy by DOC has important implications for colon carcinogenesis and for the treatment of colon cancer in conjunction with commonly used chemotherapeutic agents

Prehospital video triage of potential stroke patients in North Central London and East Kent: rapid mixed-methods service evaluation

Background In response to COVID-19, alongside other service changes, North Central London and East Kent implemented prehospital video triage: this involved stroke and ambulance clinicians communicating over FaceTime (Apple Inc., Cupertino, CA, USA) to assess suspected stroke patients while still on scene. Objective To evaluate the implementation, experience and impact of prehospital video triage in North Central London and East Kent. Design A rapid mixed-methods service evaluation (July 2020 to September 2021) using the following methods. (1) Evidence reviews: scoping review (15 reviews included) and rapid systematic review (47 papers included) on prehospital video triage for stroke, covering usability (audio-visual and signal quality); acceptability (whether or not clinicians want to use it); impact (on outcomes, safety, experience and cost-effectiveness); and factors influencing implementation. (2) Clinician views of prehospital video triage in North Central London and East Kent, covering usability, acceptability, patient safety and implementation: qualitative analysis of interviews with ambulance and stroke clinicians (n = 27), observations (n = 12) and documents (n = 23); a survey of ambulance clinicians (n = 233). (3) Impact on safety and quality: analysis of local ambulance conveyance times (n = 1400; April to September 2020). Analysis of national stroke audit data on ambulance conveyance and stroke unit delivery of clinical interventions in North Central London, East Kent and the rest of England (n = 137,650; July 2018 to December 2020). Results (1) Evidence: limited but growing, and sparse in UK settings. Prehospital video triage can be usable and acceptable, requiring clear network connection and audio-visual signal, clinician training and communication. Key knowledge gaps included impact on patient conveyance, patient outcomes and cost-effectiveness. (2) Clinician views. Usability – relied on stable Wi-Fi and audio-visual signals, and back-up processes for when signals failed. Clinicians described training as important for confidence in using prehospital video triage services, noting potential for ‘refresher’ courses and joint training events. Ambulance clinicians preferred more active training, as used in North Central London. Acceptability – most clinicians felt that prehospital video triage improved on previous processes and wanted it to continue or expand. Ambulance clinicians reported increased confidence in decisions. Stroke clinicians found doing assessments alongside their standard duties a source of pressure. Safety – clinical leaders monitored and managed potential patient safety issues; clinicians felt strongly that services were safe. Implementation – several factors enabled prehospital video triage at a system level (e.g. COVID-19) and more locally (e.g. facilitative governance, receptive clinicians). Clinical leaders reached across and beyond their organisations to engage clinicians, senior managers and the wider system. (3) Impact on safety and quality: we found no evidence of increased times from symptom onset to arrival at services or of stroke clinical interventions reducing in studied areas. We found several significant improvements relative to the rest of England (possibly resulting from other service changes). Limitations We could not interview patients and carers. Ambulance data had no historic or regional comparators. Stroke audit data were not at patient level. Several safety issues were not collected routinely. Our survey used a convenience sample. Conclusions Prehospital video triage was perceived as usable, acceptable and safe in both areas. Future research Qualitative research with patients, carers and other stakeholders and quantitative analysis of patient-level data on care delivery, outcomes and cost-effectiveness, using national controls. Focus on sustainability and roll-out of services. Study registration This study is registered as PROSPERO CRD42021254209. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 26. See the NIHR Journals Library website for further project information

Isometric force pillow: using air pressure to quantify involuntary finger flexion in the presence of hypertonia

Survivors of central nervous system injury commonly present with spastic hypertonia. The affected muscles are hyperexcitable and can display involuntary static muscle tone and an exaggerated stretch reflex. These symptoms affect posture and disrupt activities of daily living. Symptoms are typically measured using subjective manual tests such as the Modified Ashworth Scale; however, more quantitative measures are necessary to evaluate potential treatments. The hands are one of the most common targets for intervention, but few investigators attempt to quantify symptoms of spastic hypertonia affecting the fingers. We present the isometric force pillow (IFP) to quantify involuntary grip force. This lightweight, computerized tool provides a holistic measure of finger flexion force and can be used in various orientations for clinical testing and to measure the impact of assistive devices

Quantifying humpback whale song sequences to understand the dynamics of song exchange at the ocean basin scale

Humpback whales have a continually evolving vocal sexual display, or "song," that appears to undergo both evolutionary and "revolutionary" change. All males within a population adhere to the current content and arrangement of the song. Populations within an ocean basin share similarities in their songs; this sharing is complex as multiple variations of the song (song types) may be present within a region at any one time. To quantitatively investigate the similarity of song types, songs were compared at both the individual singer and population level using the Levenshtein distance technique and cluster analysis. The highly stereotyped sequences of themes from the songs of 211 individuals from populations within the western and central South Pacific region from 1998 through 2008 were grouped together based on the percentage of song similarity, and compared to qualitatively assigned song types. The analysis produced clusters of highly similar songs that agreed with previous qualitative assignments. Each cluster contained songs from multiple populations and years, confirming the eastward spread of song types and their progressive evolution through the study region. Quantifying song similarity and exchange will assist in understanding broader song dynamics and contribute to the use of vocal displays as population identifiers

Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer

BACKGROUND:Cancers often arise within an area of cells (e.g. an epithelial patch) that is predisposed to the development of cancer, i.e. a "field of cancerization" or "field defect." Sporadic colon cancer is characterized by an elevated mutation rate and genomic instability. If a field defect were deficient in DNA repair, DNA damages would tend to escape repair and give rise to carcinogenic mutations.PURPOSE:To determine whether reduced expression of DNA repair proteins Pms2, Ercc1 and Xpf (pairing partner of Ercc1) are early steps in progression to colon cancer.RESULTS:Tissue biopsies were taken during colonoscopies of 77 patients at 4 different risk levels for colon cancer, including 19 patients who had never had colonic neoplasia (who served as controls). In addition, 158 tissue samples were taken from tissues near or within colon cancers removed by resection and 16 tissue samples were taken near tubulovillous adenomas (TVAs) removed by resection. 568 triplicate tissue sections (a total of 1,704 tissue sections) from these tissue samples were evaluated by immunohistochemistry for 4 DNA repair proteins. Substantially reduced protein expression of Pms2, Ercc1 and Xpf occurred in field defects of up to 10 cm longitudinally distant from colon cancers or TVAs and within colon cancers. Expression of another DNA repair protein, Ku86, was infrequently reduced in these areas. When Pms2, Ercc1 or Xpf were reduced in protein expression, then either one or both of the other two proteins most often had reduced protein expression as well. The mean inner colon circumferences, from 32 resections, of the ascending, transverse and descending/sigmoid areas were measured as 6.6 cm, 5.8 cm and 6.3 cm, respectively. When combined with other measurements in the literature, this indicates the approximate mean number of colonic crypts in humans is 10 million.CONCLUSIONS:The substantial deficiencies in protein expression of DNA repair proteins Pms2, Ercc1 and Xpf in about 1 million crypts near cancers and TVAs suggests that the tumors arose in field defects that were deficient in DNA repair and that deficiencies in Pms2, Ercc1 and Xpf are early steps, often occurring together, in progression to colon cancer.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer

In carcinogenesis, the "field defect" is recognized clinically because of the high propensity of survivors of certain cancers to develop other malignancies of the same tissue type, often in a nearby location. Such field defects have been indicated in colon cancer. The molecular abnormalities that are responsible for a field defect in the colon should be detectable at high frequency in the histologically normal tissue surrounding a colonic adenocarcinoma or surrounding an adenoma with advanced neoplasia (well on the way to a colon cancer), but at low frequency in the colonic mucosa from patients without colonic neoplasia

In silico trials for treatment of acute ischemic stroke: Design and implementation

An in silico trial simulates a disease and its corresponding therapies on a cohort of virtual patients to support the development and evaluation of medical devices, drugs, and treatment. In silico trials have the potential to refine, reduce cost, and partially replace current in vivo studies, n

A consensus statement on perinatal mental health during the COVID-19 pandemic and recommendations for post-pandemic recovery and re-build

Introduction: The COVID-19 pandemic posed a significant lifecourse rupture, not least to those who had specific physical vulnerabilities to the virus, but also to those who were suffering with mental ill health. Women and birthing people who were pregnant, experienced a perinatal bereavement, or were in the first post-partum year (i.e., perinatal) were exposed to a number of risk factors for mental ill health, including alterations to the way in which their perinatal care was delivered. Methods: A consensus statement was derived from a cross-disciplinary collaboration of experts, whereby evidence from collaborative work on perinatal mental health during the COVID-19 pandemic was synthesised, and priorities were established as recommendations for research, healthcare practice, and policy. Results: The synthesis of research focused on the effect of the COVID-19 pandemic on perinatal health outcomes and care practices led to three immediate recommendations: what to retain, what to reinstate, and what to remove from perinatal mental healthcare provision. Longer-term recommendations for action were also made, categorised as follows: Equity and Relational Healthcare; Parity of Esteem in Mental and Physical Healthcare with an Emphasis on Specialist Perinatal Services; and Horizon Scanning for Perinatal Mental Health Research, Policy, & Practice. Discussion: The evidence base on the effect of the pandemic on perinatal mental health is growing. This consensus statement synthesises said evidence and makes recommendations for a post-pandemic recovery and re-build of perinatal mental health services and care provision

Gender comparisons of fat talk in the United Kingdom and the United States

This study compared different forms of body talk, including "fat talk," among 231 university men and women in central England (UK; n = 93) and the southeastern United States (US; n = 138). A 2 (gender) by 2 (country) repeated measures ANOVA across types of body talk (negative, self-accepting, positive) and additional Chi-square analyses revealed that there were differences across gender and between the UK and US cultures. Specifically, UK and US women were more likely to report frequently hearing or perceiving pressure to engage in fat talk than men. US women and men were also more likely to report pressure to join in self-accepting body talk than UK women and men