Can Peto\u27s paradox be used as the null hypothesis to identify the role of evolution in natural resistance to cancer? A critical review

BACKGROUND: Carcinogenesis affects not only humans but almost all metazoan species. Understanding the rules driving the occurrence of cancers in the wild is currently expected to provide crucial insights into identifying how some species may have evolved efficient cancer resistance mechanisms. Recently the absence of correlation across species between cancer prevalence and body size (coined as Peto\u27s paradox) has attracted a lot of attention. Indeed, the disparity between this null hypothesis, where every cell is assumed to have an identical probability to undergo malignant transformation, and empirical observations is particularly important to understand, due to the fact that it could facilitate the identification of animal species that are more resistant to carcinogenesis than expected. Moreover it would open up ways to identify the selective pressures that may be involved in cancer resistance. However, Peto\u27s paradox relies on several questionable assumptions, complicating the interpretation of the divergence between expected and observed cancer incidences. DISCUSSIONS: Here we review and challenge the different hypotheses on which this paradox relies on with the aim of identifying how this null hypothesis could be better estimated in order to provide a standard protocol to study the deviation between theoretical/theoretically predicted and observed cancer incidence. We show that due to the disproportion and restricted nature of available data on animal cancers, applying Peto\u27s hypotheses at species level could result in erroneous conclusions, and actually assume the existence of a paradox. Instead of using species level comparisons, we propose an organ level approach to be a more accurate test of Peto\u27s assumptions. SUMMARY: The accuracy of Peto\u27s paradox assumptions are rarely valid and/or quantifiable, suggesting the need to reconsider the use of Peto\u27s paradox as a null hypothesis in identifying the influence of natural selection on cancer resistance mechanisms

Cdx2 homeoprotein inhibits non-homologous end joining in colon cancer but not in leukemia cells

Cdx2, a gene of the paraHox cluster, encodes a homeodomain transcription factor that plays numerous roles in embryonic development and in homeostasis of the adult intestine. Whereas Cdx2 exerts a tumor suppressor function in the gut, its abnormal ectopic expression in acute leukemia is associated to a pro-oncogenic function. To try to understand this duality, we have hypothesized that Cdx2 may interact with different protein partners in the two tissues and set up experiments to identify them by tandem affinity purification. We show here that Cdx2 interacts with the Ku heterodimer specifically in intestinal cells, but not in leukemia cells, via its homeodomain. Ku proteins do not affect Cdx2 transcriptional activity. However, Cdx2 inhibits in vivo and in vitro the DNA repair activity mediated by Ku proteins in intestinal cells. Whereas Cdx2 does not affect the recruitment of Ku proteins and DNA-PKcs into the DNA repair complex, it inhibits DNA-PKcs activity. Thus, we report here a new function of Cdx2, acting as an inhibitor of the DNA repair machinery, that may contribute to its tumor suppressor function specifically in the gut

Including ELSI research questions in newborn screening pilot studies

Background The evidence review processes for adding new conditions to state newborn screening (NBS) panels rely on data from pilot studies aimed at assessing the potential benefits and harms of screening. However, the consideration of ethical, legal, and social implications (ELSI) of screening within this research has been limited. This paper outlines important ELSI issues related to newborn screening policy and practices as a resource to help researchers integrate ELSI into NBS pilot studies. Approach Members of the Bioethics and Legal Workgroup for the Newborn Screening Translational Research Network facilitated a series of professional and public discussions aimed at engaging NBS stakeholders to identify important existing and emerging ELSI challenges accompanying NBS. Results Integrating ELSI questions into pilot studies will help NBS programs to better understand the potential impact of screening for a new condition on newborns and families, and make crucial policy decisions aimed at maximized benefits and mitigating the potential negative medical or social implications of screening

Cognitive Motor Dissociation in Disorders of Consciousness.

Patients with brain injury who are unresponsive to commands may perform cognitive tasks that are detected on functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). This phenomenon, known as cognitive motor dissociation, has not been systematically studied in a large cohort of persons with disorders of consciousness. In this prospective cohort study conducted at six international centers, we collected clinical, behavioral, and task-based fMRI and EEG data from a convenience sample of 353 adults with disorders of consciousness. We assessed the response to commands on task-based fMRI or EEG in participants without an observable response to verbal commands (i.e., those with a behavioral diagnosis of coma, vegetative state, or minimally conscious state-minus) and in participants with an observable response to verbal commands. The presence or absence of an observable response to commands was assessed with the use of the Coma Recovery Scale-Revised (CRS-R). Data from fMRI only or EEG only were available for 65% of the participants, and data from both fMRI and EEG were available for 35%. The median age of the participants was 37.9 years, the median time between brain injury and assessment with the CRS-R was 7.9 months (25% of the participants were assessed with the CRS-R within 28 days after injury), and brain trauma was an etiologic factor in 50%. We detected cognitive motor dissociation in 60 of the 241 participants (25%) without an observable response to commands, of whom 11 had been assessed with the use of fMRI only, 13 with the use of EEG only, and 36 with the use of both techniques. Cognitive motor dissociation was associated with younger age, longer time since injury, and brain trauma as an etiologic factor. In contrast, responses on task-based fMRI or EEG occurred in 43 of 112 participants (38%) with an observable response to verbal commands. Approximately one in four participants without an observable response to commands performed a cognitive task on fMRI or EEG as compared with one in three participants with an observable response to commands

Multimodal Imaging in Acute Macular Neuroretinopathy

A 44-year-old woman noticed bilateral irregular scotomata associated with photopsias of 6-month duration. Ophthalmoscopic examination demonstrated multiple bilateral, pericentral, hypopigmented, petaloid, macular lesions evident on Amsler grid associated with paracentral hyperreflective lesions on optical coherence tomography in the outer plexiform and nuclear layers. Indocyanine green angiography revealed patches of choroidal ischemia consistent with acute macular neuroretinopathy

Multimodal Imaging in Acute Macular Neuroretinopathy

A 44-year-old woman noticed bilateral irregular scotomata associated with photopsias of 6-month duration. Ophthalmoscopic examination demonstrated multiple bilateral, pericentral, hypopigmented, petaloid, macular lesions evident on Amsler grid associated with paracentral hyperreflective lesions on optical coherence tomography in the outer plexiform and nuclear layers. Indocyanine green angiography revealed patches of choroidal ischemia consistent with acute macular neuroretinopathy

Towards new design tools for integrating environmental criteria in the design process of architectural and urban projects in developing countries

International audienceCities are complex systems rapidly evolving in a context of strong interweaving between problems and solutions especially in developing countries. The architectural design and the city management processes are renewed by the eruption of sustainable development. These processes are multi-scale: new geographical, temporal and political scales are emerging, calling for new tools for monitoring architectural and urban environmental changes, for implementing comprehensive plans, or for communicating between practitioners. Number of communities in developing countries has taken initiatives to develop tools based on sets of sustainability indicators. But are these tools really helpful during the architectural design or the urban management processes characterized by complexity, fussy or lacunar data, various time and space scales and multi-actors decisions? We will demonstrate in this paper, that these systems, aiming at "a posteriori" diagnosis, cannot be used directly during these fuzzy processes, especially during their early phases very critical with respect to solutions. By adjoining them multicriteria decision support techniques, they may become powerful tools for decision support. Architectural and urban designs may be evaluated using a set of weighted environmental criteria and methods to aggregate the various dimensions involved. Some Electre methods based on the comparison between pairs of solutions have been successfully used in that sense. A step further away may be performed from decision to evaluation support tools, by comparing ongoing urban designs against convolutions of systems of practitioners' values. This "value focused" approach, combined with the Electre-Tri method has been successfully integrated for evaluating the performance of urban projects, according to their distance to various user-defined systems of values

Effect of left paratracheal pressure on left carotid blood flow

peer reviewedIntroduction: Gautier et al. demonstrated that a compression in the left paratracheal region (left paratracheal pressure, LPP) can be used to seal the oesophagus. However, at this level, the left common carotid artery is very close to the carotid that could be affected during the manipulation. This study aimed to assess the hemodynamic effects of LPP on the carotid blood flow. Methods: We prospectively included 47 healthy adult volunteers. We excluded pregnant women and people with anomalies of the carotid arteries. The common and internal carotid arteries were preliminarily studied with ultrasounds to exclude atheromatous plaques or vascular malformation. A planimetry of the common and internal carotid arteries was performed. Doppler echography served to measure the peak systolic (PSV) and end-diastolic velocities (EDV) in the common and internal carotid arteries. All measurements were repeated while applying LPP. Results: Forty-seven participants were enrolled (32 women; mean [SD] age: 42 [13] years). The mean PSV difference [95% CI] in the left common carotid artery before and after LPP at the group level was −15.30 [−31.09 to 0.48] cm s−1 (p =.14). The mean surface difference [95% CI] in the left common carotid artery before and after LPP was 24.52 [6.11–42.92] mm2 (p =.11). Similarly, the same surface at the level of the left internal carotid artery changed by −18.89 [−51.59 to 13.80] mm2 after LPP (p =.58). Conclusions: Our results suggest that LPP does not have a significant effect on carotid blood flow in individuals without a carotid pathology. However, the safety of the manoeuvre should be evaluated in patients at risk of carotid anomalies