Role of Heterozygous APC Mutation in Niche Succession and Initiation of Colorectal Cancer – A Computational Study

Mutations in the adenomatous polyposis coli (APC) gene are found in most colorectal cancers. They cause constitutive activation of proliferative pathways when both alleles of the gene are mutated. However studies on individuals with familial adenomatous polyposis (FAP) have shown that a single mutated APC allele can also create changes in the precancerous colon crypt, like increased number of stem cells, increased crypt fission, greater variability of DNA methylation patterns, and higher somatic mutation rates. In this paper, using a computational model of colon crypt dynamics, we evolve and investigate a hypothesis on the effect of heterozygous APC mutation that explains these different observations. Based on previous reports and the results from the computational model we propose the hypothesis that heterozygous APC mutation has the effect of increasing the chances for a stem cell to divide symmetrically, producing two stem cell daughters. We incorporate this hypothesis into the model and perform simulation experiments to investigate the consequences of the hypothesis. Simulations show that this hypothesis links together the changes in FAP crypts observed in previous studies. The simulations also show that an APC+/− stem cell gets selective advantages for dominating the crypt and progressing to cancer. This explains why most colon cancers are initiated by APC mutation. The results could have implications for preventing or retarding the onset of colon cancer in people with inherited or acquired mutation of one APC allele. Experimental validation of the hypothesis as well as investigation into the molecular mechanisms of this effect may therefore be worth undertaking

The restorative role of annexin A1 at the blood–brain barrier

Annexin A1 is a potent anti-inflammatory molecule that has been extensively studied in the peripheral immune system, but has not as yet been exploited as a therapeutic target/agent. In the last decade, we have undertaken the study of this molecule in the central nervous system (CNS), focusing particularly on the primary interface between the peripheral body and CNS: the blood–brain barrier. In this review, we provide an overview of the role of this molecule in the brain, with a particular emphasis on its functions in the endothelium of the blood–brain barrier, and the protective actions the molecule may exert in neuroinflammatory, neurovascular and metabolic disease. We focus on the possible new therapeutic avenues opened up by an increased understanding of the role of annexin A1 in the CNS vasculature, and its potential for repairing blood–brain barrier damage in disease and aging

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Passive Anti-Icing and Active Deicing Films.

Anti-icing and deicing are the two major pathways for suppressing adhesion of ice on surfaces, yet materials with dual capabilities are rare. In this work, we have designed a perfluorododecylated graphene nanoribbon (FDO-GNR) film that takes advantage of both the low polarizability of perfluorinated carbons and the intrinsic conductive nature of graphene nanoribbons. The FDO-GNR films are superhydrophobic with a sheet resistance below 8 kΩ·sq(-1) and then exhibit an anti-icing property that prevents freezing of incoming ice-cold water down to -14 °C. After that point, voltage can be applied to the films to resistively heat and deice the surface. Further a lubricating liquid can be employed to create a slippery surface to improve the film's deicing performance. The FDO-GNR films can be easily switched between the superhydrophobic anti-icing mode and the slippery deicing mode by applying the lubricant. A spray-coating method makes it suitable for large-scale applications. The anti-icing and deicing properties render the FDO-GNR films with promise for use in extreme environments

Tin Disulfide Nanoplates on Graphene Nanoribbons for Full Lithium Ion Batteries.

A nanocomposite material made of layered tin disulfide (SnS2) nanoplates vertically grown on reduced graphene oxide nanoribbons (rGONRs) has been successfully developed as an anode in lithium ion batteries by a facile method. At a rate of 0.4 A/g, the material exhibits a high discharge capacity of 823 mAh/g even after 800 cycles. It shows excellent rate stability when the current density varies from 0.1 to 3.0 A/g with a Coulombic efficiency larger than 99%. In order to demonstrate the anode material for practical applications, SnS2-rGONR/LiCoO2 full cells were constructed. To the best of our knowledge, this is the first time that a full cell has been successfully developed using metal chalcogenides as an anode. The full cell delivers a high capacity of 642 mAh/g at 0.2 A/g, superior rate, and cycling stability after long-term cycling. Moreover, the full cell has a high output working voltage of 3.4 V. These excellent lithium storage performances in half and full cells can be mainly attributed to the synergistic effect between the highly conductive network of rGONRs and the high lithium-ion storage capability of layered SnS2 nanoplates

Composites of Graphene Nanoribbon Stacks and Epoxy for Joule Heating and Deicing of Surfaces.

A conductive composite of graphene nanoribbon (GNR) stacks and epoxy is fabricated. The epoxy is filled with the GNR stacks, which serve as a conductive additive. The GNR stacks are on average 30 nm thick, 250 nm wide, and 30 μm long. The GNR-filled epoxy composite exhibits a conductivity >100 S/m at 5 wt % GNR content. This permits application of the GNR-epoxy composite for deicing of surfaces through Joule (voltage-induced) heating generated by the voltage across the composite. A power density of 0.5 W/cm(2) was delivered to remove ∼1 cm-thick (14 g) monolith of ice from a static helicopter rotor blade surface in a -20 °C environment