Tracing oncogene-driven remodelling of the intestinal stem cell niche

Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence1–3. Although mosaic analyses in Drosophila have advanced our understanding of such interactions4,5, it has been difficult to engineer parallel approaches in vertebrates. Here we present an oncogene-associated, multicolour reporter mouse model—the Red2Onco system—that allows differential tracing of mutant and wild-type cells in the same tissue. By applying this system to the small intestine, we show that oncogene-expressing mutant crypts alter the cellular organization of neighbouring wild-type crypts, thereby driving accelerated clonal drift. Crypts that express oncogenic KRAS or PI3K secrete BMP ligands that suppress local stem cell activity, while changes in PDGFRloCD81+ stromal cells induced by crypts with oncogenic PI3K alter the WNT signalling environment. Together, these results show how oncogene-driven paracrine remodelling creates a niche environment that is detrimental to the maintenance of wild-type tissue, promoting field transformation dominated by oncogenic clones

Development of Measure Yourself Concerns and Wellbeing for informal caregivers of people with cancer – a multicentred study

Purpose: Measure Yourself Concerns and Wellbeing (MYCaW) is a validated person-centred measure of the concerns and wellbeing of people affected by cancer. Research suggests that the concerns of informal caregivers (ICs) are as complex and severely rated as people with cancer, yet MYCaW has only been used to represent cancer patients’ concerns and wellbeing. This paper reports on the development of a new qualitative coding framework for MYCaW to capture the concerns of ICs, to better understand the needs of this group. Methods: This multicentred study involved collection of data from ICs receiving support from two UK cancer support charities (Penny Brohn UK and Cavendish Cancer Care). Qualitative codes were developed through a detailed thematic analysis of ICs’ stated concerns. Results: Thematic analysis of IC questionnaire data identified key themes which were translated into a coding framework with two overarching sections; 1. ‘informal caregiver concerns for self’ and 2. ‘informal caregiver concerns for the person with cancer’. Supercategories with specific accompanying codes were developed for each section. Two further rounds of framework testing across different cohorts allowed for iterative development and refinement of the framework content. Conclusions: This is the first person-centred tool specifically designed for capturing IC’s concerns through their own words. This coding framework will allow for IC data to be analysed using a rigorous and reproducible method, and therefore reported in a standardised way. This may also be of interest to those exploring the needs of ICs of people in other situations

Lorentz violation, Gravity, Dissipation and Holography

We reconsider Lorentz Violation (LV) at the fundamental level. We show that Lorentz Violation is intimately connected with gravity and that LV couplings in QFT must always be fields in a gravitational sector. Diffeomorphism invariance must be intact and the LV couplings transform as tensors under coordinate/frame changes. Therefore searching for LV is one of the most sensitive ways of looking for new physics, either new interactions or modifications of known ones. Energy dissipation/Cerenkov radiation is shown to be a generic feature of LV in QFT. A general computation is done in strongly coupled theories with gravity duals. It is shown that in scale invariant regimes, the energy dissipation rate depends non-triviallly on two characteristic exponents, the Lifshitz exponent and the hyperscaling violation exponent.Comment: LateX, 51 pages, 9 figures. (v2) References and comments added. Misprints correcte

Spirulina maxima Derived Pectin Nanoparticles Enhance the Immunomodulation, Stress Tolerance, and Wound Healing in Zebrafish

In this study, Spirulina maxima derived pectin nanoparticles (SmPNPs) were synthesized and multiple biological effects were investigated using in vitro and in vivo models. SmPNPs were not toxic to Raw 264.7 cells and zebrafish embryos up to 1 mg/mL and 200 µg/mL, respectively. SmPNPs upregulated Il 10, Cat, Sod 2, Def 1, Def 2, and Muc 1 in Raw 264.7 cells and tlr2, tlr4b, tlr5b, il1β, tnfα, cxcl8a, cxcl18b, ccl34a.4, ccl34b.4, muc5.1, muc5.2, muc5.3, hamp, cstd, hsp70, cat, and sod1 in the larvae and adult zebrafish, suggesting immunomodulatory activity. Exposure of larvae to SmPNPs followed by challenge with pathogenic bacterium Aeromonas hydrophila resulted a two-fold reduction of reactive oxygen species, indicating reduced oxidative stress compared to that in the control group. The cumulative percent survival of larvae exposed to SmPNPs (50 µg/mL) and adults fed diet supplemented with SmPNPs (4%) was 53.3% and 76.7%, respectively. Topical application of SmPNPs on adult zebrafish showed a higher wound healing percentage (48.9%) compared to that in the vehicle treated group (38.8%). Upregulated wound healing markers (tgfβ1, timp2b, mmp9, tnfα, il1β,ccl34a.4, and ccl34b.4), enhanced wound closure, and restored pigmentation indicated wound healing properties of SmPNPs. Overall, results uncover the multiple bioactivities of SmPNPs, which could be a promising biocompatible candidate for broad range of aquatic and human therapies

Predicting results of mycobacterial culture on sputum smear reversion after anti-tuberculous treatment: a case control study

<p>Abstract</p> <p>Background</p> <p>Little is currently known regarding sputum smear reversion (acid-fast smear becomes positive again after negative conversion) during anti-tuberculous treatment. This study aimed to evaluate its occurrence in patients with pulmonary tuberculosis (TB) and identify factors predicting results of mycobacterial culture for smear-reversion of sputum samples.</p> <p>Methods</p> <p>The retrospective review was performed in a tertiary referral center and a local teaching hospital in Taiwan. From 2000 to 2007, patients with smear-positive culture-confirmed pulmonary TB experiencing smear reversion after 14 days of anti-tuberculous treatment were identified.</p> <p>Results</p> <p>The 739 patients with smear-positive pulmonary TB had 74 (10%) episodes of sputum smear reversion that grew <it>Mycobacterium tuberculosis </it>in 22 (30%) (Mtb group). The remaining 52 episodes of culture-negative sputum samples were classified as the non-Mtb group. The anti-tuberculous regimen was modified after confirming smear reversion in 15 (20%). Fourteen episodes in the Mtb group and 15 in the non-Mtb group occurred during hospitalization. All were admitted to the negative-pressure rooms at the time of smear reversion. Statistical analysis showed that any TB drug resistance, smear reversion within the first two months of treatment or before culture conversion, and the absence of radiographic improvement before smear reversion were associated with the Mtb group. None of the smear reversion was due to viable <it>M. tuberculosis </it>if none of the four factors were present.</p> <p>Conclusions</p> <p>Sputum smear reversion develops in 10% of patients with smear-positive pulmonary TB, with 30% due to viable <it>M. tuberculosis </it>bacilli. Isolation and regimen modification may not be necessary for all drug-susceptible patients who already have radiographic improvement and develop smear reversion after two months of treatment or after sputum culture conversion.</p

Impact of creatinine production on the agreement between glomerular filtration rate estimates using cystatin C-derived, and 4- and 6-variable Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations

BACKGROUND. It has recently been reported that patient selection has a strong impact on the agreement between glomerular filtration rate (GFR) estimates from serum cystatin C and creatinine. The aim of our study was to evaluate the effect of creatinine production rate (CPR) on this subject. MATERIAL AND METHODS. GFR was estimated from serum cystatin C and from creatinine using the 4- and 6-variable Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in 50 healthy subjects, 43 patients with renal failure, 794 kidney and 104 liver transplant recipients, 61 patients with heart failure, 59 patients with biliary obstruction, and 113 critically ill patients. RESULTS. In the 295 patients with impaired CPR (< 900 mg/24 h/1.73 m(2)), discordances of more than 40% between GFR(MDRD4) and GFR(cystatinC) were observed in 38% of cases, between GFR(MDRD6) and GFR(cystatinC) in 22%, and between GFR(CKD-EPI) and GFR(cystatinC) in 27% (in all cases due to GFR overestimation from creatinine). In the 929 patients with maintained CPR (> 900 mg/24 h/1.73 m(2)), greater discordances than 40% between GFR(MDRD4) and GFR(cystatinC) were observed in 8% of cases, between GFR(MDRD6) and GFR(cystatinC) in 9%, and between GFR(CKD-EPI) and GFR(cystatinC) in 7% (in the major part of cases due to GFR overestimation from cystatin C). CONCLUSION. The main source of differences of more than 40% between GFR estimates from serum creatinine and cystatin C is a GFR overestimation in patients with low CPR and GFR underestimation in patients with high CPR by the creatinine-derived equations