Emodin reduces tumor burden by diminishing M2-like macrophages in colorectal cancer

Emodin, a natural anthraquinone, has been shown to have anti-tumorigenic properties and may be an effective therapy for colorectal cancer (CRC). However, its clinical development has been hampered by a poor understanding of its mechanism of action. The purpose of this study was to 1) evaluate the efficacy of emodin in mouse models of intestinal/colorectal cancer and 2) to examine the impact of emodin on macrophage behavior in the context of CRC. We utilized a genetic model of intestinal cancer (ApcMin/+) and a chemically induced model of CRC (AOM/DSS). Emodin was administered orally (40 mg/kg or 80 mg/kg in AOM/DSS and 80mg/kg in ApcMin/+) 3x/week to observe its preventative effects. Emodin reduced polyp count and size in both rodent models (p<0.05). We further analyzed the colon microenvironment of AOM/DSS mice and found that mice treated with emodin exhibited lower pro-tumorigenic M2-like macrophages and a reduced ratio of M2/M1 macrophages within the colon (p<0.05). Despite this, we did not detect any significant changes in M2-associated cytokines (IL10, IL4, and Tgfb1) nor M1-associated cytokines (IL6, TNFα, IL1β, and IFNγ) within excised polyps. However, there was a significant increase in NOS2 expression (M1 marker) in mice treated with 80 mg/kg emodin (p<0.05). To confirm emodin's effects on macrophages, we exposed bone marrow-derived macrophages (BMDMs) to C26 colon cancer cell conditioned media. Supporting our in vivo data, emodin reduced M2-like macrophages. Overall, these data support the development of emodin as a natural compound for prevention of CRC given its ability to target pro-tumor macrophages.

Different sites of actions make different responses to thiazolidinediones between mouse and rat models of fatty liver

Therapeutic approach for NAFLD is limited and there are no approved drugs. Pioglitazone (PGZ), a thiazolidinedione (TZD) that acts via peroxisome proliferator activated receptor gamma (PPARγ) is the only agent that has shown consistent benefit and efficacy in clinical trials. However, the mechanism of its therapeutic effect on NAFLD remains unclear. The poor understanding may be due to problems with mouse, a species most used for animal experiments. TZDs exacerbate fatty liver in mouse models while they improve it in rat models like in human patients. Therefore, we compared the effects of TZDs including PGZ and rosiglitazone (RGZ) in ob/ob mice and Lepmkyo/Lepmkyo rats, models of leptin-deficient obesity, and A-ZIP/F-1 mice and seipin knockout (SKO) rats, models of generalized lipodystrophy. Pparg mRNA expression was markedly upregulated in fatty livers of mouse models while it was unchanged in rat models. TZDs exacerbated fatty liver in ob/ob and A-ZIP/F-1 mice, improved it in Lepmkyo/Lepmkyo rats and showed no effect in SKO rats. Gene expression analyses of Pparg and its target gene, Fsp27 revealed that PPARγ in the adipose tissue is the exclusive therapeutic target of TZDs in rats but PPARγ in the liver in addition to the adipose tissue is also a major site of actions for TZDs in mice. Although the response to TZDs in mice is the complete opposite of that in human patients, no report has pointed out the problem with TZD studies using mouse models so far. The present study might provide useful suggestions in research on TZDs.

Reviewing the elements of marine ice cliff instability

Antarctica’s ice sheets are the largest potential sea-level rise contributors, but projections of future sea-level rise yield wide ranges of estimates under different emission scenarios. An important factor in the variability of estimates is marine ice cliff instability (MICI). Inclusion of MICI yields the highest potential sea-level rise cases but also the largest uncertainty due to poor understanding of the factors that control it and the mechanisms of how it happens. Although evidence for MICI has been implied by paleo-ice sheet studies and observations of keel plough mark on sea-floor, recent statistical and modelling studies have suggested a lower magnitude of MICI effect on sea-level rise due to thinning of ice sheets and buttressing forces exerted on potentially failing cliffs. This paper reviews the factors that control MICI with the goal of identifying priorities for modern ice sheet studies to better bound the estimates.

Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale

Delivery of exogenous mRNA using lipid nanoparticles (LNPs) is a promising strategy for therapeutics. However, a bottleneck remains in the poor understanding of the parameters that correlate with endosomal escape versus cytotoxicity. To address this problem, we compared the endosomal distribution of six LNP-mRNA formulations of diverse chemical composition and efficacy, similar to those used in mRNA-based vaccines, in primary human adipocytes, fibroblasts, and HeLa cells. Surprisingly, we found that total uptake is not a sufficient predictor of delivery, and different LNPs vary considerably in endosomal distributions. Prolonged uptake impaired endosomal acidification, a sign of cytotoxicity, and caused mRNA to accumulate in compartments defective in cargo transport and unproductive for delivery. In contrast, early endocytic/recycling compartments have the highest probability for mRNA escape. By using super-resolution microscopy, we could resolve a single LNP-mRNA within subendosomal compartments and capture events of mRNA escape from endosomal recycling tubules. Our results change the view of the mechanisms of endosomal escape and define quantitative parameters to guide the development of mRNA formulations toward higher efficacy and lower cytotoxicity.

Proposal for a mechanical model of mobile shales

Structural systems involving mobile shale represent one of the most difficult challenges for geoscientists dedicated to exploring the subsurface structure of continental margins. Mobile-shale structures range from surficial mud volcanoes to deeply buried shale diapirs and shale-cored folds. Where mobile shales occur, seismic imaging is typically poor, drilling is hazardous, and established principles to guide interpretation are few. The central problem leading to these issues is the poor understanding of the mechanical behaviour of mobile shales. Here we propose that mobile shales are at critical state, thus we define mobile shales as “bodies of clay-rich sediment or sedimentary rock undergoing penetrative, (visco-) plastic deformation at the critical state”. We discuss how this proposition can explain key observations associated with mobile shales. The critical-state model can explain the occurrence of both fluidized (no grain contact) shales (e.g., in mud volcanoes) and more viscous shales flowing with grain-to-grain contact (e.g., in shale diapirs), mobilization of cemented and compacted shales, and the role of overpressure in shale mobility. Our model offers new avenues for understanding complex and fascinating mobile-shale structures.

Cognitive-Behavioral Styles of Dementia Care Management: Targeting and Tailoring to Style

Despite an extensive literature on the stress process of caregiving, little attention has focused on how caregivers provide care (caregiving styles). To explore caregiving styles among 100 primary caregivers for persons living with dementia, we utilize k-modes machine learning analysis. This technique clusters caregiver’s use of behavioral (Dementia Management Strategies Scale; criticism, active management, encouragement) and cognitive (Caregiver Readiness Scale; understanding, adaptability) approaches into style profiles. Three styles were identified: Managers (n=25; high use of criticism, moderate use of active management and encouragement, poor understanding and adaptability), Adapters (n=48; low use of criticism, high use of adaptive management and encouragement, good understanding and adaptability), and Avoiders (n=27; low use of all behavioral strategies, moderate adaptability and understanding). Styles differ by demographic and care characteristics. Findings suggest that caregivers have variable approaches to care that are measurable, thus, targeting/tailoring interventions to caregiver style could be an effective approach.

P-BN36 Trends in Management of Gall Bladder Polyps Over 10 Years

Background Gall Bladder (GB) polyps are abnormal growths on the inner lining that project into the lumen of the GB. They are a rare incidental radiological finding, with a prevalence ranging from 0.3% to 9.5%. The majority of these turn out to be pseudopolyps, however, correct follow up and management is essential to ensure that true polyps, which may be malignant or have malignant potential, are not missed. We hypothesised that a lack of familiarity and poor understanding of the significance of GB polyps, along with the fact that they are frequently noted as an incidental finding by non-surgical specialties, has led to variable management of GB polyps. In order to investigate this, we carried out a retrospective analysis of the management of GB polyps at our large district general hospital over the last 10 years. Methods Patients were identified for this retrospective ten-year cohort study from our database by identifying all patients coded under the ‘International Statistical Classification of Diseases and Related Health Problems (ICD 10) code K 82.8, other specified diseases of gall bladder’. Patients with other diagnoses, such as gall bladder dysfunction, were excluded after review of electronic patient record (EPR) (Sunrise, Allscripts). These records facilitated review of emergency attendances, clinic letters, investigations, and histological results for those diagnosed with a gall bladder polyp. Analysis was performed using Microsoft Excel. Results A total of 154 GB polyps were identified, of which general surgeons diagnosed 63% and 74% went on to have further management. 11% of patients in our cohort proceeded straight to laparoscopic cholecystectomy, 33% underwent planned surveillance, 20% had unplanned scans and 12% were either followed up with the GP or referred back to clinic. A further 26% were discharged. In total, 35% of patients ultimately had a laparoscopic cholecystectomy and the average time from diagnosis to operation was 19 months. There was a strong negative correlation (-0.72) in reduction in time to operation over the 10-year study period. We also identified a decline in patients being followed up over time (-0.14) and in patients receiving no further management post diagnosis (-0.19). Conclusions Management of GB polyps has historically been and continues to be very variable, however, over our 10-year study period we have identified a trend towards operating earlier, with more patients being listed for surgery straight from diagnosis, and more having a shorter period of surveillance. In our cohort there has been no change in number of patients who have further planned surveillance imaging after diagnosis or in numbers of patients discharged with no further investigation or management. We postulate that this variability in management may be due to the fact that GB polyps are often identified as an incidental finding by non-surgical specialists, together with a general lack of awareness of current guidelines and a poor understanding of the pathophysiology.

ORAL CANCER AWARENESS AMONG NON-MEDICAL PROFESSIONALS - A CROSS SECTIONAL STUDY IN LADAKH

Introduction:Oral Cancer is the fifth‑most common cancer and is the cause of 130,000 deaths worldwide annually. It is a global health problem with an increasing incidence and mortality rate and also has one of the lowest survival rates.Therefore, the aim of this study is to assess the awareness about Oral Cancer among non-medicalprofessionals in Ladakh. Methodology:A questionnaire-based survey was conducted over a period ofsixmonth among the different areas of Ladakh to assess the knowledge and awareness about Oral Cancer among non-medical professionals in Ladakh. A questionnaire containing 20 questions pertaining to awareness, signs, symptoms and risk factors of Oral Cancer was submitted to the participants. Results:Participants who completed the questionnaire had a poor understanding of Oral Cancer, particularly with regard to etiology, signs, symptoms & risk factors. Conclusion:Overall, the awareness about Oral Cancer among the non-medical professionalsin Ladakh was not satisfactory pointing to the need of mass awareness and dissemination of information about Oral Cancer and its risk factors.

Metabolic analysis of a bacterial synthetic community from maize roots provides new mechanistic insights into microbiome stability

Stability is a desirable property for agricultural microbiomes, but there is a poor understanding of the mechanisms that mediate microbial community stability. Recently, a representative bacterial synthetic community from maize roots has been proposed as a model system to study microbiome stability (Niu 2017, PNAS, 114:E2450). This SynCom assembles stably when all seven members are present, but community diversity collapses without the keystone E. cloacae strain. The aim of this study was to assess the role of metabolites for the stability of this SynCom, by defining the metabolic niches occupied by each strain, as well as their cross-feeding phenotypes and B-vitamin dependencies. We show that the individual member strains occupy complementary metabolic niches, measured by the depletion of distinct metabolites in exometabolomic experiments, as well as contrasting growth phenotypes on diverse carbon substrates. Minimal medium experiments show that the established seven-member community comprises a mixture of prototrophic and auxotrophic strains. Correspondingly, experimental cross-feeding phenotypes showed that spent media harvested from the prototrophic strains can sustain growth of two auxotrophs. We suggest that the metabolic mechanisms exhibited by this SynCom could serve as design principles to inform the rational assembly of stable plant-associated microbial communities.