Fecal microbiota transplantation (FMT) has emerged as a highly effective therapy for refractory, recurrent Clostridium difficile infection (CDI), which develops following antibiotic treatments. ...Intestinal microbiota play a critical role in the metabolism of bile acids in the colon, which in turn have major effects on the lifecycle of C. difficile bacteria. We hypothesized that fecal bile acid composition is altered in patients with recurrent CDI and that FMT results in its normalization. General metabolomics and targeted bile acid analyses were performed on fecal extracts from patients with recurrent CDI treated with FMT and their donors. In addition, 16S rRNA gene sequencing was used to determine the bacterial composition of pre- and post-FMT fecal samples. Taxonomic bacterial composition of fecal samples from FMT recipients showed rapid change and became similar to the donor after the procedure. Pre-FMT fecal samples contained high concentrations of primary bile acids and bile salts, while secondary bile acids were nearly undetectable. In contrast, post-FMT fecal samples contained mostly secondary bile acids, as did non-CDI donor samples. Therefore, our analysis showed that FMT resulted in normalization of fecal bacterial community structure and metabolic composition. Importantly, metabolism of bile salts and primary bile acids to secondary bile acids is disrupted in patients with recurrent CDI, and FMT corrects this abnormality. Since individual bile salts and bile acids have pro-germinant and inhibitory activities, the changes suggest that correction of bile acid metabolism is likely a major mechanism by which FMT results in a cure and prevents recurrence of CDI.
Epidemiology of Anal Canal Cancer Nelson, Valerie M; Benson, 3rd, Al B
Surgical oncology clinics of North America,
01/2017, Letnik:
26, Številka:
1
Journal Article
Recenzirano
Anal cancer is a rare malignancy, although its incidence has been increasingly in recent decades. This article discusses risk factors for anal cancer and how these risk factors affect the changing ...demographics of this disease.
Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal stiffening in tumours should ...identify biomarkers to stratify patients for therapy and interventions to improve outcome. We profiled lysyl hydroxylase-mediated and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in aggressive human breast cancer subtypes with the stiffest stroma. These tissues harbour the highest number of tumour-associated macrophages, whose therapeutic ablation in experimental models reduced metastasis, and decreased collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme, lysyl oxidase, had no impact on collagen crosslinking in PyMT mammary tumours, whereas stromal cell targeting did. Stromal cells in microdissected human tumours expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of biopsies from a cohort of patients with breast cancer revealed that stromal expression of lysyl hydroxylase 2, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening, correlated significantly with disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumour aggression and identify lysyl hydroxylase 2 as a stromal biomarker.
Understanding patterns of spontaneous mutations is of fundamental interest in studies of human genome evolution and genetic disease. Here, we used extremely rare variants in humans to model the ...molecular spectrum of single-nucleotide mutations. Compared to common variants in humans and human-chimpanzee fixed differences (substitutions), rare variants, on average, arose more recently in the human lineage and are less affected by the potentially confounding effects of natural selection, population demographic history, and biased gene conversion. We analyzed variants obtained from a population-based sequencing study of 202 genes in >14,000 individuals. We observed considerable variability in the per-gene mutation rate, which was correlated with local GC content, but not recombination rate. Using >20,000 variants with a derived allele frequency ≤ 10(-4), we examined the effect of local GC content and recombination rate on individual variant subtypes and performed comparisons with common variants and substitutions. The influence of local GC content on rare variants differed from that on common variants or substitutions, and the differences varied by variant subtype. Furthermore, recombination rate and recombination hotspots have little effect on rare variants of any subtype, yet both have a relatively strong impact on multiple variant subtypes in common variants and substitutions. This observation is consistent with the effect of biased gene conversion or selection-dependent processes. Our results highlight the distinct biases inherent in the initial mutation patterns and subsequent evolutionary processes that affect segregating variants.
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•Abnormalities in cell nuclear morphology is a hallmark of cancer.•Changes in nuclear morphology are utilized by pathologists in tumor grading.•Heterogeneity in DCIS grade may ...influence invasive progression.•Current pathological assessment of DCIS does not incorporate heterogeneity.•I mage analysis is a supplemental tool for pathologists to quantitatively grade DCIS.
Abnormalities in cell nuclear morphology are a hallmark of cancer. Histological assessment of cell nuclear morphology is frequently used by pathologists to grade ductal carcinoma in situ (DCIS). Objective methods that allow standardization and reproducibility of cell nuclear morphology assessment have potential to improve the criteria needed to predict DCIS progression and recurrence. Aggressive cancers are highly heterogeneous. We asked whether cell nuclear morphology heterogeneity could be incorporated into a metric to classify DCIS. We developed a nuclear heterogeneity image index to objectively, and quantitatively grade DCIS. A whole-tissue cell nuclear morphological analysis, that classified tumors by the worst ten percent in a duct-by-duct manner, identified nuclear size ranges associated with each DCIS grade. Digital image analysis further revealed increasing heterogeneity within ducts or between ducts in tissues of worsening DCIS grade. The findings illustrate how digital image analysis comprises a supplemental tool for pathologists to objectively classify DCIS and in the future, may provide a method to predict patient outcome through analysis of nuclear heterogeneity.
Recognition of specific molecule signatures of microbes, including pathogens, induces innate immune responses in plants, as well as in animals. Analogously, a nematode pheromone, the ascaroside ...ascr#18, induces hallmark plant defences including activation of (a) mitogen‐activated protein kinases, (b) salicylic acid‐ and jasmonic acid‐mediated defence signalling pathways and (c) defence gene expression and provides protection to a broad spectrum of pathogens. Ascr#18 is a member of an evolutionarily conserved family of nematode signalling molecules and is the major ascaroside secreted by plant–parasitic nematodes. Here, we report the effects of ascr#18 on resistance in four of the major economically important crops: maize, rice, wheat and soybean to some of their associated pathogens. Treatment with low nanomolar to low micromolar concentrations of ascr#18 provided from partial to strong protection in seven of eight plant–pathogen systems tested with viruses, bacteria, fungi, oomycetes and nematodes. This research may have potential to improve agricultural sustainability by reducing use of potentially harmful agrochemicals and enhance food security worldwide.
Demands for reducing energy consumption and environmental impacts are the major driving factors for the development of natural fiber–reinforced composites (NFRCs) in many sectors. Compared with ...synthesized fiber, natural fiber provides several advantages in terms of biodegradability, light weight, low price, life-cycle superiority, and satisfactory mechanical properties. However, the inherent features of plant-based natural fibers have presented challenges to the development and application of NFRCs, such as variable fiber quality, limited mechanical properties, water absorption, low thermal stability, incompatibility with hydrophobic matrices, and propensity to agglomeration. Substantial research has recently been conducted to address these challenges for improved performance of NFRCs and their applications. This article reviews the recent advancements of plant-based NFRCs, focusing on strategies and breakthroughs in enhancing the NFRCs’ performance, including fiber modification, fiber hybridization, lignocellulosic fillers incorporation, conventional processing techniques, additive manufacturing (3D printing), and new fiber source exploration. The sustainability of plant-based NFRCs using life-cycle assessment and the burgeoning applications of NFRCs with emphasis on the automotive industry are also discussed.
We investigated the relative roles of Fe and silicic acid availabilities in regulating Si uptake rates across the Polar Frontal Zone in the Pacific Sector of the Southern Ocean (59–68°S, 170°W) ...during the US JGOFS Antarctic Environment Southern Ocean Process Study (AESOPS). Meridional gradients in silicic acid concentration (Si(OH)
4) of about 0.25–0.56
μM
km
−1 were observed in this area during austral spring and summer, 1997–1998, with Si(OH)
4 ranging from <1 to 15
μM on the north side of the gradient to 40–60
μM on the south side. In two pairs of shipboard bottle-enrichment experiments conducted north and south of the Si gradient in spring and summer, we measured the effects of Fe, Zn and Si additions on
32
Si(OH)
4
and
15
NO
3−
uptake rates, biogenic silica concentrations and Si(OH)
4
:
NO
3
− uptake ratios. Fe addition had little or no effect on Si uptake rates in enrichments conducted in the low-Si waters north of the Si gradient. However, Fe addition increased Si uptake rates 3–5 times over controls in enrichments conducted in the high-Si waters south of the gradient, in both spring and summer. Fe addition decreased Si(OH)
4
:
NO
3
− uptake ratios by 2–5 times, largely due to stimulation of NO
3
− uptake rates. Zn addition had no effect on Si(OH)
4 and NO
3
− uptake rates. Short-term (24
h) Si additions had varying effects on Si uptake rates, depending on season and location. In spring, additions of 40
μM Si to water from bottle enrichments, conducted north of the Si gradient (in situ Si(OH)
4 ∼15
μM) did not increase Si uptake rates initially, but did increase uptake rates after 8 days. In the summer enrichment north of the Si gradient (in situ Si(OH)
4 ∼5
μM), 50
μM
Si additions doubled in situ Si uptake rates in the initial water collected for the enrichment, and increased Si uptake rates as much as 16-fold during the experiment. South of the Si gradient, where in situ Si(OH)
4 was >40
μM in both spring and summer, Si addition had no effect on in situ Si uptake rates in the initial enrichment water nor on any Si uptake rates measured during the experiment. Our results indicate that both Fe and Si availabilities regulate Si uptake rates and silica production in the Southern Ocean along 170°W. Fe limitation appears to restrict Si uptake rates south of the Si gradient and plays a role in preventing Si depletion south of the ACC, where ambient Si(OH)
4 never fell below 40
μM during 1997–1998. Our experiments in the Seasonal Ice Zone at 62° suggest that Si uptake in this area switched from being Fe-limited in the spring, when in situ Si(OH)
4 was >40
μM, to Si-limited in the summer, when Si(OH)
4 was <5
μM. Thus, while Fe limitation could be reducing Si uptake rates in this area, it does not prevent eventual Si drawdown. Our experiments also indicate that Si and Fe co-limitation may occur north of the Si gradient, such that Si uptake rates will not reach maximal levels until both Si and Fe limitations are relieved. The interaction between Fe and Si limitation in these waters and the high Si(OH)
4
:
NO
3
− uptake ratios observed at in situ dissolved Fe concentrations can have a large impact on Si and N biogeochemistry in the Southern Ocean.
Although the potential impact of food fortification to improve the micronutrient status of populations has been demonstrated beyond a doubt, it is constrained in practice by critical gaps in program ...design and implementation. These are partly linked to suboptimal decision making.
We aimed to demonstrate how the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Evidence to Decision (EtD) framework for health system and public health decisions can be applied to formulate recommendations and make decisions in national food fortification programming.
Following a program impact pathway, we reviewed the literature to define the key decision types and identify the corresponding decision makers necessary for designing and implementing effective food fortification programs. We then applied the GRADE EtD framework to the Nigerian fortification program to illustrate how evidence-informed assessments and conclusions can be made.
Fortification program decisions were classified into 5 types: 1) program initiation; 2) program design; 3) program delivery; 4) program impact; and 5) program continuation. Policymakers, food processors, and (in cases dependent on or considering external funding) development partners are the main decision makers in a fortification program, whereas technical partners play important roles in translating evidence into contextualized recommendations. The availability and certainty of evidence for fortification programs are often low (e.g., quality and coverage data are not routinely collected and there are challenges evaluating impact in such population-based programs using randomized controlled trials) yet decisions must still be made, underscoring the importance of using available evidence. Furthermore, when making program initiation and continuation decisions, coordination with overlapping micronutrient interventions is needed where they coexist.
This framework is a practical tool to strengthen decision-making processes in fortification programs. Using evidence in a systematic and transparent way for decision making can improve fortification program design, delivery, and ultimately health impacts.
This article demonstrates how a decision-making framework for health system and public health decisions can be applied to national food fortification programs.
Both the addition of neoadjuvant chemoradiation therapy and improvements in surgical techniques have improved local control and overall survival for locally advanced rectal cancer patients over the ...past few decades. The addition of adjuvant chemotherapy has likely improved outcomes as well, though the contribution has been more difficult to quantify. At present, the majority of resected locally advanced rectal cancer patients receive adjuvant chemotherapy, though there is great variability in this practice based on both patient and institution characteristics. Recently, questions have been raised regarding which sub-groups of patients benefit most from adjuvant chemotherapy. As pathologic complete response (pCR) is increasingly found to be a reasonable surrogate for long-term favorable outcomes, some have questioned the need for adjuvant therapy in this select group of patients. Multiple retrospective analyses have shown minimal to no benefit for adjuvant chemotherapy in this group. Indeed, the patients most consistently shown to benefit from adjuvant therapy both in terms of disease free survival (DFS) and overall survival (OS) are those who achieve an intermediate pathologic response to neoadjuvant treatment. Tumors that have high expression of thymidylate synthetase have also shown to benefit from adjuvant therapy. More study is needed into clinical and molecular features that predict patient benefit from adjuvant therapy.
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