The majority of dietary fibre (DF) originates from plant cell walls. Chemically, DF mostly comprise carbohydrate polymers, which resist hydrolysis by digestive enzymes in the mammalian small ...intestine, but can be fermented by large intestinal bacteria. One of the main benefits of DF relate to its fermentability, which affects microbial diversity and function within the gastro-intestinal tract (GIT), as well as the by-products of the fermentation process. Much work examining DF tends to focus on various purified ingredients, which have been extracted from plants. Increasingly, the validity of this is being questioned in terms of human nutrition, as there is evidence to suggest that it is the actual complexity of DF which affects the complexity of the GIT microbiota. Here, we review the literature comparing results of fermentation of purified DF substrates, with whole plant foods. There are strong indications that the more complex and varied the diet (and its ingredients), the more complex and varied the GIT microbiota is likely to be. Therefore, it is proposed that as the DF fermentability resulting from this complex microbial population has such profound effects on human health in relation to diet, it would be appropriate to include DF fermentability in its characterization-a functional approach of immediate relevance to nutrition.
Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to ...evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols.
Tumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared.
Molecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg, > 35% for urothelial cancers and < 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so.
We demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens.
The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, the largest national precision oncology study to date (> 1,100 sites) of patients with relapsed or refractory ...malignancies, assigned patients to targeted therapy in parallel phase II studies based on tumor molecular alterations. The anti-programmed death receptor 1 inhibitor nivolumab previously showed activity in mismatch repair (MMR)-deficient colon cancer. We hypothesized that nivolumab would have activity in patients with MMR-deficient, noncolorectal tumors.
Eligible patients with relapsed or refractory tumors, good end-organ function, and Eastern Cooperative Oncology Group performance status of ≤ 1 underwent tumor biopsy for centralized screening of molecular alterations. MMR deficiency was defined by complete loss of nuclear expression of
or
MMR gene products by immunohistochemistry (IHC). Patients with MMR-deficient colorectal cancer were excluded. Nivolumab, 3 mg/kg every 2 weeks (28-day cycles) and 480 mg every 4 weeks after cycle 4, was administered intravenously. Disease reassessment was performed every 2 cycles. The primary end point was RECIST 1.1 objective response rate (ORR).
Two percent of 4,902 screened patients had an MMR-deficient cancer by IHC. Forty-two evaluable patients were enrolled, with a median age of 60 years and a median of 3 prior therapies. The most common histologies were endometrioid endometrial adenocarcinoma (n = 13), prostate adenocarcinoma (n = 5), and uterine carcinosarcoma (n = 4). ORR was 36% (15 of 42 patients). An additional 21% of patients had stable disease. The estimated 6-, 12-, and 18-month progression-free survival rates were 51.3% (90% CI, 38.2% to 64.5%), 46.2% (90% CI, 33.1% to 59.3%), and 31.4% (90% CI, 18.7% to 44.2%), respectively. Median overall survival was 17.3 months. Toxicity was predominantly low grade.
A variety of refractory cancers (2.0% of those screened) had MMR deficiency as defined in NCI-MATCH. Nivolumab has promising activity in MMR-deficient noncolorectal cancers of a wide variety of histopathologic types.
Although correlations between RNA polymerase II (RNAPII) transcription stress, R-loops, and genome instability have been established, the mechanisms underlying these connections remain poorly ...understood. Here, we used a mutant version of the transcription elongation factor TFIIS (TFIISmut), aiming to specifically induce increased levels of RNAPII pausing, arrest, and/or backtracking in human cells. Indeed, TFIISmut expression results in slower elongation rates, relative depletion of polymerases from the end of genes, and increased levels of stopped RNAPII; it affects mRNA splicing and termination as well. Remarkably, TFIISmut expression also dramatically increases R-loops, which may form at the anterior end of backtracked RNAPII and trigger genome instability, including DNA strand breaks. These results shed light on the relationship between transcription stress and R-loops and suggest that different classes of R-loops may exist, potentially with distinct consequences for genome stability.
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•Inducing transcription stress via TFIISmut results in reduced nascent RNA synthesis•TFIISmut affects expression of long genes and mRNA splicing•TFIISmut expression leads to increased R-loop formation and genomic instability•R-loops may form both anterior and posterior of RNAPII
Inducing transcription stress via expression of a TFIIS mutant results in increased R-loop formation. The R-loops may be formed anterior to the backtracking RNA polymerase II and result in increased genomic instability.
Respiratory syncytial virus (RSV) is a major cause of hospitalized acute respiratory illness (ARI) among young children. With RSV vaccines and immunoprophylaxis agents in clinical development, we ...sought to update estimates of US pediatric RSV hospitalization burden.
Children <5 years old hospitalized for ARI were enrolled through active, prospective, population-based surveillance from November 1, 2015, to June 30, 2016, at 7 US pediatric hospital sites. Clinical information was obtained from parent interviews and medical records. Midturbinate nasal and throat flocked swabs were collected and tested for RSV by using molecular diagnostic assays at each site. We conducted descriptive analyses and calculated population-based rates of RSV-associated hospitalizations.
Among 2969 hospitalized children included in analyses, 1043 (35%) tested RSV-positive; 903 (87%) children who were RSV-positive were <2 years old, and 526 (50%) were <6 months old. RSV-associated hospitalization rates were 2.9 per 1000 children <5 years old and 14.7 per 1000 children <6 months old; the highest age-specific rate was observed in 1-month-old infants (25.1 per 1000). Most children who were infected with RSV (67%) had no underlying comorbid conditions and no history of preterm birth.
During the 2015-2016 season, RSV infection was associated with one-third of ARI hospitalizations in our study population of young children. Hospitalization rates were highest in infants <6 months. Most children who were RSV-positive had no history of prematurity or underlying medical conditions, suggesting that all young children could benefit from targeted interventions against RSV.
Interactions between human gut microbiota and dietary fibres (DF) are influenced by the complexity and diversity of both individual microbiota and sources of DF. Based on 480 in vitro fermentations, ...a full factorial experiment was performed with six faecal inocula representing two enterotypes and three DF sources with nanometer, micrometer, and millimeter length-scales (apple pectin, apple cell walls and apple particles) at two concentrations. Increasing DF size reduced substrate disappearance and fermentation rates but not biomass growth. Concentrated DF enhanced butyrate production and lactate cross-feeding. Enterotype differentiated final microbial compositions but not biomass or fermentation metabolite profiles. Individual donor microbiota differences did not influence DF type or concentration effects but were manifested in the promotion of different functional microbes within each population with the capacity to degrade the DF substrates. Overall, consistent effects (independent of donor microbiota variation) of DF type and concentration on kinetics of substrate degradation, microbial biomass production, gas kinetics and metabolite profiles were found, which can form the basis for informed design of DF for desired rates/sites and consequences of gut fermentation. These results add further evidence to the concept that, despite variations between individuals, the human gut microbiota represents a community with conserved emergent properties.
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NCI-MATCH is a nationwide, histology-agnostic, signal-finding, molecular profile-driven trial for patients with refractory cancers, lymphomas, or myelomas. Patients with tumors harboring actionable ...aberration(s) in fibroblast growth factor receptor (
)
were treated with AZD4547, an oral FGFR1-3 inhibitor.
Patients' tumors were screened by next-generation sequencing for predefined
amplification, activating mutations, or fusions. Patients were treated with AZD4547, 80 mg orally twice daily until progression of disease or drug intolerance. A response rate of 16% was considered promising.
Between July 2016 and June 2017, 70 patients were assigned and 48 received protocol therapy and are eligible for analysis. Patients' tumors harbored
or
amplification (n = 20),
or
single-nucleotide variants (n = 19), or
or
fusions (n = 9). The most common primary tumors were breast (33.3%), urothelial (12.5%), and cervical cancer (10.4%).Grade 3 adverse events were consistent with those described in previous clinical trials. Confirmed partial responses were seen in 8% (90% CI, 3% to 18%) and were observed only in patients whose tumors harbored
point mutations or fusions. Stable disease was observed in 37.5% (90% CI, 25.8% to 50.4%). The median progression-free survival (PFS) was 3.4 months, and the 6-month PFS rate was 15% (90% CI, 8% to 31%). For patients with tumors harboring
fusions, the response rate was 22% (90% CI, 4.1% to 55%), and 6-month PFS rate was 56% (90% CI, 31% to 100%).
Preliminary signals of activity appeared to be limited to cancers harboring
activating mutations and fusions, although AZD4547 did not meet the primary end point. Different
somatic alterations may confer different levels of signaling potency and/or oncogene dependence.
Abstract
The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data. The ...expanding number of chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure characterization, continue to underscore the need for new approaches. In 2005, EPA charted a new course to address this challenge by embracing computational toxicology (CompTox) and investing in the technologies and capabilities to push the field forward. The return on this investment has been demonstrated through results and applications across a range of human and environmental health problems, as well as initial application to regulatory decision-making within programs such as the EPA’s Endocrine Disruptor Screening Program. The CompTox initiative at EPA is more than a decade old. This manuscript presents a blueprint to guide the strategic and operational direction over the next 5 years. The primary goal is to obtain broader acceptance of the CompTox approaches for application to higher tier regulatory decisions, such as chemical assessments. To achieve this goal, the blueprint expands and refines the use of high-throughput and computational modeling approaches to transform the components in chemical risk assessment, while systematically addressing key challenges that have hindered progress. In addition, the blueprint outlines additional investments in cross-cutting efforts to characterize uncertainty and variability, develop software and information technology tools, provide outreach and training, and establish scientific confidence for application to different public health and environmental regulatory decisions.
SCOPE: Grape seed polyphenol extract (GSPE) is receiving increasing attention for its potential preventative and therapeutic roles in Alzheimer's disease (AD) and other age‐related neurodegenerative ...disorders. The intestinal microbiota is known to actively convert many dietary polyphenols, including GSPE, to phenolic acids. There is limited information on the bioavailability and bioactivity of GSPE‐derived phenolic acid in the brain. METHODS AND RESULTS: We orally administered GSPE to rats and investigated the bioavailability of 12 phenolic acids known to be generated by microbiota metabolism of anthocyanidins. GSPE treatment significantly increased the content of two of the phenolic acids in the brain: 3‐hydroxybenzoic acid and 3‐(3´‐hydroxyphenyl)propionic acid, resulting in the brain accumulations of the two phenolic acids at micromolar concentrations. We also provided evidence that 3‐hydroxybenzoic acid and 3‐(3´‐hydroxyphenyl)propionic acid potently interfere with the assembly of β‐amyloid peptides into neurotoxic β‐amyloid aggregates that play key roles in AD pathogenesis. CONCLUSION: Our observation suggests important contribution of the intestinal microbiota to the protective activities of GSPE (as well as other polyphenol preparations) in AD. Outcomes from our studies support future preclinical and clinical investigations exploring the potential contributions of the intestinal microbiota in protecting against the onset/progression of AD and other neurodegenerative conditions.
Objective
Fibromyalgia (FM) is characterized by pain and fatigue, particularly during physical activity. Transcutaneous electrical nerve stimulation (TENS) activates endogenous pain inhibitory ...mechanisms. This study was undertaken to investigate if using TENS during activity would improve movement‐evoked pain and other patient‐reported outcomes in women with FM.
Methods
Participants were randomly assigned to receive active TENS (n = 103), placebo TENS (n = 99), or no TENS (n = 99) and instructed to use it at home during activity 2 hours each day for 4 weeks. TENS was applied to the lumbar and cervicothoracic regions using a modulated frequency (2–125 Hz) at the highest tolerable intensity. Participants rated movement‐evoked pain (primary outcome measure) and fatigue on an 11‐point scale before and during application of TENS. The primary outcome measure and secondary patient‐reported outcomes were assessed at baseline (time of randomization) and at 4 weeks.
Results
After 4 weeks, a greater reduction in movement‐evoked pain was reported in the active TENS group versus the placebo TENS group (group mean difference –1.0 95% confidence interval –1.8, –0.2; P = 0.008) and versus the no TENS group (group mean difference –1.8 95% confidence interval –2.6, –1.0; P < 0.0001). A reduction in movement‐evoked fatigue was also reported in the active TENS group versus the placebo TENS group (group mean difference –1.4 95% confidence interval –2.4, –0.4; P = 0.001) and versus the no TENS group (group mean difference –1.9 95% confidence interval –2.9, –0.9; P = <0.0001). A greater percentage of the patients in the active TENS group reported improvement on the global impression of change compared to the placebo TENS group (70% versus 31%; P < 0.0001) and the no TENS group (9%; P < 0.0001). There were no TENS‐related serious adverse events, and <5% of participants experienced minor adverse events from TENS.
Conclusion
Among women who had FM and were on a stable medication regimen, 4 weeks of active TENS use compared to placebo TENS or no TENS resulted in a significant improvement in movement‐evoked pain and other clinical outcomes. Further research is needed to examine effectiveness in a real‐world setting to establish the clinical importance of these findings.
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