Background
Retroperitoneal soft tissue sarcomas comprise a heterogeneous group of rare tumors of mesenchymal origin that include several well-defined histologic subtypes. In 2015, the Transatlantic ...Australasian RPS Working Group (TARPSWG) published consensus recommendations for the best management of primary retroperitoneal sarcoma (RPS). Since then, through international collaboration, new evidence and knowledge have been generated, creating the need for an updated consensus document.
Methods
The primary aim of this study was to critically evaluate the current evidence and develop an up-to-date consensus document on the approach to these difficult tumors. The resulting document applies to primary RPS that is non-visceral in origin, with exclusion criteria as previously described. The relevant literature was evaluated and an international group of experts consulted to formulate consensus statements regarding the best management of primary RPS. A level of evidence and grade of recommendation were attributed to each new/updated recommendation.
Results
Management of primary RPS was considered from diagnosis to follow-up. This rare and complex malignancy is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, and an individualized management plan should be made based on the 29 consensus statements included in this article, which were agreed upon by all of the authors. Whenever possible, patients should be enrolled in prospective trials and studies.
Conclusions
Ongoing international collaboration is critical to expand upon current knowledge and further improve outcomes of patients with RPS. In addition, prospective data collection and participation in multi-institution trials are strongly encouraged.
Background We examined the longitudinal associations between changes in cardiovascular biomarkers and cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer treated with ...cardotoxic cancer therapy. Methods and Results Repeated measures of high-sensitivity cardiac troponin T (hs-cTnT), NT-proBNP (N-terminal pro-B-type natriuretic peptide), myeloperoxidase, placental growth factor, and growth differentiation factor 15 were assessed longitudinally in a prospective cohort of 323 patients treated with anthracyclines and/or trastuzumab followed over a maximum of 3.7 years with serial echocardiograms. CTRCD was defined as a ≥10% decline in left ventricular ejection fraction to a value <50%. Associations between changes in biomarkers and left ventricular ejection fraction were evaluated in repeated-measures linear regression models. Cox regression models assessed the associations between biomarkers and CTRCD. Early increases in all biomarkers occurred with anthracycline-based regimens. hs-cTnT levels >14 ng/L at anthracycline completion were associated with a 2-fold increased CTRCD risk (hazard ratio, 2.01; 95% CI, 1.00-4.06). There was a modest association between changes in NT-proBNP and left ventricular ejection fraction in the overall cohort; this was most pronounced with sequential anthracycline and trastuzumab (1.1% left ventricular ejection fraction decline 95% CI, -1.8 to -0.4 with each NT-proBNP doubling). Increases in NT-proBNP were also associated with CTRCD (hazard ratio per doubling, 1.56; 95% CI, 1.32-1.84). Increases in myeloperoxidase were associated with CTRCD in patients who received sequential anthracycline and trastuzumab (hazard ratio per doubling, 1.28; 95% CI, 1.04-1.58). Conclusions Cardiovascular biomarkers may play an important role in CTRCD risk prediction in patients with breast cancer who receive cardiotoxic cancer therapy, particularly in those treated with sequential anthracycline and trastuzumab therapy. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01173341.
Summary
Ester‐linked p‐coumarate (pCA) is a hallmark feature of the secondary cell walls in commelinid monocot plants. It has been shown that pCA groups arise during lignin polymerisation from the ...participation of monolignol conjugates assembled by p‐coumaroyl‐CoA:monolignol transferase (PMT) enzymes, members of the BAHD superfamily of acyltransferases.
Herein, we report that a eudicot species, kenaf (Hibiscus cannabinus), naturally contains p‐coumaroylated lignin in the core tissues of the stems but not in the bast fibres. Moreover, we identified a novel acyltransferase, HcPMT, that shares <30% amino acid identity with known monocot PMT sequences.
Recombinant HcPMT showed a preference in enzyme assays for p‐coumaroyl‐CoA and benzoyl‐CoA as acyl donor substrates and sinapyl alcohol as an acyl acceptor. Heterologous expression of HcPMT in hybrid poplar trees led to the incorporation of pCA in lignin, but no improvement in the saccharification potential of the wood.
This work illustrates the value in mining diverse plant taxa for new monolignol acyltransferases. Furthermore, the occurrence of pCA outside monocot lineages may represent another example of convergent evolution in lignin structure. This discovery expands textbook views on cell wall biochemistry and provides a new molecular tool for engineering the lignin of biomass feedstock plants.
The agouti viable yellow (A
) allele is an insertional mutation in the mouse genome caused by a variably methylated intracisternal A particle (VM-IAP) retrotransposon. A
expressivity is sensitive to ...a range of early-life chemical exposures and nutritional interventions, suggesting that environmental perturbations can have long-lasting effects on the methylome. However, the extent to which VM-IAP elements are environmentally labile with phenotypic implications is unknown. Using a recently identified repertoire of VM-IAPs, we assessed the epigenetic effects of different environmental contexts. A longitudinal aging analysis indicated that VM-IAPs are stable across the murine lifespan, with only small increases in DNA methylation detected for a subset of loci. No significant effects were observed after maternal exposure to the endocrine disruptor bisphenol A, an obesogenic diet or methyl donor supplementation. A genetic mouse model of abnormal folate metabolism exhibited shifted VM-IAP methylation levels and altered VM-IAP-associated gene expression, yet these effects are likely largely driven by differential targeting by polymorphic KRAB zinc finger proteins. We conclude that epigenetic variability at retrotransposons is not predictive of environmental susceptibility.
The hydroxycinnamic acids p‐coumaric acid (pCA) and ferulic acid (FA) add diversity to the portfolio of products produced by using grass‐fed lignocellulosic biorefineries. The level of lignin‐bound ...pCA in Zea mays was modified by the alteration of p‐coumaroyl‐CoA monolignol transferase expression. The biomass was processed in a lab‐scale alkaline‐pretreatment biorefinery process and the data were used for a baseline technoeconomic analysis to determine where to direct future research efforts to couple plant design to biomass utilization processes. It is concluded that future plant engineering efforts should focus on strategies that ramp up accumulation of one type of hydroxycinnamate (pCA or FA) predominantly and suppress that of the other. Technoeconomic analysis indicates that target extraction titers of one hydroxycinnamic acid need to be >50 g kg−1 biomass, at least five times higher than observed titers for the impure pCA/FA product mixture from wild‐type maize. The technical challenge for process engineers is to develop a viable process that requires more than 80 % reduction of the isolation costs.
Stream on: A competitive lignocellulosic biorefinery will need to produce multiple product streams that include liquid fuel, solid fuel, and commodity chemicals. In this study, some key parameters are identified for the extraction of the valuable commodity chemicals p‐coumaric acid and ferulic acid from one of the waste streams in an alkaline‐pretreatment‐based biorefinery.
Identifying drivers of infectious disease patterns and impacts at the broadest scales of organisation is one of the most crucial challenges for modern science, yet answers to many fundamental ...questions remain elusive. These include what factors commonly facilitate transmission of pathogens to novel host species, what drives variation in immune investment among host species, and more generally what drives global patterns of parasite diversity and distribution? Here we consider how the perspectives and tools of macroecology, a field that investigates patterns and processes at broad spatial, temporal and taxonomic scales, are expanding scientific understanding of global infectious disease ecology. In particular, emerging approaches are providing new insights about scaling properties across all living taxa, and new strategies for mapping pathogen biodiversity and infection risk. Ultimately, macroecology is establishing a framework to more accurately predict global patterns of infectious disease distribution and emergence.
The cell walls of leaf base tissues of the Canary Island date palm (Phoenix canariensis) contain lignins with the most complex compositions described to date. The lignin composition varies by tissue ...region and is derived from traditional monolignols (ML) along with an unprecedented range of ML conjugates: ML-acetate, ML-benzoate, ML-p-hydroxybenzoate, ML-vanillate, ML-p-coumarate, and ML-ferulate. The specific functions of such complex lignin compositions are unknown. However, the distribution of the ML conjugates varies depending on the tissue region, indicating that they may play specific roles in the cell walls of these tissues and/or in the plant's defense system.
This study determined the effects of doxorubicin and/or trastuzumab on diastolic function and the relationship between diastolic function and systolic dysfunction.
Doxorubicin and trastuzumab can ...result in left ventricular ejection fraction (LVEF) declines. However, the effects of these therapies on diastolic function remain incompletely defined.
In a rigorously phenotyped, longitudinal cohort study of 362 breast cancer participants treated with doxorubicin, doxorubicin followed by trastuzumab, or trastuzumab alone, changes in diastolic function were evaluated using linear models estimated via generalized estimating equations. Associations between baseline and changes in diastolic function with LVEF and longitudinal strain were also determined using generalized estimating equations. The Kaplan-Meier estimator derived the proportion of participants who experienced incident diastolic dysfunction. Cox proportional hazards models estimated the associations between participant characteristics and diastolic dysfunction risk, and between diastolic function and cancer therapy−related cardiac dysfunction risk, defined by an LVEF decline of ≥10% to <50%.
Over a median of 2.1 years (interquartile range IQR: 1.3 to 4.2 years), participants treated with doxorubicin or doxorubicin followed by trastuzumab demonstrated a persistent worsening in diastolic function, with reductions in the E/A ratio, lateral and septal e′ velocities, and increases in E/e′ (p < 0.01). These changes were not observed with trastuzumab alone. Incident abnormal diastolic function grade occurred in 60% at 1 year, 70% by 2 years, and 80% by 3 years. Abnormal diastolic function grade was associated with a subsequent decrease in LVEF (−2.1%; 95% confidence intervals CI: −3.1 to −1.2; p < 0.001) and worsening in longitudinal strain (0.6%; 95% CI: 0.1 to 1.1; p = 0.013) over time. Changes in E/e′ ratio were modestly associated with worsening longitudinal strain (0.1%; 95% CI: 0.0 to 0.2; p = 0.022).
A modest, persistent worsening of diastolic function is observed with contemporary breast cancer therapy. Abnormal and worsening diastolic dysfunction is associated with a small risk of subsequent systolic dysfunction. (Cardiotoxicity of Cancer Therapy CCT; NCT01173341)
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is an opportunistic pathogen whose treatment is confounded by widespread multidrug resistance. The therapeutic use of bacteriophages against
infections offers a potential alternative approach, ...although the spectrum of phage susceptibilities among
isolates is not known. We determined the phage infection profiles of 82
recent clinical isolates and find that colony morphotype-rough or smooth-is a key indicator of phage susceptibility. None of the smooth strains are efficiently killed by any phages, whereas 80% of rough strains are infected and efficiently killed by at least one phage. The repertoire of phages available for potential therapy of rough morphotype infections includes those with relatively broad host ranges, host range mutants of
phages, and lytically propagated viruses derived from integrated prophages. The rough colony morphotype results from indels in the glycopeptidolipid synthesis genes
and
, negating reversion to smooth as a common route to phage resistance. Resistance is thus rare, and although mutations in polyketide synthesis,
, and
can confer resistance, these likely also impair survival
The expanded therapeutic repertoire and the resistance profiles show that small cocktails or single phages could be suitable for controlling infections with rough strains.
infections in cystic fibrosis patients are challenging to treat due to widespread antibiotic resistance. The therapeutic use of lytic bacteriophages presents a new potential strategy, but the great variation among clinical
isolates demands determination of phage susceptibility prior to therapy. Elucidation of the variation in phage infection and factors determining it, expansion of the suite of therapeutic phage candidates, and a greater understanding of phage resistance mechanisms substantially advances the potential for broad implementation of new therapeutic options for
infections.
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