ATR inhibitors (ATRi) are in early phase clinical trials and have been shown to sensitize to chemotherapy and radiotherapy preclinically. Limited data have been published about the effect of these ...drugs on the tumor microenvironment.
We used an immunocompetent mouse model of HPV-driven malignancies to investigate the ATR inhibitor AZD6738 in combination with fractionated radiation (RT). Gene expression analysis and flow cytometry were performed posttherapy.
Significant radiosensitization to RT by ATRi was observed alongside a marked increase in immune cell infiltration. We identified increased numbers of CD3
and NK cells, but most of this infiltrate was composed of myeloid cells. ATRi plus radiation produced a gene expression signature matching a type I/II IFN response, with upregulation of genes playing a role in nucleic acid sensing. Increased MHC I levels were observed on tumor cells, with transcript-level data indicating increased antigen processing and presentation within the tumor. Significant modulation of cytokine gene expression (particularly CCL2, CCL5, and CXCL10) was found
, with
data indicating CCL3, CCL5, and CXCL10 are produced from tumor cells after ATRi + RT.
We show that DNA damage by ATRi and RT leads to an IFN response through activation of nucleic acid-sensing pathways. This triggers increased antigen presentation and innate immune cell infiltration. Further understanding of the effect of this combination on the immune response may allow modulation of these effects to maximize tumor control through antitumor immunity.
Cholangiocarcinomas (CCAs) comprise of a heterogeneous group of cancers arising in the biliary tract (intrahepatic or iCCA, perihilar or pCCA and distal or dCCA; the latter are known under the ...collective term of eCCA), each subtype having its own particularities in carcinogenesis, management and prognosis. The increasing incidence in recent decades, limited treatment options and high mortality rates, even in the early stages, have led to an imperious need for more in-depth understanding and development of tailored treatments for this type of aggressive tumour. The wide use of molecular profiling has increased the understanding of biology and identified key molecular drivers, for example, IDH1 mutations or FGFR2 fusions for iCCA, or BRAF mutations in eCCA. Most recently, the FDA approved pemigatinib, an FGFR inhibitor and ivosidenib, an IDH1 inhibitor, but even though progress has been made to better understand the mechanisms of tumorigenesis, genetic make-up, and tumour resistance to standard chemotherapy and targeted therapies, cholangiocarcinomas still represent an important challenge in the daily clinical practice of oncology. The purpose of this review is to highlight the recent progress in the systemic treatment of advanced/metastatic CCAs with a focus on targeted drugs and their biomarkers currently evaluated in early-phase clinical trials.
Gastric cancer is responsible for a high burden of disease globally. Although more extensive use of chemotherapy together with the recent introduction of the two targeted agents trastuzumab and ...ramucirumab have contributed to marginal outcome prolongation, overall survival for patients with advanced stage disease remains poor. Over the last decade, a number of novel agents have been examined in clinical trials with largely disappointing results. Potential explanations for this are the absence of molecularly selected trial populations or weak predictive biomarkers within the context of a highly heterogeneous disease. In the recently published gastric cancer The Cancer Genome Atlas (TCGA) project a new classification of four different tumour subtypes according to different molecular characteristics has been proposed. With some overlap, several relatively distinct and potentially targetable pathways have been identified for each subtype. In this perspective review we match recent trial results with the subtypes described in the gastric cancer TCGA aiming to highlight data regarding novel agents under evaluation and to discuss whether this publication might provide a framework for future drug development.
Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need ...for better patient selection.
Patients with
mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (K
), enhancing fraction (EF) and their product KEF (summarised median values of K
× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal
mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.
Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04).
mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07-1.04), p=0.06).
Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.
The aim of this study was to investigate the relationship between the energy cost of running (Cr) and speed and its mechanical determinants by comparing running in normal 100% body weight (BW) and ...reduced (20% and 60% BW) gravity conditions at several speeds (2.25, 3.17, 4.08, and 5.00 m·s
) in experienced runners.
Twelve experienced runners (24.6 ± 5.4 year) ran on an
treadmill in a partially randomized order at the four running speeds and at the three gravity conditions in order to assess Cr, spatiotemporal parameters, spring-mass characteristics and elastic energy (EL) during running.
For the three gravity conditions, the speed-Cr per kg of body mass relationship was curvilinear (significant speed effect:
< 0.001) and was significantly downward shifted with reduced gravity (100%>60%>20% BW;
< 0.001). EL, expressed in J·step
, was significantly higher at 100% BW than at 60 and 20% BW and at 60% BW than at 20% BW (significant gravity effect:
< 0.001) with a significant increase in EL per step at faster speeds for the 3 gravity conditions (
< 0.001). EL, expressed in J·kg
·m
, was significantly downward shifted with gravity (100%>60%>20% BW;
< 0.001), with no significant speed effect (
= 0.39).
Our findings showed that, for the three gravity conditions, the speed-Cr relationship was curvilinear, and the optimization of the stretch-shortening cycle and muscle activation in the muscle-tendon unit may be involved to explain these U-shaped relationships, especially at normal terrestrial gravitational conditions (100% BW). The U-shaped speed-Cr per kg of the body mass relationship was shifted downward in hypogravity conditions, which was characterized by decreased EL compared to 100% BW. These mechanisms may contribute to the less than proportional decrease in Cr per kg of body mass relative to gravity.
Background
Food exchange lists allow health professionals to generate healthy eating plans adapted to individual or population needs. The objective of this study was to develop the first food ...exchange list based on the macronutrients and energy provided by the various food groups of the Ecuadorian diet.
Methods
The list of Ecuadorian food exchanges was constructed by going through the following phases: (1) Selection of household measurements; (2) Selection of tables and databases of the nutritional composition of food items; (3) Definition of food groups and quantities; (4) Determination of the average energy and macronutrient values of each group; and (5) Photographic record. For the definition of food quantities, statistical criteria were applied according to a standard deviation of ±2SD; thus, for carbohydrates: ±5 g, total fat: ±2 g, and protein: ±3 g. To ensure the inclusion of the food items in the groups, a coefficient of variation of less than 30% and a Z value of ±2 were also considered.
Results
The list of food exchanges is presented with eight general groups according to the predominant nutrient (carbohydrates, proteins, or fats), and, where necessary, subgroups are included according to the second predominant nutrient. The list includes 404 food items with their photographic record, represented by their net weights and corresponding household measurement. All food items met the statistical criteria that help to reduce the variability of the nutritional composition of the food items in each group.
Conclusion
This is the first list of Ecuadorian food exchanges based on statistical criteria. It represents a novel tool for public health professionals as well as researchers. Resulting healthier eating plans may improve daily dietetic practice, facilitate better clinical trial designs and help establish guidelines according to Ecuador’s cultural and dietary patterns. The described methodology can further be used to develop other food exchanges lists for patients with specific nutritional requirements.
Introduction: A household's nutritional status and food security can be affected after a natural disaster, especially in families who live in risk situations. The objective of this study was to ...determine the prevalence of food insecurity, inadequate dietary diversity and poor nutritional status of mothers and children under 5 years old from vulnerable families residing in the rural community of La Punta, after the earthquake in Ecuador on 16 April 2016.
Methods: Through a non-probabilistic sampling, 28 families were selected. The levels of food insecurity in households were determined by applying a food safety scale and household dietary diversity score. Moreover, Z-scores were used to evaluate the nutritional status of children, while body mass index was used in mothers.
Results: All households suffered food insecurity, with mild food insecurity being the most prevalent (51.9%), followed by severe food insecurity (33.3%). Although all households had high diversity scores, the products they most consumed have low nutritional value, such as rice, soft drinks and oils. There was a low consumption of whole grains, fruits and vegetables. Additionally, there was a high percentage of overweight and obese mothers (57.1%) and a high prevalence of chronic undernutrition (40.9%) and global undernutrition (13.6%) in children under 5 years old.
Conclusion: The predominance of severe food insecurity occurred in overweight and obese mothers with inadequate dietary diversity. This probably happened because of a lack of access to food to adequately meet the nutritional needs of each member of the family. The results suggest that health promotion with actions aimed at food security is a priority within an integral action plan for natural disasters.
Goal: This study aimed to propose a procedure to survey of the Critical success Factors (CSF) in the reverse flow inventory management.
Design/Methodology/Approach: A problem structuring method (PSM) ...combined with an approach for analysis of strategic map were used to facilitate and share information in a participatory process, considering all the stakeholder’s perspectives in order to identify and analyse the CSF. A case study of returnable packaging in the metallurgy and steel industry was conducted to validate the proposal.
Results: The proposal was able to minimize conflicts and it facilitated the discussions on the CFSs surveyed. In addition, the decision makers have confirmed that their viewpoints were well represented in the strategic map, and they will use the CFS to evaluate the operations performance.
Limitations of the investigation: Although the surveyed CSFs are specific to the presented case study, the procedure may be replicated in other organizations to identify their own CSF.
Practical implications: The adequate survey of CSFs is fundamental because they have potential to explain the success or failure of a company, since CSFs impact directly on profits, processes performance and competitive environment.
Originality/Value: The main contribution was to propose a methodology to survey critical success factors in the reverse flow environment adequate to messy, complex and unstructured situations, as well as this methodology was able to make a cyclic analysis and comprehension of the multiple perspectives, important in group decision maker environments.
Major Depressive Disorder (MDD) is a disabling illness affecting more than 5% of the elderly population. Higher female prevalence and sex-specific symptomatology have been observed, suggesting that ...biologically-determined dimensions might affect the disease onset and outcome. Rumination and executive dysfunction characterize adult-onset MDD, but sex differences in these domains and in the related brain mechanisms are still largely unexplored. The present pilot study aimed to explore any interactions between adult-onset MDD and sex on brain morphology and brain function during a Go/No-Go paradigm. We hypothesized to detect diagnosis by sex effects on brain regions involved in self-referential processes and cognitive control. Twenty-four subjects, 12 healthy (HC) (mean age 68.7 y, 7 females and 5 males) and 12 affected by adult-onset MDD (mean age 66.5 y, 5 females and 7 males), underwent clinical evaluations and a 3T magnetic resonance imaging (MRI) session. Diagnosis and diagnosis by sex effects were assessed on regional gray matter (GM) volumes and task-related functional MRI (fMRI) activations. The GM volume analyses showed diagnosis effects in left mid frontal cortex (
< 0.01), and diagnosis by sex effects in orbitofrontal, olfactory, and calcarine regions (
< 0.05). The Go/No-Go fMRI analyses showed MDD effects on fMRI activations in left precuneus and right lingual gyrus, and diagnosis by sex effects on fMRI activations in right parahippocampal gyrus and right calcarine cortex (
< 0.001, ≥ 40 voxels). Our exploratory results suggest the presence of sex-specific brain correlates of adult-onset MDD-especially in regions involved in attention processing and in the brain default mode-potentially supporting cognitive and symptom differences between sexes.
Different classes of
mutations are present in colorectal and other cancers. Non-V600 mutations are rare; however, their detection rate will increase as the use of next-generation sequencing ramps up ...quickly in clinical practice. Different biochemical signaling pathways are active in non-V600
-mutant cancers and may affect treatment response.
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