Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues

Preliminary results on the apparent size of the sources of type III bursts observed at low frequencies

We present preliminary results on the apparent angular size of the sources of four type III bursts observed between 3500 and 50 kHz from the IMP-6 spacecraft. The observations were made with a dipole rotating in the plane of the ecliptic where the sources are assumed to be. The apparent angular sizes obtained are unexpectedly large. We discuss different explanations for the results. It seems that the scattering of radio waves by electron density inhomogeneities is the most likely cause.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43742/1/11207_2004_Article_BF00149873.pd

Moderate-vigorous physical activity and health-related quality of life among Hispanic/Latino adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

BackgroundPhysical activity is a modifiable healthy behavior that has been shown to positively influence health-related quality of life. However, research examining the link between physical activity and health-related quality of life among Hispanic/Latino adults is limited and inconsistent. The purpose of this study is to assess whether accelerometer-measured moderate-vigorous physical activity (MVPA) is associated with self-reported (a) mental health-related quality of life, and (b) physical health-related quality of life among diverse Hispanic/Latino adults in the US.MethodsCross-sectional data from 12,379 adults ages 18-74 years in 2008-2011, who participated in HCHS/SOL and had complete data were analyzed using complex survey design methods. Accelerometer data were categorized into no MVPA, low, moderate, and high MVPA. Health-related quality of life was assessed with the Short-Form 12 and we used the mental and physical component subscales where higher scores indicate better health-related quality of life. Multivariate linear regression models were used to derive adjusted means with 95% confidence intervals and linear trends.ResultsWe observed no significant linear trend between accelerometer-measured MVPA and mental health-related quality of life (ptrend = 0.73). There was a significant positive association between MVPA and physical health-related quality of life (ptrend < 0.001) where higher MVPA corresponded with higher scores in physical health-related quality of life. The adjusted means were 46.67 (44.85-48.48) for no MVPA, 49.33 (49.03-49.63) for low MVPA, 50.61 (50.09-51.13) for moderate MVPA, and 51.36 (50.86-51.86) for high MVPA.ConclusionsAmong diverse Hispanic/Latino adults in the US, accelerometer-measured MVPA was associated with physical health-related quality of life, but not mental health-related quality of life. Future interventions should evaluate if increases in MVPA lead to improvements in health-related quality of life

Heliographic longitude distribution of the flares associated with type III bursts observed at kilometric wavelengths

We have grouped observed type III solar bursts according to the discrete frequencies of observation in the kilometric wavelength range. For each group we have obtained the bursts' frequency of occurrence as a function of the heliographic longitude of the associated optical flares. We found that flares occurring east of a certain cutoff longitude do not produce bursts observable near the earth below a given frequency. The cutoff on the west is determined by observational limitation for flares beyond the limb. The mean longitude and the extreme eastern end of the longitude distribution both shift to the west as the radio frequency decreases. We interpret these findings in terms of radio wave propagation effects and curved trajectories of the bursts' exciter particles.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43732/1/11207_2004_Article_BF00152824.pd

Decay time of type III solar bursts observed at kilometric wavelengths

Type III bursts were observed between 3.5 MHz and 50 kHz by the University of Michigan radio astronomy experiment aboard the OGO-5 satellite.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43731/1/11207_2004_Article_BF00156186.pd

Widespread Hypomethylation Occurs Early and Synergizes with Gene Amplification during Esophageal Carcinogenesis

Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and transcriptomic datasets obtained from endoscopic biopsies of neoplastic progression within the same individual, we are uniquely able to define the molecular events associated progression of Barrett esophagus. We find that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis. Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia. In contrast, gene-specific hypermethylation is observed at a restricted number of loci and, in combination with hemi-allelic deletions, leads to downregulatation of selected transcripts during multistep progression. We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined “CpG islands,” but may also occur through a mechanism of differential methylation outside of these regions. Finally, validation of novel upregulated targets (CXCL1 and 3, GATA6, and DMBT1) in a larger independent panel of samples confirms the utility of integrative analysis in cancer biomarker discovery

A Novel Therapy for Melanoma Developed in Mice: Transformation of Melanoma into Dendritic Cells with Listeria monocytogenes

Listeria monocytogenes is a gram-positive bacteria and human pathogen widely used in cancer immunotherapy because of its capacity to induce a specific cytotoxic T cell response in tumours. This bacterial pathogen strongly induces innate and specific immunity with the potential to overcome tumour induced tolerance and weak immunogenicity. Here, we propose a Listeria based vaccination for melanoma based in its tropism for these tumour cells and its ability to transform in vitro and in vivo melanoma cells into matured and activated dendritic cells with competent microbicidal and antigen processing abilities. This Listeria based vaccination using low doses of the pathogen caused melanoma regression by apoptosis as well as bacterial clearance. Vaccination efficacy is LLO dependent and implies the reduction of LLO-specific CD4+ T cell responses, strong stimulation of innate pro-inflammatory immune cells and a prevalence of LLO-specific CD8+ T cells involved in tumour regression and Listeria elimination. These results support the use of low doses of pathogenic Listeria as safe melanoma therapeutic vaccines that do not require antibiotics for bacterial removal

Surgical treatment for colorectal cancer: Analysis of the influence of an enhanced recovery programme on long-term oncological outcomes-a study protocol for a prospective, multicentre, observational cohort study

Introduction The evidence currently available from enhanced recovery after surgery (ERAS) programmes concerns their benefits in the immediate postoperative period, but there is still very little evidence as to whether their correct implementation benefits patients in the long term. The working hypothesis here is that, due to the lower response to surgical aggression and lower rates of postoperative complications, ERAS protocols can reduce colorectal cancer-related mortality. The main objective of this study is to analyse the impact of an ERAS programme for colorectal cancer on 5-year survival. As secondary objectives, we propose to analyse the weight of each of the predefined items in the oncological results as well as the quality of life. Methods and analysis A multicentre prospective cohort study was conducted in patients older than 18 years of age who are scheduled to undergo surgery for colorectal cancer. The study involved 12 hospitals with an implemented enhanced recovery protocol according to the guidelines published by the Spanish National Health Service. The intervention group includes patients with a minimum implementation level of 70%, and the control group includes those who fail to reach this level. Compliance will be studied using 18 key performance indicators, and the results will be analysed using cancer survival indicators, including overall survival, cancer-specific survival and relapse-free survival. The time to recurrence, perioperative morbidity and mortality, hospital stay and quality of life will also be studied, the latter using the validated EuroQol Five questionnaire. The propensity index method will be used to create comparable treatment and control groups, and a multivariate regression will be used to study each variable. The Kaplan-Meier estimator will be used to estimate survival and the log-rank test to make comparisons. A p value of less than 0.05 (two-tailed) will be considered to be significant. Ethics and dissemination Ethical approval for this study was obtained from the Aragon Ethical Committee (C.P.-C.I. PI20/086) on 4 March 2020. The findings of this study will be submitted to peer-reviewed journals (BMJ Open, JAMA Surgery, Annals of Surgery, British Journal of Surgery). Abstracts will be submitted to relevant national and international meetings.The present research study was awarded a Ministerio de Ciencia e Innovación health research project grant (PI19/00291) from the Carlos III Institute of the Spanish National Health Service as part of the 2019 call for Strategic Action in Health

Limited carbon and biodiversity co-benefits for tropical forest mammals and birds

The conservation of tropical forest carbon stocks offers the opportunity to curb climate change by reducing greenhouse gas emissions from deforestation and simultaneously conserve biodiversity. However, there has been considerable debate about the extent to which carbon stock conservation will provide benefits to biodiversity in part because whether forests that contain high carbon density in their aboveground biomass also contain high animal diversity is unknown. Here, we empirically examined medium to large bodied ground-dwelling mammal and bird (hereafter "wildlife") diversity and carbon stock levels within the tropics using camera trap and vegetation data from a pantropical network of sites. Specifically, we tested whether tropical forests that stored more carbon contained higher wildlife species richness, taxonomic diversity, and trait diversity. We found that carbon stocks were not a significant predictor for any of these three measures of diversity, which suggests that benefits for wildlife diversity will not be maximized unless wildlife diversity is explicitly taken into account; prioritizing carbon stocks alone will not necessarily meet biodiversity conservation goals. We recommend conservation planning that considers both objectives because there is the potential for more wildlife diversity and carbon stock conservation to be achieved for the same total budget if both objectives are pursued in tandem rather than independently. Tropical forests with low elevation variability and low tree density supported significantly higher wildlife diversity. These tropical forest characteristics may provide more affordable proxies of wildlife diversity for future multi-objective conservation planning when fine scale data on wildlife are lacking

The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53- Independent Manner in Colon and Breast Cancer Cells

The chemotherapeutic drug 5-FU is widely used in the treatment of a range of cancers, but resistance to the drug remains a major clinical problem. Since defects in the mediators of apoptosis may account for chemo-resistance, the identification of new targets involved in 5-FU-induced apoptosis is of main clinical interest. We have identified the ds-RNA-dependent protein kinase (PKR) as a key molecular target of 5-FU involved in apoptosis induction in human colon and breast cancer cell lines. PKR distribution and activation, apoptosis induction and cytotoxic effects were analyzed during 5-FU and 5-FU/IFNα treatment in several colon and breast cancer cell lines with different p53 status. PKR protein was activated by 5-FU treatment in a p53-independent manner, inducing phosphorylation of the protein synthesis translation initiation factor eIF-2α and cell death by apoptosis. Furthermore, PKR interference promoted a decreased response to 5-FU treatment and those cells were not affected by the synergistic antitumor activity of 5-FU/IFNα combination. These results, taken together, provide evidence that PKR is a key molecular target of 5-FU with potential relevance in the clinical use of this drug