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

Modelling crop yield and harvest index: the role of carbon assimilation and allocation parameters

Crop yield improvement during the last decades has relied on increasing the ratio of the economic organ to the total aboveground biomass, known as the harvest index (HI). In most crop models, HI is set as a parameter; this empirical approach does not consider that HI not only depends on plant genotype, but is also affected by the environment. An alternative is to simulate allocation mechanistically, as in the LPJ-GUESS crop model, which simulates HI based on daily growing conditions and the crop development stage. Simulated HI is critical for agricultural research due to its economic importance, but it also can validate the robust representation of production processes. However, there is a challenge to constrain parameter values globally for the allocation processes. Therefore, this paper aims to evaluate the sensitivity of yield and HI of wheat and maize simulated with LPJ-GUESS to eight production allocation-related parameters and identify the most suitable parameter values for global simulations. The nitrogen demand reduction after anthesis, the minimum leaf carbon to nitrogen ratio (C:N) and the range of leaf C:N strongly affected carbon assimilation and yield, while the retranslocation of labile stem carbon to grains and the retranslocation rate of nitrogen and carbon from vegetative organs to grains after anthesis mainly influenced HI. A global database of observed HI for both crops was compiled for reference to constrain simulations before calibrating parameters for yield against reference data. Two high- and low-yielding maize cultivars emerged from the calibration, whilst spring and winter cultivars were found appropriate for wheat. The calibrated version of LPJ-GUESS improved the simulation of yield and HI at the global scale for both crops, providing a basis for future studies exploring crop production under different climate and management scenarios

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

The Maternal and Infant Environmental Health Riskscape study of perinatal disparities in greater Houston: rationale, study design and participant profiles

IntroductionThe Maternal and Infant Environmental Health Riskscape (MIEHR) Center was established to address the interplay among chemical and non-chemical stressors in the biological, physical, social, and built environments that disproportionately impact perinatal health among Black pregnant people in a large and diverse urban area with documented disparities in the U.S.MethodsThe MIEHR cohort is recruiting non-Hispanic Black and non-Hispanic white pregnant people who deliver their infants at major obstetric hospitals in Houston, Texas. At enrollment, all participants are asked to provide urine samples for chemical [metals, cotinine, and polycyclic aromatic hydrocarbons (PAHs)] analyses and blood samples. A subset of the cohort is asked to provide oral and vaginal swabs, and fecal samples. Questionnaire and electronic health record data gather information about residential address history during pregnancy, pregnancy history and prenatal care, sociodemographic and lifestyle factors, experiences of discrimination and stress, and sources of social support. Using information on where a participant lived during their pregnancy, features of their neighborhood environment are characterized. We provide summaries of key individual- and neighborhood-level features of the entire cohort, as well as for Black and white participants separately.ResultsBetween April 2021 and February 2023, 1,244 pregnant people were recruited. Nearly all participants provided urine samples and slightly less than half provided blood samples. PAH exposure patterns as assessed on 47% of participants thus far showed varying levels depending on metabolite as compared to previous studies. Additionally, analyses suggest differences between Black and white pregnant people in experiences of discrimination, stress, and levels of social support, as well as in neighborhood characteristics.DiscussionOur findings to date highlight racial differences in experiences of discrimination, stress, and levels of support, as well as neighborhood characteristics. Recruitment of the cohort is ongoing and additional neighborhood metrics are being constructed. Biospecimens will be analyzed for metals and PAH metabolites (urine samples), miRNAs (plasma samples) and the microbiome (oral swabs). Once enrollment ends, formal assessments are planned to elucidate individual- and neighborhood-level features in the environmental riskscape that contribute to Black-White disparities in perinatal health

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

Native diversity buffers against severity of non-native tree invasions

Determining the drivers of non-native plant invasions is critical for managing native ecosystems and limiting the spread of invasive species. Tree invasions in particular have been relatively overlooked, even though they have the potential to transform ecosystems and economies. Here, leveraging global tree databases, we explore how the phylogenetic and functional diversity of native tree communities, human pressure and the environment influence the establishment of non-native tree species and the subsequent invasion severity. We find that anthropogenic factors are key to predicting whether a location is invaded, but that invasion severity is underpinned by native diversity, with higher diversity predicting lower invasion severity. Temperature and precipitation emerge as strong predictors of invasion strategy, with non-native species invading successfully when they are similar to the native community in cold or dry extremes. Yet, despite the influence of these ecological forces in determining invasion strategy, we find evidence that these patterns can be obscured by human activity, with lower ecological signal in areas with higher proximity to shipping ports. Our global perspective of non-native tree invasion highlights that human drivers influence non-native tree presence, and that native phylogenetic and functional diversity have a critical role in the establishment and spread of subsequent invasions