Distinct sets of molecular characteristics define tumor-rejecting neoantigens.

Challenges in identifying tumor-rejecting neoantigens limit the efficacy of neoantigen vaccines to treat cancers, including cutaneous squamous cell carcinoma (cSCC). A minority of human cSCC tumors shared neoantigens, supporting the need for personalized vaccines. Using a UV-induced mouse cSCC model which recapitulated the mutational signature and driver mutations found in human disease, we found that CD8 T cells constrain cSCC. Two MHC class I neoantigens were identified that constrained cSCC growth. Compared to the wild-type peptides, one tumor-rejecting neoantigen exhibited improved MHC binding and the other had increased solvent accessibility of the mutated residue. Across known neoantigens that do not impact MHC binding, structural modeling of the peptide/MHC complexes indicated that increased solvent accessibility, which will facilitate TCR recognition of the neoantigen, distinguished tumor-rejecting from non-immunogenic neoantigens. This work reveals characteristics of tumor-rejecting neoantigens that may be of considerable importance in identifying optimal vaccine candidates in cSCC and other cancers.

Poor oral health is associated with inflammation, aortic valve calcification, and brain volume among forager-farmers.

Poor oral health is associated with cardiovascular disease and dementia. Potential pathways include sepsis from oral bacteria, systemic inflammation, and nutritional deficiencies. However, in post-industrialized populations, links between oral health and chronic disease may be confounded because the lower socioeconomic exposome (poor diet, pollution, low physical activity) often entails insufficient dental care. We assessed tooth loss, caries, and damaged teeth, in relation to cardiovascular and brain aging among the Tsimane, a subsistence population living a relatively traditional forager-horticulturalist lifestyle with poor dental health, but minimal cardiovascular disease and dementia. Dental health was assessed by a physician in 739 participants aged 40-92 years with cardiac and brain health measured by chest computed tomography (CT) (n=728) and brain CT (n=605). A subset of 356 individuals aged 60+ were also assessed for dementia and mild cognitive impairment (n=33 impaired). Tooth loss was highly prevalent, with 2.2 teeth lost per decade and a 2-fold greater loss in women. The number of teeth with exposed pulp was associated with higher inflammation, as measured by cytokine levels and white blood cell counts, and lower body mass index. Coronary artery calcium and thoracic aortic calcium were not associated with tooth loss or damaged teeth. However, aortic valve calcification and brain tissue loss were higher in those that had more teeth with exposed pulp. Overall, these results suggest that dental health is associated with indicators of chronic diseases in the absence of typical confounds, even in a population with low cardiovascular and dementia risk factors.

Testosterone is positively associated with coronary artery calcium in a low cardiovascular disease risk population.

Background: In industrialized populations, low male testosterone is associated with higher rates of cardiovascular mortality. However, coronary risk factors like obesity impact both testosterone and cardiovascular outcomes. Here, we assess the role of endogenous testosterone on coronary artery calcium in an active subsistence population with relatively low testosterone levels, low cardiovascular risk and low coronary artery calcium scores. Methodology: In this cross-sectional community-based study, 719 Tsimane forager-horticulturalists in the Bolivian Amazon aged 40+ years underwent computed tomography (49.8% male, mean age 57.6 years). Results: Coronary artery calcium levels were low; 84.5% had no coronary artery calcium. Zero-inflated negative binomial models found testosterone was positively associated with coronary artery calcium for the full sample (Incidence Rate Ratio [IRR] = 1.477, 95% Confidence Interval [CI] 1.001-2.170, P = 0.031), and in a male-only subset (IRR = 1.532, 95% CI 0.993-2.360, P = 0.053). Testosterone was also positively associated with clinically relevant coronary atherosclerosis (calcium >100 Agatston units) in the full sample (Odds Ratio [OR] = 1.984, 95% CI 1.202-3.275, P = 0.007) and when limited to male-only sample (OR = 2.032, 95% CI 1.118-4.816, P = 0.024). Individuals with coronary artery calcium >100 had 20% higher levels of testosterone than those with calcium <100 (t = -3.201, P = 0.007). Conclusions and Implications: Among Tsimane, testosterone is positively associated with coronary artery calcium despite generally low normal testosterone levels, minimal atherosclerosis and rare cardiovascular disease (CVD) events. Associations between low testosterone and CVD events in industrialized populations are likely confounded by obesity and other lifestyle factors.

Apolipoprotein-ε4 is associated with higher fecundity in a natural fertility population.

In many populations, the apolipoprotein-ε4 (APOE-ε4) allele increases the risk for several chronic diseases of aging, including dementia and cardiovascular disease; despite these harmful effects at later ages, the APOE-ε4 allele remains prevalent. We assess the impact of APOE-ε4 on fertility and its proximate determinants (age at first reproduction, interbirth interval) among the Tsimane, a natural fertility population of forager-horticulturalists. Among 795 women aged 13 to 90 (20% APOE-ε4 carriers), those with at least one APOE-ε4 allele had 0.3 to 0.5 more children than (ε3/ε3) homozygotes, while those with two APOE-ε4 alleles gave birth to 1.4 to 2.1 more children. APOE-ε4 carriers achieve higher fertility by beginning reproduction 0.8 years earlier and having a 0.23-year shorter interbirth interval. Our findings add to a growing body of literature suggesting a need for studies of populations living in ancestrally relevant environments to assess how alleles that are deleterious in sedentary urban environments may have been maintained by selection throughout human evolutionary history.

Brain volume, energy balance, and cardiovascular health in two nonindustrial South American populations.

Little is known about brain aging or dementia in nonindustrialized environments that are similar to how humans lived throughout evolutionary history. This paper examines brain volume (BV) in middle and old age among two indigenous South American populations, the Tsimane and Moseten, whose lifestyles and environments diverge from those in high-income nations. With a sample of 1,165 individuals aged 40 to 94, we analyze population differences in cross-sectional rates of decline in BV with age. We also assess the relationships of BV with energy biomarkers and arterial disease and compare them against findings in industrialized contexts. The analyses test three hypotheses derived from an evolutionary model of brain health, which we call the embarrassment of riches (EOR). The model hypothesizes that food energy was positively associated with late life BV in the physically active, food-limited past, but excess body mass and adiposity are now associated with reduced BV in industrialized societies in middle and older ages. We find that the relationship of BV with both non-HDL cholesterol and body mass index is curvilinear, positive from the lowest values to 1.4 to 1.6 SDs above the mean, and negative from that value to the highest values. The more acculturated Moseten exhibit a steeper decrease in BV with age than Tsimane, but still shallower than US and European populations. Lastly, aortic arteriosclerosis is associated with lower BV. Complemented by findings from the United States and Europe, our results are consistent with the EOR model, with implications for interventions to improve brain health.

Multi-modal efficacy of a chimeric vesiculovirus expressing the Morreton glycoprotein in sarcoma.

Vesiculoviruses are attractive oncolytic virus platforms due to their rapid replication, appreciable transgene capacity, broad tropism, limited preexisting immunity, and tumor selectivity through type I interferon response defects in malignant cells. We developed a synthetic chimeric virus (VMG) expressing the glycoprotein (G) from Morreton virus (MorV) and utilizing the remaining structural genes from vesicular stomatitis virus (VSV). VMG exhibited in vitro efficacy by inducing oncolysis in a broad range of sarcoma subtypes across multiple species. Notably, all cell lines tested showed the ability of VMG to yield productive infection with rapid replication kinetics and induction of apoptosis. Furthermore, pilot safety evaluations of VMG in immunocompetent, non-tumor-bearing mice showed an absence of toxicity with intranasal doses as high as 1e10 50% tissue culture infectious dose (TCID50)/kg. Locoregional administration of VMG in vivo resulted in tumor reduction in an immunodeficient Ewing sarcoma xenograft at doses as low as 2e5 TCID50. In a murine syngeneic fibrosarcoma model, while no tumor inhibition was achieved with VMG, there was a robust induction of CD8+ T cells within the tumor. The studies described herein establish the promising potential for VMG to be used as a novel oncolytic virotherapy platform with anticancer effects in sarcoma.

Characterization of Morreton virus as an oncolytic virotherapy platform for liver cancers.

BACKGROUND: Morreton virus (MORV) is an oncolytic Vesiculovirus , genetically distinct from vesicular stomatitis virus (VSV). AIM: To report that MORV induced potent cytopathic effects (CPEs) in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) in vitro models. APPROACH AND RESULTS: In preliminary safety analyses, high intranasal doses (up to 10 10 50% tissue culture infectious dose [TCID 50 ]) of MORV were not associated with significant adverse effects in immune competent, non-tumor-bearing mice. MORV was shown to be efficacious in a Hep3B hepatocellular cancer xenograft model but not in a CCA xenograft HuCCT1 model. In an immune competent, syngeneic murine CCA model, single intratumoral treatments with MORV (1 × 10 7 TCID 50 ) triggered a robust antitumor immune response leading to substantial tumor regression and disease control at a dose 10-fold lower than VSV (1 × 10 8 TCID 50 ). MORV led to increased CD8 + cytotoxic T cells without compensatory increases in tumor-associated macrophages and granulocytic or monocytic myeloid-derived suppressor cells. CONCLUSIONS: Our findings indicate that wild-type MORV is safe and can induce potent tumor regression via immune-mediated and immune-independent mechanisms in HCC and CCA animal models without dose limiting adverse events. These data warrant further development and clinical translation of MORV as an oncolytic virotherapy platform.

Natural selection of immune and metabolic genes associated with health in two lowland Bolivian populations.

A growing body of work has addressed human adaptations to diverse environments using genomic data, but few studies have connected putatively selected alleles to phenotypes, much less among underrepresented populations such as Amerindians. Studies of natural selection and genotype-phenotype relationships in underrepresented populations hold potential to uncover previously undescribed loci underlying evolutionarily and biomedically relevant traits. Here, we worked with the Tsimane and the Moseten, two Amerindian populations inhabiting the Bolivian lowlands. We focused most intensively on the Tsimane, because long-term anthropological work with this group has shown that they have a high burden of both macro and microparasites, as well as minimal cardiometabolic disease or dementia. We therefore generated genome-wide genotype data for Tsimane individuals to study natural selection, and paired this with blood mRNA-seq as well as cardiometabolic and immune biomarker data generated from a larger sample that included both populations. In the Tsimane, we identified 21 regions that are candidates for selective sweeps, as well as 5 immune traits that show evidence for polygenic selection (e.g., C-reactive protein levels and the response to coronaviruses). Genes overlapping candidate regions were strongly enriched for known involvement in immune-related traits, such as abundance of lymphocytes and eosinophils. Importantly, we were also able to draw on extensive phenotype information for the Tsimane and Moseten and link five regions (containing PSD4, MUC21 and MUC22, TOX2, ANXA6, and ABCA1) with biomarkers of immune and metabolic function. Together, our work highlights the utility of pairing evolutionary analyses with anthropological and biomedical data to gain insight into the genetic basis of health-related traits.

The role of Neanderthal introgression in liver cancer.

BACKGROUND: Neanderthal introgressed DNA has been linked to different normal and disease traits including immunity and metabolism-two important functions that are altered in liver cancer. However, there is limited understanding of the relationship between Neanderthal introgression and liver cancer risk. The aim of this study was to investigate the relationship between Neanderthal introgression and liver cancer risk. METHODS: Using germline and somatic DNA and tumor RNA from liver cancer patients from The Cancer Genome Atlas, along with ancestry-match germline DNA from unaffected individuals from the 1000 Genomes Resource, and allele specific expression data from normal liver tissue from The Genotype-Tissue Expression project we investigated whether Neanderthal introgression impacts cancer etiology. Using a previously generated set of Neanderthal alleles, we identified Neanderthal introgressed haplotypes. We then tested whether somatic mutations are enriched or depleted on Neanderthal introgressed haplotypes compared to modern haplotypes. We also computationally assessed whether somatic mutations have a functional effect or show evidence of regulating expression of Neanderthal haplotypes. Finally, we compared patterns of Neanderthal introgression in liver cancer patients and the general population. RESULTS: We find Neanderthal introgressed haplotypes exhibit an excess of somatic mutations compared to modern haplotypes. Variant Effect Predictor analysis revealed that most of the somatic mutations on these Neanderthal introgressed haplotypes are not functional. We did observe expression differences of Neanderthal alleles between tumor and normal for four genes that also showed a pattern of enrichment of somatic mutations on Neanderthal haplotypes. However, gene expression was similar between liver cancer patients with modern ancestry and liver cancer patients with Neanderthal ancestry at these genes. Provocatively, when analyzing all genes, we find evidence of Neanderthal introgression regulating expression in tumor from liver cancer patients in two genes, ARK1C4 and OAS1. Finally, we find that most genes do not show a difference in the proportion of Neanderthal introgression between liver cancer patients and the general population. CONCLUSION: Our results suggest that Neanderthal introgression provides opportunity for somatic mutations to accumulate, and that some Neanderthal introgression may impact liver cancer risk.

Cell-Free Tumor DNA Dominant Clone Allele Frequency Is Associated With Poor Outcomes in Advanced Biliary Cancers Treated With Platinum-Based Chemotherapy.

PURPOSE: This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment. MATERIALS AND METHODS: We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS). RESULTS: The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9. CONCLUSION: DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.

High GILT Expression Is Associated with Improved Survival in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition.

Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II restricted presentation of multiple melanoma antigens. There is variable GILT protein expression in malignant melanocytes in melanoma specimens. High GILT mRNA expression in melanoma specimens is associated with improved overall survival, before the advent of immune checkpoint inhibitors (ICI). However, the association of GILT in metastatic melanoma with survival in patients treated with ICI and the cell type expressing GILT associated with survival have not been determined. Using RNA sequencing datasets, high GILT mRNA expression in metastatic melanoma specimens was associated with improved progression-free and overall survival in patients treated with ICI. A clinical dataset of metastatic melanoma specimens was generated and annotated with clinical information. Positive GILT immunohistochemical staining in antigen presenting cells and melanoma cells was observed in 100% and 65% of metastatic melanoma specimens, respectively. In the subset of patients treated with ICI in the clinical dataset, high GILT protein expression within melanoma cells was associated with improved overall survival. The association of GILT mRNA and protein expression with survival was independent of cancer stage. These studies support that high GILT mRNA expression in bulk tumor samples and high GILT protein expression in melanoma cells is associated with improved survival in ICI-treated patients. These findings support further investigation of GILT as a biomarker to predict the response to ICI.

NeoScore Integrates Characteristics of the Neoantigen:MHC Class I Interaction and Expression to Accurately Prioritize Immunogenic Neoantigens.

Accurate prioritization of immunogenic neoantigens is key to developing personalized cancer vaccines and distinguishing those patients likely to respond to immune checkpoint inhibition. However, there is no consensus regarding which characteristics best predict neoantigen immunogenicity, and no model to date has both high sensitivity and specificity and a significant association with survival in response to immunotherapy. We address these challenges in the prioritization of immunogenic neoantigens by (1) identifying which neoantigen characteristics best predict immunogenicity; (2) integrating these characteristics into an immunogenicity score, the NeoScore; and (3) demonstrating a significant association of the NeoScore with survival in response to immune checkpoint inhibition. One thousand random and evenly split combinations of immunogenic and nonimmunogenic neoantigens from a validated dataset were analyzed using a regularized regression model for characteristic selection. The selected characteristics, the dissociation constant and binding stability of the neoantigen:MHC class I complex and expression of the mutated gene in the tumor, were integrated into the NeoScore. A web application is provided for calculation of the NeoScore. The NeoScore results in improved, or equivalent, performance in four test datasets as measured by sensitivity, specificity, and area under the receiver operator characteristics curve compared with previous models. Among cutaneous melanoma patients treated with immune checkpoint inhibition, a high maximum NeoScore was associated with improved survival. Overall, the NeoScore has the potential to improve neoantigen prioritization for the development of personalized vaccines and contribute to the determination of which patients are likely to respond to immunotherapy.

Cancer Neoantigens: Challenges and Future Directions for Prediction, Prioritization, and Validation.

Prioritization of immunogenic neoantigens is key to enhancing cancer immunotherapy through the development of personalized vaccines, adoptive T cell therapy, and the prediction of response to immune checkpoint inhibition. Neoantigens are tumor-specific proteins that allow the immune system to recognize and destroy a tumor. Cancer immunotherapies, such as personalized cancer vaccines, adoptive T cell therapy, and immune checkpoint inhibition, rely on an understanding of the patient-specific neoantigen profile in order to guide personalized therapeutic strategies. Genomic approaches to predicting and prioritizing immunogenic neoantigens are rapidly expanding, raising new opportunities to advance these tools and enhance their clinical relevance. Predicting neoantigens requires acquisition of high-quality samples and sequencing data, followed by variant calling and variant annotation. Subsequently, prioritizing which of these neoantigens may elicit a tumor-specific immune response requires application and integration of tools to predict the expression, processing, binding, and recognition potentials of the neoantigen. Finally, improvement of the computational tools is held in constant tension with the availability of datasets with validated immunogenic neoantigens. The goal of this review article is to summarize the current knowledge and limitations in neoantigen prediction, prioritization, and validation and propose future directions that will improve personalized cancer treatment.

FGFR2-IIIb Expression by Immunohistochemistry Has High Specificity in Cholangiocarcinoma with FGFR2 Genomic Alterations.

BACKGROUND: FGFR2 genomic alterations are observed in 10-20% of cholangiocarcinoma (CCA). Although FGFR2 fusions are an important actionable target, FGFR2 protein expression has not been thoroughly characterized. AIMS: To evaluate FGFR2 protein expression in cholangiocarcinoma harboring FGFR2 genomic alterations. METHODS: FGFR2 protein expression was evaluated in 99 CCA cases with two different antibodies. FGFR2 genomic alterations were confirmed via next-generating sequencing (NGS) or FISH. Primary objective was to determine the specificity and sensitivity of FGFR2 immunohistochemistry staining for detecting FGFR2 genomic alterations. Secondary objectives included overall FGFR2 immunohistochemistry staining in CCA patients, and evaluation of whether FGFR2 expression correlates with clinical outcomes including overall survival (OS), progression-free survival (PFS), and time-to-tumor recurrence (TTR). RESULTS: Immunohistochemistry staining with two antibodies against FGFR2, FPR2-D, and clone 98706 showed high accuracy (78.7% and 91.9%) and specificity (82.9% and 97.7%), and moderate sensitivity (53.9% and 57.1%), respectively, when compared with the standard methods for detecting FGFR2 genomic alterations. In a median follow-up of 72 months, there were no statistically significant differences in OS, PFS, and TTR, for patients with positive or negative FGFR2 staining. CONCLUSION: FGFR2 protein expression by immunohistochemistry has high specificity and therefore could be used to imply the presence of FGFR2 genomic alterations in the context of a positive test. In the case of a negative test, NGS or FISH would be necessary to ascertain cases with FGFR2 genomic alterations.

Synergistic combination of cytotoxic chemotherapy and cyclin-dependent kinase 4/6 inhibitors in biliary tract cancers.

BACKGROUND AND AIMS: Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin-dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive. APPROACH AND RESULTS: Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy-induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine. CONCLUSIONS: As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.

APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population.

In post-industrial settings, apolipoprotein E4 (APOE4) is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, the APOE4 allele confers benefits by reducing innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia (N = 1266, 50% female), APOE4 is associated with 30% lower C-reactive protein, and higher total cholesterol and oxidized LDL. Blood lipids were either not associated, or negatively associated with inflammatory biomarkers, except for associations of oxidized LDL and inflammation which were limited to obese adults. Further, APOE4 carriers maintain higher levels of total and LDL cholesterol at low body mass indices (BMIs). These results suggest that the relationship between APOE4 and lipids may be beneficial for pathogen-driven immune responses and unlikely to increase cardiovascular risk in an active subsistence population.

Genes contain the instructions needed for a cell to make molecules called proteins, which perform various roles in the body. Different variants of a gene can affect how the protein works, and in some cases, can increase a person's risk to develop certain diseases. For example, people who carry a version of the apolipoprotein E gene called APOE4 have a greater risk of developing Alzheimer's disease or heart disease. Individuals with two copies of this genetic variant have a 45% higher risk of heart disease and 12 times higher risk of Alzheimer's disease. Studies in industrialized countries suggest this increased risk may be the result of higher cholesterol and inflammation in people with APOE4. But if APOE4 is harmful, why does it continue to be so common worldwide? One potential explanation is that APOE4, which has been around since before modern humans, may be beneficial in some contexts. Cholesterol is essential for many vital tasks in the body. In physically demanding environments where parasitic infections are common ­ conditions similar to those experienced by early humans ­ APOE4 might be beneficial. Under those circumstances, having more cholesterol might help fuel metabolic activities, fight infections, or reduce inflammation caused by infections. Garcia et al. investigated the link between the APOE4 genetic variant, cholesterol and inflammation in 1,266 Indigenous Tsimane people from 80 villages in Bolivia. Tsimane people live an active lifestyle foraging and farming for food. Parasite infections are a common problem in their communities, but obesity rates are very low. Garcia et al. found that Tsimane people with at least one copy of the APOE4 have lower levels of inflammation and higher levels of cholesterol than those who have two copies of the APOE3 version of the gene. Very lean people with APOE4 had especially high levels of the so called "bad" low density lipoprotein (LDL) cholesterol compared to people with APOE3 only. However, in this situation, storing a little extra cholesterol may not be so bad. The findings contradict other studies that have linked obesity to higher LDL levels and APOE4 to higher levels of inflammation. For the majority of human history, humans lived in more physically strenuous and calorically restrictive environments, with less access to clean water. Garcia et al. suggest that the harmful effects of APOE4 seen in studies in more industrialized societies ­ where people tend to be more sedentary and have less exposure to pathogens ­ may reflect a mismatch between a person's environment and their genes. More studies that capture the diversity of environmental conditions under which people live will help clarify the role of APOE4 health and disease.

Shared Gene Expression and Immune Pathway Changes Associated with Progression from Nevi to Melanoma.

There is a need to identify molecular biomarkers of melanoma progression to assist the development of chemoprevention strategies to lower melanoma incidence. Using datasets containing gene expression for dysplastic nevi and melanoma or melanoma arising in a nevus, we performed differential gene expression analysis and regularized regression models to identify genes and pathways that were associated with progression from nevi to melanoma. A small number of genes distinguished nevi from melanoma. Differential expression of seven genes was identified between nevi and melanoma in three independent datasets. C1QB, CXCL9, CXCL10, DFNA5 (GSDME), FCGR1B, and PRAME were increased in melanoma, and SCGB1D2 was decreased in melanoma, compared to dysplastic nevi or nevi that progressed to melanoma. Further supporting an association with melanomagenesis, these genes demonstrated a linear change in expression from benign nevi to dysplastic nevi to radial growth phase melanoma to vertical growth phase melanoma. The genes associated with melanoma progression showed significant enrichment of multiple pathways related to the immune system. This study demonstrates (1) a novel application of bioinformatic approaches to aid clinical trials of melanoma chemoprevention and (2) the feasibility of determining a gene signature biomarker of melanomagenesis.

Characteristics of Patients With Chronic Hepatitis B Virus Infection With Genotype E Predominance in Burkina Faso.

Hepatitis B virus (HBV) genotype E (HBV-E) accounts for the majority of chronic hepatitis B (CHB) infections in West Africa. We aimed to determine factors associated with HBV-E-induced hepatocellular carcinoma (HCC) in West Africa. Data on patients from Burkina Faso who were hepatitis B surface antigen positive (HBsAg+) and had CHB were analyzed. HBV viral load and hepatitis B e antigen (HBeAg) status were measured in 3,885 individuals with CHB without HCC (CHB HCC-) and 59 individuals with CHB with HCC (CHB HCC+). HBV genotyping was performed for 364 subjects with CHB HCC- and 41 subjects with CHB HCC+. Overall, 2.5% of the CHB HCC- group was HBeAg+ compared with 0% of the CHB HCC+ group. Of the 364 patients who were CHB HCC- with available genotyping, the frequencies of HBV genotypes E and C/E were 70.3% and 12.9%, respectively. Age (odds ratio [OR] for older age, 1.08; 95% confidence interval [CI], 1.06-1.10 per 1-year increase in age), male sex (OR, 2.03; 95% CI, 1.11-3.69), and HBV viremia (OR, 1.48; 95% CI, 1.31-1.67 per 1 log10 IU/mL) were each associated with HCC diagnosis. Patients with genotype E had a lower HBeAg prevalence (6.3% vs. 14.9%), lower HBV viral load, and higher prevalence of cirrhosis (14.5% vs. 4.8%) than patients with genotype C/E. Conclusion: HBV-E is the most common circulating strain (70.3%) in West African patients. HCC was associated with older age, male sex, and high HBV viral load. It is expected that these results will further inform guidance on clinical management of HBV infection in West Africa.

Novel Mechanisms of Cancer Emerge When Accounting for Sex as a Biological Variable.

There is a large gap between the aspiration of considering sex as biological variable and the execution of such studies, particularly in genomic studies of human cancer. This represents a lost opportunity to identify sex-specific molecular etiologies that may underpin the dramatic sex differences in cancer incidence and outcome. There are conceptual and practical challenges associated with considering sex as a biological variable, including the definition of sex itself and the need for novel study designs. A better understanding of cancer mechanisms, resulting in improved outcomes, will reward the effort invested in incorporating sex as a biological variable.