Publications

The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells into T helper 17 cells or regulatory T cells creates subtype-specific enhancer-promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.

An increasing number of emerging tick-borne diseases has been reported in the United States since the 1970s. Using metagenomic next generation sequencing, we detected nucleic acid sequences from 2 novel viruses in the family Bunyaviridae and an emerging human rickettsial pathogen, Rickettsia philipii, in a population of the Pacific Coast tick, Dermacentor occidentalis in Mendocino County sampled annually from 2011 to 2014. A total of 250 adults of this human-biting, generalist tick were collected from contiguous chaparral and grassland habitats, and RNA from each individually extracted tick was deep sequenced to an average depth of 7.3 million reads. We detected a Francisella endosymbiont in 174 ticks (70%), and Rickettsia spp. in 19 ticks (8%); Rickettsia-infected ticks contained R. rhipicephali (16 of 250, 6.4%) or R. philipii (3 of 250,1.2%), the agent of eschar-associated febrile illness in humans. The genomes of 2 novel bunyaviruses (>99% complete) in the genera Nairovirus and Phlebovirus were also identified and found to be present in 20-91% of ticks, depending on the year of collection. The high prevalence of these bunyaviruses in sampled Dermacentor ticks suggests that they may be viral endosymbionts, although further studies are needed to determine whether they are infectious for vertebrate hosts, especially humans, and their potential role in tick ecology.

PURPOSE

Fatigue is the most common symptom associated with cancer and its treatment. Investigation of molecular mechanisms associated with fatigue in oncology patients may identify new therapeutic targets. The objectives of this study were to evaluate the relationships between gene expression and perturbations in biological pathways and evening fatigue severity in oncology patients who received chemotherapy (CTX).

METHODS

The Lee Fatigue Scale (LFS) and latent class analysis were used to identify evening fatigue phenotypes. We measured 47,214 ribonucleic acid transcripts from whole blood collected prior to a cycle of CTX. Perturbations in biological pathways associated with differential gene expression were identified from public data sets (i.e., Kyoto Encyclopedia Gene and Genomes, BioCarta).

RESULTS

Patients were classified into Moderate (n = 65, mean LFS score 3.1) or Very High (n = 195, mean LFS score 6.4) evening fatigue groups. Compared to patients with Moderate fatigue, patients with Very High fatigue exhibited differential expression of 29 genes. A number of the perturbed pathways identified validated prior mechanistic hypotheses for fatigue, including alterations in immune function, inflammation, neurotransmission, energy metabolism, and circadian rhythms. Based on our findings, energy metabolism was further divided into alterations in carbohydrate metabolism and skeletal muscle energy. Alterations in renal function-related pathways were identified as a potential new mechanism.

CONCLUSIONS

This study identified differential gene expression and perturbed biological pathways that provide new insights into the multiple and likely inter-related mechanisms associated with evening fatigue in oncology patients.

OBJECTIVE

Hepatic steatosis is common in HIV-infected individuals. Magnetic resonance spectroscopy (MRS) is the preferred noninvasive method for hepatic steatosis measurement but is expensive. Controlled attenuation parameter (CAP) also assesses hepatic steatosis and is conveniently performed concomitantly with transient elastography. We aimed to assess the accuracy of CAP in the setting of HIV infection.

DESIGN

Cross-sectional study.

METHODS

CAP and MRS were performed in 82 study participants (39 HIV monoinfected; seven hepatitis C virus (HCV) monoinfected; 21 HIV/HCV coinfected; 15 with neither infection). We used concordance correlation coefficients to compare log-transformed and standardized CAP and MRS values and linear regression to examine factors associated with CAP and MRS-measured hepatic steatosis (MRS-HS). The accuracy of CAP to detect at least mild hepatic steatosis, defined as MRS-liver fat fraction more than 0.05, and the factors associated with discordance between CAP and MRS were evaluated.

RESULTS

Overall, CAP-measured hepatic steatosis and MRS-HS correlated moderately well (rc = 0.63; P < 0.001), and correlation was strongest in the HIV-monoinfected group (rc = 0.67; P < 0.001). Body composition factors (higher BMI, waist circumference, visceral and abdominal subcutaneous adipose tissue) and insulin resistance were significantly associated with both greater CAP-measured hepatic steatosis and MRS-HS. Using a validated CAP cut-off of at least 238 dB/m, sensitivity and specificity for at least mild hepatic steatosis were 84% and 75% in the entire cohort; 89% and 80% in the HIV-monoinfected group. Participants with higher body composition parameters were more likely to be misclassified as having hepatic steatosis by CAP.

CONCLUSION

Our findings suggest CAP is an acceptable noninvasive surrogate for hepatic steatosis in HIV-infected individuals but may overestimate hepatic steatosis prevalence, especially in individuals with high BMI. Evaluation of factors that improve CAP accuracy and determination of optimal cut-offs are warranted.

Latino children are more likely to be obese than non-Hispanic white children, and feeding patterns that begin in infancy may contribute to this disparity. The objective of this study was to elucidate beliefs and practices related to the introduction of solids and solid food feeding in the first year of life among low-income Latino parents residing in Northern California. We conducted 26 semi-structured interviews that explored the timing of introduction of solids, selection of foods to serve to infants, feeding strategies, sources of information on solid food feeding and concerns about infant weight. We found that most parents relied on traditional practices in selecting first foods for infants and had a strong preference for homemade food, which was often chicken soup with vegetables. Parents generally described responsive feeding practices; however a minority used pressuring practices to encourage infants to eat more. Very few parents practiced repeated gentle introduction of unfamiliar food to increase acceptance. High calorie low nutrient foods were typically introduced at around 12 months of age and parents struggled to limit such foods once children were old enough to ask for them. Parents were concerned about the possibility of infants becoming overweight and considered health care providers to be an important source of information on infant weight status. The results of this study can be used to inform the development of interventions to prevent obesity in Latino children with similar demographics to our study population.

BACKGROUND

Breast cancer treatments can change women's hormonal milieu and alter their symptom experience. Little is known about associations between menopausal status and menopausal symptoms in women with breast cancer before surgery.

OBJECTIVE

The purpose of this study was to evaluate for differences in occurrence, severity, and distress of symptoms between premenopausal and postmenopausal women before breast cancer surgery.

METHODS

A total of 312 women with breast cancer completed the Menopausal Symptoms Scale, a self-report measure that evaluated the occurrence, severity, and distress of 46 common symptoms associated with menopause. Regression analyses were used to evaluate for between-group differences in these symptoms.

RESULTS

Of the 312 patients enrolled, 37.4% (n = 116) were premenopausal, and 62.6% (n = 196) were postmenopausal. In the multivariate analysis that adjusted for 7 covariates, premenopausal patients reported higher occurrence rates for urinary frequency (P = .006) and reported lower occurrence rates for joint pain/stiffness (P = .011), difficulty falling asleep (P = .025), and vaginal dryness (P = .002). A significant interaction was found between age and menopausal status for hot flashes (P = .002), wake during the night (P = .025), and headache (P = .040).

CONCLUSION

Regardless of menopausal status, women reported high occurrence rates for several menopausal symptoms. Associations between some symptom occurrence rates and menopausal status depended on the patients' age.

IMPLICATIONS FOR PRACTICE

As part of a preoperative symptom assessment, clinicians need to consider a woman's menopausal status and salient demographic and clinical characteristics. The identification of women with a higher symptom burden will assist with more effective management.