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Hot Papers

Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) are often published in high-impact journals. Read some of our recent articles:

Authors: Gierach GL, Curtis RE, Pfeiffer RM, Mullooly M, Ntowe EA, Hoover RN, Nyante SJ, Feigelson HS, Glass AG, Berrington de Gonzalez A

Journal: JAMA Oncol. 2016 Oct 6. doi: 10.1001/jamaoncol.2016.3340. [Epub ahead of print]

IMPORTANCE:  Within 10 years after breast cancer diagnosis, roughly 5% of patients develop contralateral breast cancer (CBC). Randomized trials have found that therapy including tamoxifen citrate and aromatase inhibitors (AIs) reduces CBC risk. But little is known about the magnitude and duration of protective associations within the context of real-world clinical management settings, where varying durations of and gaps in treatment are common.
OBJECTIVE:  To determine the association between adjuvant tamoxifen and AI therapy and CBC risk within a general community setting.
DESIGN, SETTING, AND PARTICIPANTS:  A retrospective cohort study of CBC risk among 7541 patients diagnosed with a first primary unilateral invasive breast cancer at Kaiser Permanente Institute for Health Research (Colorado) or Kaiser Permanente Northwest Center for Health Research (Oregon) between January 1, 1990, and December 31, 2008. Data were analyzed from 1 year after diagnosis of the first breast cancer through the earliest of the following events: CBC diagnosis, other second cancer diagnosis, death, last tumor registry follow-up, exit from the Kaiser Permanente health care plan, or end of study follow-up (December 31, 2010, for Oregon and December 31, 2011, for Colorado).
EXPOSURES:  Adjuvant tamoxifen use and AI therapy were treated as time-dependent exposures, assessed using electronic prescription records.
MAIN OUTCOMES AND MEASURES:  Incident CBC based on long-term systematic follow-up.
RESULTS:  Among 7541 women with invasive breast cancer, median age at initial breast cancer diagnosis was 60.6 years (age range, 24.9-84.9 years). Women were predominantly (92.9% [7009 of 7541]) of white race. During a median of 6.3 years (range, 1-20.9 years) of follow-up, 248 women developed CBC (45 in situ and 203 invasive). Contralateral breast cancer risk decreased significantly with increasing tamoxifen therapy duration. In current users, the relative risk (RR) per year of tamoxifen use was 0.76 (95% CI, 0.64-0.89), with an estimated 66% (RR, 0.34; 95% CI, 0.29-0.40) RR reduction for 4 years of use compared with nonusers. Risk reductions were slightly smaller for past users but were still significant at least 5 years after stopping tamoxifen therapy (RR per year of use, 0.85; 95% CI, 0.71-0.995). In addition, AI use without tamoxifen therapy was associated with reduced CBC risk (RR for AI users compared with nonusers, 0.48; 95% CI, 0.22-0.97). Risk reductions were most apparent among women whose primary and CBCs were estrogen receptor positive.
CONCLUSIONS AND RELEVANCE:  Tamoxifen therapy was associated with reduced CBC risk during treatment and after its cessation, with risk progressively decreasing as tamoxifen therapy duration increased. Among those surviving at least 5 years, tamoxifen use for at least 4 years was estimated to prevent 3 CBCs per 100 women by 10 years after an estrogen receptor-positive first breast cancer, an absolute risk reduction that is consistent with findings from clinical trials. If adjuvant endocrine therapy is indicated for breast cancer treatment, these findings in concert with trial data suggest that women should be encouraged to complete the full course.

Authors: Middlebrooks CD1, Banday AR1, Matsuda K2, Udquim KI1, Onabajo OO1, Paquin A1, Figueroa JD3, Zhu B4, Koutros S4, Kubo M5, Shuin T6, Freedman ND4, Kogevinas M7,8,9, Malats N10, Chanock SJ4, Garcia-Closas M4, Silverman DT4, Rothman N4, Prokunina-Olsson L1.

Journal: Nat Genet. 2016 Sep 19. doi: 10.1038/ng.3670. [Epub ahead of print]

High rates of APOBEC-signature mutations are found in many tumors, but factors affecting this mutation pattern are not well understood. Here we explored the contribution of two common germline variants in the APOBEC3 region. SNP rs1014971 was associated with bladder cancer risk, increased APOBEC3B expression, and enrichment with APOBEC-signature mutations in bladder tumors. In contrast, a 30-kb deletion that eliminates APOBEC3B and creates an APOBEC3A-APOBEC3B chimera was not important in bladder cancer, whereas it was associated with breast cancer risk and enrichment with APOBEC-signature mutations in breast tumors. In vitro, APOBEC3B expression was predominantly induced by treatment with a DNA-damaging drug in bladder cancer cell lines, and APOBEC3A expression was induced as part of the antiviral interferon-stimulated response in breast cancer cell lines. These findings suggest a tissue-specific role of environmental oncogenic triggers, particularly in individuals with germline APOBEC3 risk variants.

Authors: Zhou Q, Yu X, Demirkaya E, Deuitch N, Stone D, Tsai WL, Kuehn HS, Wang H, Yang D, Park YH, Ombrello AK, Blake M, Romeo T, Remmers EF, Chae JJ, Mullikin JC, Güzel F, Milner JD, Boehm M, Rosenzweig SD, Gadina M, Welch SB, Özen S, Topaloglu R, Abinun M, Kastner DL, Aksentijevich I

Journal: Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10127-32. doi: 10.1073/pnas.1612594113. Epub 2016 Aug 24.

Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients' fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.

Authors: Wen X, Jin T, Xu X

Journal: J Vis Exp. 2016 Sep 14;(115). doi: 10.3791/54511.

Eukaryotic cells sense and move towards a chemoattractant gradient, a cellular process referred as chemotaxis. Chemotaxis plays critical roles in many physiological processes, such as embryogenesis, neuron patterning, metastasis of cancer cells, recruitment of neutrophils to sites of inflammation, and the development of the model organism Dictyostelium discoideum. Eukaryotic cells sense chemo-attractants using G protein-coupled receptors. Visual chemotaxis assays are essential for a better understanding of how eukaryotic cells control chemoattractant-mediated directional cell migration. Here, we describe detailed methods for: 1) real-time, high-resolution monitoring of multiple chemotaxis assays, and 2) simultaneously visualizing the chemoattractant gradient and the spatiotemporal dynamics of signaling events in neutrophil-like HL60 cells.

Authors: Heske CM, Mendoza A, Edessa LD, Baumgart JT, Lee S, Trepel J, Proia DA, Neckers L, Helman LJ

Journal: Oncotarget. 2016 Sep 6. doi: 10.18632/oncotarget.11869. [Epub ahead of print]

Long-term survival in patients with metastatic, relapsed, or recurrent Ewing sarcoma and rhabdomyosarcoma is dismal. Irinotecan, a topoisomerase 1 inhibitor, has activity in these sarcomas, but due to poor bioavailability of its active metabolite (SN-38) has had limited clinical efficacy. In this study we have evaluated the efficacy and toxicity of STA-8666, a novel drug conjugate which uses an HSP90 inhibitor to facilitate intracellular, tumor-targeted delivery of the topoisomerase 1 inhibitor SN-38, thus preferentially delivering and concentrating SN-38 within tumor tissue. We present in vivo evidence from mouse xenograft models that STA-8666 results in more persistent inhibition of topoisomerase 1 and prolonged DNA damage compared to irinotecan. This translates into superior antitumor efficacy and survival in multiple aggressive models of both diseases in mouse xenografts, as well as in an irinotecan-resistant model of pediatric osteosarcoma, demonstrated by dramatic tumor shrinkage, durable remission and prolonged complete regressions following short-term treatment, compared to conventional irinotecan. Gene expression analysis performed on xenograft tumors treated with either irinotecan or STA-8666 showed that STA-8666 affected expression of DNA damage and repair genes more robustly than irinotecan. These results suggest that STA-8666 may be a promising new agent for patients with pediatric-type sarcoma.

Authors: Ha NH, Long J, Cai Q, Shu XO, Hunter KW

Journal: PLoS Genet. 2016 Sep 22;12(9):e1006267. doi: 10.1371/journal.pgen.1006267. eCollection 2016.

Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ) and low metastatic (MOLF/EiJ) mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL) SNPs with disease-free survival, consistent with the mouse studies.

Authors: LeDoux JE, Pine DS

Journal: Am J Psychiatry. 2016 Sep 9:appiajp201616030353.

Tremendous progress has been made in basic neuroscience in recent decades. One area that has been especially successful is research on how the brain detects and responds to threats. Such studies have demonstrated comparable patterns of brain-behavior relationships underlying threat processing across a range of mammalian species, including humans. This would seem to be an ideal body of information for advancing our understanding of disorders in which altered threat processing is a key factor, namely, fear and anxiety disorders. But research on threat processing has not led to significant improvements in clinical practice. The authors propose that in order to take advantage of this progress for clinical gain, a conceptual reframing is needed. Key to this conceptual change is recognition of a distinction between circuits underlying two classes of responses elicited by threats: 1) behavioral responses and accompanying physiological changes in the brain and body and 2) conscious feeling states reflected in self-reports of fear and anxiety. This distinction leads to a "two systems" view of fear and anxiety. The authors argue that failure to recognize and consistently emphasize this distinction has impeded progress in understanding fear and anxiety disorders and hindered attempts to develop more effective pharmaceutical and psychological treatments. The two-system view suggests a new way forward.

Authors: Xi L, Pham T, Payabyab EC, Sherry RM, Rosenberg SA, Raffeld M

Journal: Clin Cancer Res. 2016 Aug 1. pii: clincanres.0613.2016. [Epub ahead of print]

PURPOSE: Adoptive transfer of activated autologous tumor-infiltrating lymphocytes (TIL) can mediate complete, durable regressions in patients with metastatic melanoma (MM). Responding patients generally do not have significant changes in non-cutaneous RECIST targets before 30-60 days following TIL infusion, and complete responses are often not confirmed for 1-2 years. There is a critical need for a biomarker that can provide early information regarding the likelihood and duration of a response to enable rational decisions about altering therapy. We wished to evaluate the role of ctDNA in separating responding from non-responding patients.

EXPERIMENTAL DESIGN: We studied BRAF V600E ctDNA levels by a sensitive allele specific PCR assay in 388 serum samples from 48 patients who received TIL immunotherapy at the National Cancer Institute, and correlated differences in the dynamic patterns of their ctDNA measurements with response outcomes.

RESULTS: A strong correlation was found between the presence or absence of an early serum peak of V600E ctDNA, and the likelihood of an objective response. Furthermore, patients that developed an early ctDNA peak and cleared their serum of V600E ctDNA were highly likely to achieve a complete response over the next 1-2 years. Patients that showed no peak of V600E ctDNA failed to achieve an objective response, with one exception.

CONCLUSIONS: We show that the dynamic changes occurring in BRAF V600E ctDNA levels within the first month following T-cell transfer immunotherapy in MM can be used to rapidly identify responding from non-responding patients, potentially allowing clinicians to make critical treatment-related decisions in a more timely manner. These data also suggest that the majority of tumor killing by TIL occurs very early after the initiation of therapy.

Authors: Ghazizadeh A, Griggs W, Hikosaka O

Journal: Front Neurosci. 2016 Aug 19;10:378. doi: 10.3389/fnins.2016.00378. eCollection 2016.

Among many objects around us, some are more salient than others (i.e., attract our attention automatically). Some objects may be inherently salient (e.g., brighter), while others may become salient by virtue of their ecological relevance through experience. However, the role of ecological experience in automatic attention has not been studied systematically. To address this question, we let subjects (macaque monkeys) view a large number of complex objects (>300), each experienced repeatedly (>5 days) with rewarding, aversive or no outcome association (mere-perceptual exposure). Test of salience was done on separate days using free viewing with no outcome. We found that gaze was biased among the objects from the outset, affecting saccades to objects or fixations within objects. When the outcome was rewarding, gaze preference was stronger (i.e., positive) for objects with larger or equal but uncertain rewards. The effects of aversive outcomes were variable. Gaze preference was positive for some outcome associations (e.g., airpuff), but negative for others (e.g., time-out), possibly due to differences in threat levels. Finally, novel objects attracted gaze, but mere perceptual exposure of objects reduced their salience (learned negative salience). Our results show that, in primates, object salience is strongly influenced by previous ecological experience and is supported by a large memory capacity. Owing to such high capacity for learned salience, the ability to rapidly choose important objects can grow during the entire life to promote biological fitness.

Authors: Shin HY, Willi M, Yoo KH, Zeng X, Wang C, Metser G, Hennighausen L

Journal: Nat Genet. 2016 Aug;48(8):904-11. doi: 10.1038/ng.3606. Epub 2016 Jul 4.

Super-enhancers comprise dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate the role of super-enhancers in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-seq analysis for the master regulator STAT5A, the glucocorticoid receptor, H3K27ac and MED1 identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5-binding sites within its constituent enhancers. Individually, the most distal site displayed the greatest enhancer activity. However, combinatorial mutation analysis showed that the 1,000-fold induction in gene expression during pregnancy relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer. Altogether, these data suggest a temporal and functional enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insights into the regulation of cell-type-specific expression of hormone-sensing genes.