Publications

Take a deeper look into all the publications produced by researchers at The Dartmouth Institute.

Prabhat AM, Kuppusamy ML, Bognár B, Kálai T, Hideg K, Kuppusamy P

2018 Dec 14;doi: 10.1007/s12013-018-0862-5

The synthesis and antiproliferative effect of a novel curcumin analog, 4,4'-disulfonyldiarylidenyl piperidone, are reported. The design of the molecule is based on the fusion of an antiproliferative segment, namely diarylidenyl piperidone (DAP), with N-hyroxypyrroline, which is known to metabolically convert to nitroxide and protect healthy cells. Cellular uptake, metabolic conversion, cytotoxicity and antiproliferative effect of the DAP derivative against HCT-116 human colon cancer cells have been determined. Based on cell viability and proliferation assays as well as western-blot analysis of major transcription factors and inhibitory proteins, it is determined that the DAP compound is cytotoxic by inhibiting cell survival and proliferation pathways. The findings may have important implications in the design and development of effective anticancer agents.

Cell Biochem Biophys|2018 Dec 14

Achtyes ED, Ben-Zeev D, Luo Z, Mayle H, Burke B, Rotondi AJ, Gottlieb JD, Brunette MF, Mueser KT, Gingerich S, Meyer-Kalos PS, Marcy P, Schooler NR, Robinson DG, Kane JM

2018 Dec 11;pii: S0920-9964(18)30677-7. doi: 10.1016/j.schres.2018.11.026

Technology-delivered healthcare interventions may enhance dissemination of evidence-based treatments in low-resource areas. These interventions may be accessed 'on-demand,' including after hours. Patients with schizophrenia do engage with technological aids but when/how they would utilize these tools is not known.

Schizophr Res|2018 Dec 11

Rosen CS, Bernardy NC, Chard KM, Clothier B, Cook JM, Crowley J, Eftekhari A, Kehle-Forbes SM, Mohr DC, Noorbaloochi S, Orazem RJ, Ruzek JI, Schnurr PP, Smith BN, Sayer NA

2018 Nov 20;62:53-60doi: 10.1016/j.janxdis.2018.11.003

The United States Department of Veterans Affairs (VA) provides Cognitive Processing Therapy (CPT) and Prolonged Exposure therapy (PE) for PTSD at all of its facilities, but little is known about systematic differences between patients who do and do not initiate these treatments. VA administrative data were analyzed for 6,251 veterans receiving psychotherapy over one year in posttraumatic stress disorder (PTSD) specialty clinics at nine VA medical centers. CPT and PE were initiated by 2,173 (35%) patients. Veterans' probability of initiating either CPT or PE (considered together) was 29% lower (adjusted odds ratio = .61) if they had a psychiatric hospitalization within the same year, and 15% lower (AOR = .78) if they had service-connected disability for PTSD. Veterans' probability of starting CPT or PE was 19% lower (AOR = .74) if they were Hispanic or Latino, 10% lower (AOR = .84), if they were male rather than female, and 9% lower (AOR = .87) if they were divorced, separated or widowed rather than currently married. Probability of receiving CPT or PE was also lower if verans had more co-occurring psychiatric diagnoses (AOR per diagnosis = .88), were older (AOR per every five years = .95), or lived further away from the VA clinic (AOR per every ten miles = .98). Nonetheless, most patients initiating CPT or PE had two or more comorbidities and were service-connected for PTSD. Observed gender, age and ethnic differences in initiation of CPT and PE appear unrelated to clinical suitability and warrant further study.

J Anxiety Disord|2018 Nov 20

Shahbaz S, Bozorgmehr N, Koleva P, Namdar A, Jovel J, Fava RA, Elahi S

2018 Dec 14;16(12):e2006649doi: 10.1371/journal.pbio.2006649

Cell-surface transferrin receptor (CD71+) erythroid cells are abundant in newborns with immunomodulatory properties. Here, we show that neonatal CD71+ erythroid cells express significant levels of V-domain Immunoglobulin (Ig) Suppressor of T Cell Activation (VISTA) and, via constitutive production of transforming growth factor (TGF)- β, play a pivotal role in promotion of naïve CD4+ T cells into regulatory T cells (Tregs). Interestingly, we discovered that CD71+VISTA+ erythroid cells produce significantly higher levels of TGF-β compared to CD71+VISTA- erythroid cells and CD71+ erythroid cells from the VISTA knock-out (KO) mice. As a result, CD71+VISTA+ erythroid cells-compared to CD71+VISTA- and CD71+ erythroid cells from the VISTA KO mice-significantly exceed promotion of naïve CD4+ T cells into induced Tregs (iTreg) via TGF-β in vitro. However, depletion of CD71+ erythroid cells had no significant effects on the frequency of Tregs in vivo. Surprisingly, we observed that the remaining and/or newly generated CD71+ erythroid cells following anti-CD71 antibody administration exhibit a different gene expression profile, evidenced by the up-regulation of VISTA, TGF-β1, TGF-β2, and program death ligand-1 (PDL-1), which may account as a compensatory mechanism for the maintenance of Treg population. We also observed that iTreg development by CD71+ erythroid cells is mediated through the inhibition of key signaling molecules phosphorylated protein kinase B (phospho-Akt) and phosphorylated mechanistic target of rapamycin (phospho-mTOR). Finally, we found that elimination of Tregs using forkhead box P3 (FOXP3)-diptheria toxin receptor (DTR) mice resulted in a significant expansion in the frequency of CD71+ erythroid cells in vivo. Collectively, these studies provide a novel, to our knowledge, insight into the cross-talk between CD71+ erythroid cells and Tregs in newborns. Our results highlight the biological role of CD71+ erythroid cells in the neonatal period and possibly beyond.

PLoS Biol|2018 Dec 14

Ochs-Balcom HM, Nguyen LM, Ma C, Isackson PJ, Luzum JA, Kitzmiller JP, Tarnopolsky M, Weisman M, Christopher-Stine L, Peltier W, Wortmann RL, Vladutiu GD

2018 Dec 13;doi: 10.1002/mus.26397

Statins reduce cardiovascular disease risk and are generally well-tolerated, yet up to 0.5% of statin-treated patients develop incapacitating muscle symptoms including rhabdomyolysis. Our objective was to identify clinical factors related to statin-associated muscle symptoms (SAMS).

Muscle Nerve|2018 Dec 13

Rice K, Sharma K, Li C, Butterly L, Gersten J, DeGroff A

2018 Dec 12;doi: 10.1002/cncr.31864

Colonoscopy is the most widely used colorectal cancer (CRC) screening test in the United States. Through the detection and removal of potentially precancerous polyps, it can prevent CRC. However, CRC screening remains low among adults who are recommended for screening. The New Hampshire Colorectal Cancer Screening Program implemented a patient navigation (PN) intervention to increase colonoscopy screening among low-income patients in health centers in New Hampshire. In the current study, the authors examined the cost-effectiveness of this intervention.

Cancer|2018 Dec 12

Varn FS, Wang Y, Cheng C

2019;8(1):e1513440doi: 10.1080/2162402X.2018.1513440

Immune checkpoint inhibitors have shown great potential in treating solid tumors, inducing durable remission and prolonged survival time in responders. Despite their promise, a large fraction of patients remains unresponsive to these treatments highlighting the need for biomarkers that can predict patient sensitivity. Pre-treatment gene expression profiles for patients receiving immune checkpoint inhibitors have recently become available, establishing a new medium by which to discover biomarkers that predict therapy response. In this study, we mined for transcriptomic correlates of response by applying immune cell-derived gene expression signatures to publicly available datasets containing matched gene expression and response efficacy information. These datasets were comprised of urothelial carcinoma patients receiving anti-PD-L1 (n = 25), melanoma patients receiving anti-PD-1 (n = 28), and melanoma patients receiving anti-CTLA-4 (n = 42). We identified one signature, derived from a subpopulation of B cells, with scores that were significantly and reproducibly elevated in patients experiencing clinical benefit following therapy targeting the PD-1/PD-L1 axis and were additionally elevated in patients responsive to anti-CTLA-4 therapy. Multivariate models revealed that this signature was associated with response independent of other response-predictive biomarkers, including tumor mutation burden. Functional annotation of the signature revealed it to be associated with features indicative of an immunologically active microenvironment, including B and T cell activation as well as antigen presentation activity. The preliminary findings presented detail a transcriptomic signature associated with response to multiple checkpoint inhibitors and suggest novel biological associations that warrant further investigation.

Oncoimmunology|2019

Kamal Y, Cheng C, Frost HR, Amos CI

2019;8(1):e1500106doi: 10.1080/2162402X.2018.1500106

Renal clear cell carcinoma (RCC) is the most common type of kidney cancer and has a high propensity for metastasis. While treatment with immune checkpoint inhibitors, such as anti-PD-1, have shown modest improvements in survival for RCC, it is difficult to identify responders from non-responders. Attempts to elucidate the mechanisms associated with differential response to checkpoint inhibitors have been limited by small sample size making it difficult to detect meaningful associations. We utilized existing large datasets from The Cancer Genome Atlas (TCGA) to first find predictors of disease aggressiveness in the tumor microenvironment (TME) and hypothesized that these same predictors may influence response to immunotherapy. We found primary metastatic (M1-stage IV) tumors exhibit high immune infiltration, and high TP53-inactivation induced senescence activity compared to non-metastatic (M0-Stage I/II) tumors. Moreover, some TME features inferred from deconvolution algorithms, which differ between M0 and M1 tumors, also influence overall survival. A focused analysis identified interactions between tumor TP53-inactivation induced senescence activity and expression of inflammatory molecules in pre-treatment RCC tumors, which predict both change in tumor size and response to checkpoint blockade therapy. We also noted frequency of inactivating mutations in the protein polybromo-1 (PBRM1) gene was found to be negatively associated with TP53-inactivation induced senescence enrichment. Our findings suggest a mechanism by which tumor TP53-inactivation induced senescence can modulate the TME and thereby influence outcome from checkpoint blockade therapy.

Oncoimmunology|2019

Wallach JD, Egilman AC, Ross JS, Woloshin S, Schwartz LM

2018 Dec 12;doi: 10.1007/s11606-018-4779-x

J Gen Intern Med|2018 Dec 12

Hembrook-Short JR, Mock VL, Usrey WM, Briggs F

2018 Dec 12;pii: 2164-18. doi: 10.1523/JNEUROSCI.2164-18.2018

Attention is a critical component of visual perception, however the mechanisms of attention at the granular level are poorly understood. One possible mechanism by which attention modulates neuronal activity is to control the efficacy of communication between connected neurons, however it is unclear whether attention alters communication efficacy across a variety of neuronal circuits. In parallel, attentional modulation of neuronal firing rate is not uniform, but depends upon the match between neuronal feature selectivity and the feature required for successful task completion. Here we tested whether modulation of communication efficacy is a viable mechanism of attention by assessing whether it is consistent across a variety of neuronal circuits and dependent upon the type of information conveyed in each circuit. We identified monosynaptically connected pairs of V1 neurons through cross-correlation of neuronal spike trains recorded in adult female macaque monkeys performing attention-demanding contrast-change detection tasks. Attention toward the stimulus in the receptive field of recorded neurons significantly facilitated the efficacy of communication among connected pairs of V1 neurons. The amount of attentional enhancement depended upon neuronal physiology, with larger facilitation for circuits conveying information about task-relevant features. Furthermore, presynaptic activity was more determinant of attentional enhancement of communication efficacy than postsynaptic activity; and feedforward local circuits often displayed the largest facilitation with attention. Together, these findings highlight attentional modulation of communication efficacy as a generalized mechanism of attention and demonstrate that attentional modulation at the granular level depends on the relevance of feature-specific information conveyed by neuronal circuits.How we pay attention to objects and locations in the visual environment has a profound impact on visual perception. Individual neurons in the visual cortex are similarly regulated by shifts in visual attention, however the rules that govern whether and how attention alters neuronal activity are not known. In this study, we explored whether attention regulates communication between connected pairs of neurons in the primary visual cortex. We observed robust attentional facilitation of communication among these circuits. Furthermore, the extent to which the circuits were facilitated by attention depended on whether the information they conveyed was relevant for the particular attention task.

J Neurosci|2018 Dec 12

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