Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149569/1/ijc32379_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149569/2/ijc32379-sup-0001-Supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149569/3/ijc32379.pd

Computational exploration of molecular receptive fields in the olfactory bulb reveals a glomerulus-centric chemical map

© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Progress in olfactory research is currently hampered by incomplete knowledge about chemical receptive ranges of primary receptors. Moreover, the chemical logic underlying the arrangement of computational units in the olfactory bulb has still not been resolved. We undertook a large-scale approach at characterising molecular receptive ranges (MRRs) of glomeruli in the dorsal olfactory bulb (dOB) innervated by the MOR18-2 olfactory receptor, also known as Olfr78, with human ortholog OR51E2. Guided by an iterative approach that combined biological screening and machine learning, we selected 214 odorants to characterise the response of MOR18-2 and its neighbouring glomeruli. We found that a combination of conventional physico-chemical and vibrational molecular descriptors performed best in predicting glomerular responses using nonlinear Support-Vector Regression. We also discovered several previously unknown odorants activating MOR18-2 glomeruli, and obtained detailed MRRs of MOR18-2 glomeruli and their neighbours. Our results confirm earlier findings that demonstrated tunotopy, that is, glomeruli with similar tuning curves tend to be located in spatial proximity in the dOB. In addition, our results indicate chemotopy, that is, a preference for glomeruli with similar physico-chemical MRR descriptions being located in spatial proximity. Together, these findings suggest the existence of a partial chemical map underlying glomerular arrangement in the dOB. Our methodology that combines machine learning and physiological measurements lights the way towards future high-throughput studies to deorphanise and characterise structure-activity relationships in olfaction.Peer reviewe

Environmental barriers to sociality in an obligate eusocial sweat bee

This is the final version of the article. Available from Springer Verlag via the DOI in this record.All data generated or analysed during this study are included in this published article and its supplementary materials.Understanding the ecological and environmental contexts in which eusociality can evolve is fundamental to elucidating its evolutionary origins. A sufficiently long active season is postulated to have been a key factor facilitating the transition to eusociality. Many primitively eusocial species exhibit an annual life cycle, which is thought to preclude the expression of eusociality where the active season is too short to produce successive worker and reproductive broods. However, few studies have attempted to test this idea experimentally. We investigated environmental constraints on the expression of eusociality in the obligate primitively eusocial sweat bee Lasioglossum malachurum, by transplanting nest foundresses from the south to the far north of the United Kingdom, far beyond the natural range of L. malachurum. We show that transplanted bees can exhibit eusociality, but that the short length of the season and harsher environmental conditions could preclude its successful expression. In one year, when foundresses were transplanted only after provisioning first brood (B1) offspring, workers emerged in the north and provisioned a second brood (B2) of reproductives. In another year, when foundresses were transplanted prior to B1 being provisioned, they were just as likely to initiate nesting and provisioned just as many B1 cells as foundresses in the south. However, the life cycle was delayed by approximately 7 weeks and nests suffered 100% B1 mortality. Our results suggest that short season length together with poor weather conditions represent an environmental barrier to the evolution and expression of eusociality in sweat bees.This work formed part of a studentship (1119965) awarded to PJD funded by the Natural Environment Research Council and the University of Sussex, supervised by JF

Light Perception in Two Strictly Subterranean Rodents: Life in the Dark or Blue?

BACKGROUND: The African mole-rats (Bathyergidae, Rodentia) are strictly subterranean, congenitally microphthalmic rodents that are hardly ever exposed to environmental light. Because of the lack of an overt behavioural reaction to light, they have long been considered to be blind. However, recent anatomical studies have suggested retention of basic visual capabilities. In this study, we employed behavioural tests to find out if two mole-rat species are able to discriminate between light and dark, if they are able to discriminate colours and, finally, if the presence of light in burrows provokes plugging behaviour, which is assumed to have a primarily anti-predatory function. METHODOLOGY/PRINCIPAL FINDING: We used a binary choice test to show that the silvery mole-rat Heliophobius argenteocinereus and the giant mole-rat Fukomys mechowii exhibit a clear photoavoidance response to full-spectrum ("white"), blue and green-yellow light, but no significant reaction to ultraviolet or red light during nest building. The mole-rats thus retain dark/light discrimination capabilities and a capacity to perceive short to medium-wavelength light in the photopic range of intensities. These findings further suggest that the mole-rat S opsin has its absorption maximum in the violet/blue part of the spectrum. The assay did not yield conclusive evidence regarding colour discrimination. To test the putative role of vision in bathyergid anti-predatory behaviour, we examined the reaction of mole-rats to the incidence of light in an artificial burrow system. The presence of light in the burrow effectively induced plugging of the illuminated tunnel. CONCLUSION/SIGNIFICANCE: Our findings suggest that the photopic vision is conserved and that low acuity residual vision plays an important role in predator avoidance and tunnel maintenance in the African mole-rats

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Background: Most $\textit{BRCA1}$ or $\textit{BRCA2}$ mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both $\textit{BRCA1}$ and $\textit{BRCA2}$ are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female $\textit{BRCA1/2}$ mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at $\textit{BRCA1}$ (SH1) or $\textit{BRCA2}$ (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; $p$ = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 ($p$ = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 ($p$ = 0.231), but was on average 4.5 years younger in TH than in SH2 ($p$ < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive ($p$ = 0.010) or progesterone receptor (PR) positive ($p$ = 0.013) than in SH1, but less likely to be ER positive ($p$ < 0.001) or PR positive ($p$ = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for $\textit{BRCA1}$ or $\textit{BRCA2}$ in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.ACA and the CIMBA data management are funded by Cancer Research UK (C12292/A20861 and C12292/A11174). TRR was supported by R01-CA083855, R01-CA102776, and P50-CA083638. KLN, TMF, and SMD are supported by the Basser Research Center at the University of Pennsylvania. BP is supported by R01-CA112520. Cancer Research UK provided financial support for this work. ACA is a Senior Cancer Research UK Cancer Research Fellow. DFE is Cancer Research UK Principal Research Fellow. Tumor analysis was funded by STOP CANCER (to SJR). Study-specific acknowledgements are as provided in the manuscript

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, $\textit{cis}$-acting variants represent an important source of phenotypic variation. Consequently, $\textit{cis}$-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, $\textit{P}$ = 5.6x10$^{-6}$). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, $\textit{HELQ}$, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, $\textit{MRPS18C}$ encoding the Mitochondrial Ribosomal Protein S18C and $\textit{FAM175A (ABRAXAS)}$, encoding a $\textit{BRCA1}$ BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with $\textit{HELQ }$ ($\textit{P}$ = 8.28x10$^{-14}$), $\textit{MRPS18C}$ ($\textit{P}$ = 1.94x10$^{-27}$) and $\textit{FAM175A }$ ($\textit{P}$ = 3.83x10$^{-3}$), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.Information regarding funding can be found in the published article or the publisher's website. Funders include Cancer Research UK and the National Institute for Health Research

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigatedfor the first time to our knowledgeassociations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction.Materials and MethodsWe genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.ResultsIn male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 x 10(-6)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 x 10(-9)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively.ConclusionPRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.Peer reviewe

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression:Identification of a modifier of breast cancer risk at locus 11q22.3

Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of similar to 320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 x 10(-6)). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.</p