bluuebunny/crossref_metadata_2025 huggingface dataset:
RARE-26. WHOLE GENOME SEQUENCING OF AN OSSEOUS METASTASIS DURING CHECKPOINT-CONTROLLED INTRACRANIAL GLIOBLASTOMA REVEALS NEW INSIGHTS INTO POTENTIAL MECHANISMS OF IMMUNE ESCAPE
Authors: Mohme Malte , Maire Cecile , Schliffke Simon , Joosse Simon , Alawi Malik , Lamszus Katrin , Westphal Manfred
Published: November 2019

Glioblastoma (GBM) has a devastating prognosis and recent advances in the treatment of a variety of cancer entities, e.g. through checkpoint inhibition, could so far not be translated into improved outcome in newly-diagnosed GBM. Characterizing rare cases of peripheral metastases which succeeded in overcoming immune control, can help to understand the mechanisms of immune escape. Here we describe the first reported case of a detailed genetic and immunological characterization of a peripheral bone metastasis from a GBM which was controlled intracranially by anti-PD1 checkpoint inhibition We performed whole genome sequencing (WGS) of the primary- and recurrent tumor, as well as the bone metastasis. Genomic data was analyzed for copy number variations and mutational profiles. In addition, immune monitoring with flow cytometric phenotyping and next-generation sequencing of the peripheral T-cell repertoire was used. A 70-year old patient developed multiple osseous metastases in the spine, while his IDHwt GBM recurrence was immunologically controlled with checkpoint inhibition. Biopsy confirmed peripheral GBM metastases. Immunophenotyping reflected the effective activation of the peripheral T-cell response, with, however, simultaneous upregulation of regulatory T-cells during disease progression. WGS sequencing demonstrated a distinct molecular profile of the GBM metastasis, with amplifications in chromosome 3 and 9, as well as genomic loss on chromosomes 4, 10 and 11. The peripheral metastasis was distinguished by mutations in mismatch repair genes, such as MSH4 and MLH1, associated with a hypermutated phenotype. Among the mutated genes we found potential candidates involved in immune escape of circulating tumor cells. This case represents a unique opportunity to analyze potential mechanisms of GBM-mediated immune escape during immune activation with anti-PD1 checkpoint therapy. It highlights the fact, that although an effective, disinhibited immune response can control the cranial GBM disease, hypermutated tumor clones can evade the tumor-specific T-cell response and disseminate to distant organs.
RARE-29. AZD8055 ENHANCES IN VIVO EFFICACY OF AFATINIB IN CHORDOMAS
Authors: Zhao Tianna , Siu I-Mei , Williamson Tara , Zhang Haoyu , Ji Chenchen , Burger Peter , Cottone Lucia , Flanagan Adrienne , Hann Christine , Gallia Gary
Published: November 2019

INTRODUCTION

Chordomas are rare, locally aggressive bone tumors that arise in cranial base, mobile spine, and sacrum. Currently, there are no FDA-approved therapies for chordoma patients, thus there is a high unmet need to develop effective treatments. In this study, we aim to evaluate the anti-tumor efficacy of small molecule inhibitors that target crucial oncogenic pathways in chordoma, as single agents or in combination, to identify novel therapies with the greatest translation potential.

METHODS

A panel of small molecule compounds that had exhibited in vitro efficacy against human chordoma cell lines or target known chordoma drivers was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and their efficacy was further evaluated using chordoma cell lines and xenograft models.

RESULTS

The in vivo activity of compounds identified in a NIH Chemical Genomics Center screen utilizing chordoma cell lines, together with inhibitors of c-MET and PDGFR, were evaluated in PDX models of chordoma that were previously described or recently established for this study. Inhibitors of EGFR (BIBX1382, erlotinib and afatinib), c-MET (crizotinib) or mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, co-inhibition of EGFR and mTOR also synergistically suppressed tumor growth in vivo, showing improved disease control.

CONCLUSION

Single inhibition of EGFR, c-MET or mTOR suppresses chordoma growth both in vitro and in vivo. Co-inhibition of EGFR and mTOR synergistically inhibits chordoma growth in a range of preclinical models. The insights gained from our study provide a novel combination therapeutic strategy for patients with chordoma.
RARE-40. OUTCOMES AFTER PROTON THERAPY FOR SKULL-BASE CHORDOMA: A PROSPECTIVE STUDY
Authors: Holtzman Adam , Rotondo Ronny , Rutenberg Michael , Indelicato Daniel , Rao Dinesh , Louis Debbie , Morris Christopher , Mendenhall William
Published: November 2019

We evaluated treatment outcomes following definitive or adjuvant high-dose, image-guided proton therapy in 91 patients with skull-base chordoma enrolled on a prospective outcomes tracking protocol and treated between February 2007 and February 2018. The median age was 53 years (range, 22–78 years). Patients received passively scattered 3-dimensional conformal proton therapy to a median dose of 73.8 GyRBE (range, 69.6–75.6 GyRBE). Two patients received a component of intensity-modulated radiotherapy. Seventy percent (n=64) were men and 30% (n=27) were woman. Eighty-two percent (n=75) of patients had macroscopic disease at the time of radiotherapy; 18% (n=16) had undergone a macroscopic gross total resection. Overall survival, cause-specific survival, local control, and RT-related grade 3 toxicity-free survival were calculated. Proton therapy-related toxicities were scored using CTCAE v4.0. With a median follow-up of 3.7 years (range, 0.2–10 years), 26 patients experienced disease recurrence, including 26 local, 0 regional, and 1 distant recurrence. The median time to local progression was 2.2 years (range, 0.4–7.0 years). At the time of last follow-up, 66 patients were alive (56 with no evidence of disease progression) and 25 were deceased (18 with disease progression). There were no acute grade 3 toxicities related to the radiation therapy. The 4-year actuarial rates of overall survival, cause-specific survival, local control, and radiation therapy-related grade 3 toxicity-free survival were 83%, 87%, 76% and 83%, respectively. Definitive or adjuvant high-dose passively scattered 3-dimensional conformal proton therapy for skull-base chordoma provides acceptable local control, comparing favorably to historic photon data, with no acute grade ≥3 radiation-related toxicity and an acceptable rate of grade ≥3 late toxicity. Further follow-up of this cohort is necessary to better characterize long-term disease control and late toxicities.
RARE-42. INCIDENCE AND BEHAVIOR OF CENTRAL NERVOUS SYSTEM INVOLVEMENT IN PATIENTS WITH HODGKIN’S LYMPHOMA
Authors: Eduardo Silva Correia Carlos , Malani Rachna , DeAngelis Lisa , Moskowitz Alison
Published: November 2019

INTRODUCTION

Central nervous system (CNS) involvement from Hodgkin’s Lymphoma (HL) is rare, with a reported incidence of 0.07–0.5%. There is a paucity of data regarding its natural history and management.

METHODS

In this retrospective single-institution review, we analyzed all adult patients with HL for CNS involvement (parenchymal or meningeal), who were evaluated at Memorial Sloan Kettering Cancer Center from January 2008 until December 2018.

RESULTS

A total of 3478 patients with HL were identified, and CNS involvement was found in 10 patients (0.3%). All patients were symptomatic from CNS disease. Four patients had a synchronous presentation. The other 6 patients had a median time from systemic diagnosis to CNS involvement of 8 years (2.5–14). Two patients had radiographic evidence of leptomeningeal disease, however 4 had positive cerebrospinal fluid (CSF) cytology. At time of CNS involvement, 2 patients had confirmed transformation to Non-Hodgkin-Lymphoma on biopsy. 2 patients had EBV-positive HL. One patient died before treatment. Five patients received high-dose methotrexate (HD-MTX) for CNS disease. Of these patients, 1 died during treatment, 2 had partial responses, and 2 had complete response of both systemic and CNS disease; to date they are in remission. Three patients had varied responses to immunotherapy and cytotoxic chemotherapy. Removal of an immunosuppressive agent resolved disease in one EBV-positive patient. Median overall survival (OS) from diagnosis of HL was 10.6 years (1.1–21.2), and OS from time to CNS involvement was 6 years (0.2–15).

CONCLUSION

The median time from diagnosis to CNS involvement, and OS from time of CNS involvement are higher than previously reported, which may be related to newer therapies for systemic disease. Neuroimaging should be used in conjunction with CSF for diagnostic accuracy. HD-MTX can be used to treat CNS and refractory systemic disease, as historically used for the latter.
RARE-53. THE ROLE OF RADIATION AND CHEMOTHERAPY IN ADULT PATIENTS WITH HIGH-GRADE BRAINSTEM GLIOMAS
Authors: Kerezoudis Panagiotis , Lu Victor , Alvi Mohammed , Goyal Anshit , Bydon Mohamad , Kizilbash Sani , Burns Terry
Published: November 2019

BACKGROUND

High-grade gliomas (HGGs) of the brainstem represent a rarer subtype of central nervous system tumors compared to their supratentorial counterpart. Predictors of survival and patterns of care have not yet been established on a national, multi-institutional scale.

METHODS

The National Cancer Database was queried for adult cases surgically diagnosed with brainstem high-grade glioma. An array of patient demographics, comorbidities, tumor characteristics and treatment parameters were captured. Predictors of survival were investigated using multivariable Cox proportional hazards regression analysis adjusting for age, insurance status, Charlson comorbidity score, tumor grade, tumor size and type of treatment.

RESULTS

A total of 422 patients (median 51 years, 60% males) were analyzed. Two hundred eighty one received postoperative radiation with chemotherapy (66.6%), thirty-nine had radiation alone (9.2%), while the remaining had no adjuvant treatment (24.2%). Median radiation dosage was 54Gy. Overall median survival was 9.8 months (95% CI 8.8–12). Survival was significantly longer (p< .001) in the chemotherapy+radiation group (median: 14.2 months, 95% CI 11.7–17.1) compared to radiation alone (median: 5.7 months, 95% CI 3.7–12) and no adjuvant treatment (median:1.8 months, 95% CI 1.4–4). In multivariable analysis, increasing age (HR 1.87, 95% CI 1.47–2.37, p< .001) was associated with worse survival, whereas radiation with chemotherapy (HR 0.67, 95% CI 0.46–0.98, p=0.038) were associated with lower hazards of death compared to radiation alone. In subgroup analysis, the effect of adjuvant chemotherapy with radiation remained significant for grade IV (HR 0.46, 95% CI 0.28–0.76, p=0.003), but not for grade III tumors (HR 0.87, 95% CI 0.48–1.58, p=0.65).

CONCLUSION

Findings of the present analysis demonstrate the effectiveness of radiation with chemotherapy for adult patients with high-grade brainstem gliomas, particularly grade IV. Further research should aim on identifying specific patient profiles and molecular subgroups that are more likely to benefit from multimodality therapy.
RARE-56. RECURRENCE PATTERN AND SURVIVAL FOR RELAPSED INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMORS: A SINGLE-INSTITUTION EXPERIENCE
Authors: Wen Lei , Zhou Zhaoming , Li Juan , Zhou Cheng , Lai Mingyao , Cai Linbo
Published: November 2019

PURPOSE

Intracranial non-germinomatous germ cell tumors (NGGCTs) have lower overall survival than germinoma because higher recurrence usually occurs after first line therapy in NGGCTs.

METHODS

Between January 2003 and December 2017, 23 patients with clinically or pathologically diagnosed recurrent NGGCTs after first line therapy were reviewed at our institution. Data of first line treatment, salvage treatment, clinicopathological features and survival were collected and analyzed.

RESULTS

First line therapy including craniospinal irradiation (CSI) in 15 patients, surgery in 3 patients, Gamma knife in 2 patients, chemotherapy in 2 patients and whole brain radiotherapy (WBRT) in 1 patient. The median time to recurrence was 13.8 months (5.8 to 89.2). With reference to the distribution of relapsed lesions, there were 8 patients within the primary site, 6 with distant intracranially, 1 ventricularly, 5 in spinal cords, 1 with dual sites in both primary site and intracranially, and 1 patient evidenced only serologically positive. Three patients did not receive further treatment and was lost during follow-up. Of the other patients, 16 patients received salvage chemotherapy with or without surgery, 4 received CSI or radiosurgery. After median follow up of 54 months, 7 patients died of disease progression. The 4-year overall survival rate after recurrence was 55.4%.

CONCLUSION

Protracted follow-up is recommended because late recurrence is not uncommon. Primary tumor site and distant intracranial are the most prevalent relapsed location. Patients who relapsed could benefited from salvage chemotherapy.
STEM-05. NEURAL G0: A NOVEL QUIESCENT-LIKE STATE IN PROLIFERATING HUMAN NEURAL STEM AND GLIOBLASTOMA TUMOR CELLS
Authors: Feldman Heather , Arora Sonali , Hoellerbauer Pia , Pollard Steven , Patel Anoop , Plaisier Christopher , Paddison Patrick
Published: November 2019

Single cell (sc) genomic technologies are rapidly transforming our understanding of cellular states in normal and diseased tissues. Here, we applied scRNA-seq to cultures of proliferating human neural stem cells (NSCs) to better understand the relationship between cell cycle dynamics and developmental gene expression. This analysis revealed both conventional cell cycle states (S, G2, M) and novel G1 and G0-like states. Of note, we identified a Neural G0 phase representing a subpopulation enriched for expression of genes associated with adult quiescent NSCs, including CLU, HOPX, ID3, OLIG2, PTN, SYT11, S100B, SOX9, PTPRZ1, and TTYH1. Remarkably, by applying our hNSC cell cycle phase classifier to human glioblastoma (GBM) tumors, we found that Neural G0 subpopulations as a prominent tumor-specific cellular subclass of GBM tumors, which, similar to NSCs, does not overlap with proliferative cell cycle phases. We further identified modulators of Neural G0 via CRISPR-Cas9 screens, revealing highly significant enrichment for tumor suppressor genes associated with brain tumors. In depth analysis of five of these Neural G0 modulatory genes, including CREBBP, NF2, PTPN14, TAOK1, or TP53, revealed that they promote compartmentalization of G0/G1 phase and expression of genes associated with Neural G0. Our results suggest that Neural G0 is a dynamic cell state in mammalian NSCs, that a subset of GBM cells maintain and is modulated by genes commonly found altered in GBM.
STEM-06. TISSUE FACTOR SIGNALING IN GLIOBLASTOMA TUMOR-INITIATING CELLS
Authors: Tran Anh , Unruh Dusten , Mirkov Snezana , Horbinski Craig
Published: November 2019

Glioblastoma (GBM) is an aggressive form of brain cancer with few treatment options, characterized by over-activation of receptor tyrosine kinases (RTKs). Brain tumor-initiating cells (BTICs) is a subpopulation of cells in GBM which have the unique capacity to self-renew, facilitating recurrence. Tissue Factor (TF), normally involved in blood coagulation, is elevated in GBM and strongly correlates with more aggressive behavior. We hypothesize that TF promotes malignant behavior in glioblastoma by activating protease-activated receptor 2 (PAR2), leading to RTK stimulation and the maintenance of brain tumor-initiating cells. Therefore, our approaches are to determine: the mechanisms by which TF-PAR2 stimulates RTK signaling in GBM; the role of RTKs in mediating TF-induced BTIC maintenance in GBM, and the effect of blocking TF signaling on RTK-based therapies against GBM. Our data indicate that TF can activate multiple classes of tumor-promoting RTKs, and sustains cell proliferation through its main receptor, PAR2, even in the presence of an RTK inhibitor. We also found that TF suppression impairs the BTIC phenotype in high TF-expressing, RTK-driven GBM. This project will advance our understanding of how TF promotes malignant behavior, identify a powerful means by which cancers can resist RTK inhibitors currently in clinical use, and demonstrate the therapeutic potential of blocking TF-PAR2 signaling in cancer.
STEM-11. CD146/MCAM REGULATES MESENCHYMAL PROPERTIES, STEMNESS, RADIO-RESISTANCE AND YAP ACTIVITY IN GLIOBLASTOMA
Authors: Liang Yuan-Ke , Voshart Daniëlle , den Dunnen Wilfred , Barazzuol Lara , Kruyt Frank
Published: November 2019

Glioblastoma (GBM), a highly malignant and lethal brain tumor, is characterized by diffuse invasion into the brain and chemoradiotherapy resistance resulting in recurrences and poor prognosis. In this study we examined if the cell adhesion molecule CD146/ MCAM is contributing to the malignant properties of GBM, as it is known to have multiple protumorigenic functions in other tumor types. TCGA GBM database analyses revealed enhanced levels of CD146 in GBM compared to normal brain. A panel of patient-derived GBM spheroids, enriched for GBM stem cells (GSC), displayed variable and modest expression of CD146 that was strongly enhanced by cell adherence mediated by serum differentiation or ECM-coating. TGF-β-induced mesenchymal transition in U87 cells was accompanied by induction of CD146 expression, whereas ectopic overexpression of CD146/GFP in GG16 spheroids increased mesenchymal marker expression and cell invasion. Conversely, CRISPR/Cas9-generated CD146 knockouts in GSC23 spheroids led to reduced mesenchymal marker expression and invasion. These results were confirmed by applying embryonic stem cell-derived brain organoids as models to study invasion. Hence, GBM spheroid - brain organoid fusions demonstrated a stimulatory function of CD146 on invasion. Moreover, stem cell marker expression and clonogenic assays showed that CD146 increases the stem cell potential of GBM cells. The CD146 ectopic overexpression and knockout models also demonstrated involvement of CD146 in resistance to radiation that could be mechanistically linked with CD146-dependent suppression of p53 accumulation and activation of NF-kB. Interestingly, exploration of additional mechanisms potentially involved in CD146 functioning, led to the discovery that the oncogenic protein Yes-associated protein (YAP) is also regulated by CD146. Together, our findings demonstrate the importance of CD146 in controlling tumor aggressiveness and radioresistance in GBM cells.
STEM-15. RADIATION-INDUCED MODULATION OF NEURODEVELOPMENTAL PATHWAYS IN CLASSICAL GLIOMA STEM CELLS
Authors: Lo Cascio Costanza , Luna Melendez Ernesto , McNamara James , Schultz Robert , Tien An-Chi , Plaisier Christopher , Mehta Shwetal
Published: November 2019

The current standard-of-care treatment for GBM is ineffective and fails to significantly prolong survival. Following exposure to aggressive multimodal treatment, GBMs have been shown to frequently shift their biological features upon recurrence, acquiring a more resistant phenotype. However, the temporal dynamics and molecular mechanisms that facilitate GBM recurrence are poorly understood. The objective of our study was to assess the acute response to ionizing radiation in glioma stem cells (GSCs) from the Classical subtype of GBM in vitro and in vivo. We find that Classical GSCs rapidly undergo dramatic molecular and cellular changes in response to single and fractionated doses of ionizing radiation, resulting in a heterogeneous cell population. Ionizing radiation causes a transient decrease in the expression of key stemness genes (e.g., SOX2) followed by drastic morphological changes and a concomitant significant increase in the levels of key cell fate markers expressed in adult quiescent neural stem cells. Radiation-induced alteration of SOX2 levels in Classical GSCs is dependent on intact p53 signaling. GSCs previously exposed to radiation are more radio-resistant upon re-treatment compared to their naïve, untreated counterparts – suggesting that the aforementioned phenotypic shift to a quiescent neural stem cell phenotype promotes treatment resistance. Our results suggest that cell-intrinsic factors dictate how GSCs respond to radiation, and that Classical GSCs are neurodevelopmentally predisposed to shift towards an astrocytic/neural stem cell identity in response to cellular stress.
STEM-16. DUAL INHIBITION OF PROTEIN ARGININE METHYLTRANSFERASE 5 AND PROTEIN PHOSPHATASE 2A ENHANCES THE ANTI-TUMOR EFFICACY IN PRIMARY GLIOBLASTOMA NEUROSPHERES
Authors: Sur Hannah , Gangaplara Arunakumar , Wang Xiang , Ray-Chaudhury Abhik , Zhuang Zhengping , Kumar Sachin , Heiss John , Young Yoo Ji , Kaur Balveen , Kumar Banasavadi-Siddegowda Yeshavanth
Published: November 2019

INTRODUCTION

Glioblastoma (GBM) is the most common malignant primary brain tumor and has a heterogeneous tumor cell population. The median survival of GBM patients is less than two years with current multi-model therapy of maximal surgical resection followed by chemotherapy, radiation and tumor treating fields. Protein Arginine Methyltransferase 5 (PRMT5) regulates cellular functions through symmetric di-methylation of arginine residues of histone and non-histone proteins. Our recent findings show that PRMT5 is overexpressed in GBM; its inhibition causes apoptosis and senescence of mature and immature GBM tumor cells respectively. Protein Phosphatase 2A (PP2A), a serine-threonine phosphatase, is associated with senescent tumor cells that contribute to therapy resistance; LB100 is a first-in-class small molecule inhibitor of PP2A that can sensitize tumor cells that are chemo- and radiation-therapy resistant. In this study, using patient-derived primary GBM neurospheres (GBMNS), we tested the anti-GBM effect of concurrent PRMT5 and PP2A inhibition.

METHODS

Patient-derived primary GBM neurospheres transfected with PRMT5 target-specific siRNA were treated with LB100 and subjected to in vitro assays such as proliferation assay, cell cycle analysis, cytotoxicity assay, PP2A activity and western blot.

RESULTS

LB100 treatment significantly reduced the viability of PRMT5-depleted GBM cells as compared to PRMT5 intact cells. LB100 caused G1 cell cycle arrest through inactivation of Rb protein; this effect is further enhanced in combination with PRMT5-depletion. Combination therapy also increased the expression of phospho-MLKL; Necrostatin-1 rescued PRMT5-depleted cells from the cytotoxic effects of LB100 indicating that necroptosis caused the enhanced cytotoxicity in combination therapy. We also found that PRMT5-depletion increased the PP2A activity in GBM neurospheres.

CONCLUSION

Combining the PRMT5 inhibition and PP2A inhibition produced greater antitumor effects than with PRMT5 inhibition alone.
STEM-19. RESISTANCE IS FUTILE: UNDERSTANDING AND TARGETING THE CDK5-CREB1-MCL1 AXIS TO PREVENT RADIATION RESISTANCE IN GLIOMA STEM CELLS
Authors: Mukherjee Subhas , Olson Cheryl , Dunder Bilge , Sharma Nitya , Markwell Steven , Brat Daniel
Published: November 2019

Glioblastoma is a WHO Grade IV malignant brain tumor with a 95% mortality rate within 2–5 years of diagnosis. This prognosis has not improved in the last 30 years, and with standardized radiation therapy, the cancer always recurs. It is not yet clear why the disease relapses, however recent studies have found that a smaller subset of cells called glioma stem cells (GSCs) are known to be radiation-resistant and cause recurrence of glioblastoma. Thus, to develop precision/personalized cancer medicine that can eliminate GSCs to regress tumor growth and prevent glioblastoma recurrence, it is important to understand the molecular mechanism(s) that causes GSCs to become resistant to radiation therapy. We have found that the atypical protein kinase CDK5 regulates self-renewal in primary GSCs through CREB1. Interestingly, CDK5 inhibition also makes GSCs vulnerable to radiation. Our further investigation revealed that CDK5 may regulate MCL1, an anti-apoptotic BCL2 family protein known to cause radiation resistance. We found that CDK5 regulates MCL1 by directly phosphorylating and stabilizing the protein and also by boosting CREB1 mediated transcription of MCL1. Specific suppression of MCL1 makes GSCs more susceptible to radiation. In collaboration with Dr. Oren Becher, we are generating a new RCAS/tv-a mouse model expressing human MCL1 in tumors to see the accelerated tumorigenicity of MCL1 followed by effectivity of MCL1 suppression in radiation therapy. Thus, in this study, we are aiming to understand and target the unique CDK5-CREB1-MCL1 axis that could be critical for developing therapies to combat glioblastoma radiation resistance.
STEM-25. HDAC1 IS ESSENTIAL FOR GLIOMA STEM CELL SURVIVAL
Authors: Lo Cascio Costanza , McNamara James , Luna Melendez Ernesto , Mehta Shwetal
Published: November 2019

OLIG2 is a central nervous system-specific transcription factor that is expressed in almost all diffuse gliomas. It is also one of the key core transcription factors that can reprogram differentiated glioma cells to highly tumorigenic glioma stem-like cells (GSCs). We have previously shown that expression of OLIG2 is critical for glioma growth both in a genetically relevant mouse model as well as in patient-derived xenograft models. Our work suggests that a small molecule inhibitor of OLIG2 could serve as a highly targeted therapy for high-grade glioma; however, transcription factors are generally very difficult to target because their interactions with DNA and co-regulatory proteins involve large and complex surface area contacts. Our laboratory has shown that OLIG2 functions are regulated through interactions with distinct co-regulator proteins in normal neural stem cells. However, there are currently no reports on interactors that promote the proto-oncogenic functions of OLIG2 in malignant glioma. In this study, we employed two independent proteomics screens identify tumor-specific, druggable OLIG2 co-regulators as possible surrogate targets to suppress OLIG2 function in glioma. These screens led to the identification of a novel OLIG2 partner protein: Histone Deacetylase 1 (HDAC1). We confirmed that this interaction occurs in both murine and human glioma models. Although HDACs are ubiquitously expressed and are known to be functionally redundant, we show that ablation of HDAC1 alone significantly decreases the stemness and proliferation capacity of patient-derived GSCs in a p53-dependent manner, while having a minimal impact on normal human neural stem cells and astrocytes. Furthermore, we demonstrate that knockdown of HDAC1, in combination with ionizing radiation treatment, significantly alters the growth pattern of intracranial tumors in vivo. We demonstrate that HDAC1 function is critical for GSC growth and provide a strong rationale for targeting the OLIG2-HDAC1 interaction in malignant glioma.
Incorporating healthy dietary changes in addition to an increase in fruit and vegetable intake further improves the status of cardiovascular disease risk factors: A systematic review, meta-regression, and meta-analysis of randomized controlled trials
Authors: Toh Darel Wee Kiat , Koh Evangelyn Sihui , Kim Jung Eun
Published: November 2019

Context

Fruit and vegetable (FV) intake has been associated with a reduced risk of cardiovascular disease (CVD). Beyond increasing FV intake, the incorporation of other healthy dietary changes may help to further attenuate CVD risk.

Objective

A systematic review and meta-analysis was conducted to determine the effect of increasing FV intake to > 3 servings daily as well as incorporating other healthy dietary changes on classical CVD risk factors through a systematic review, meta-regression, and meta-analysis of randomized controlled trials.

Data Sources

The following databases were searched: PubMed, CINAHL Plus with Full Text, Medline (ProQuest), and Cochrane Library.

Data Extraction

82, 24, and 10 articles were selected for the systematic review, meta-regression, and meta-analysis, respectively.

Data Analysis

Meta-regression analysis showed a dose-dependent response between the number of FV servings consumed in each intervention group and the blood triglyceride change value. Pooled weighted mean differences from the meta-analysis suggested that increasing FV intake to > 3 servings daily contributes to significant decreases in triglyceride (−0.10 mmol/L; 95%CI, −0.18 to −0.01) and diastolic blood pressure (−1.99 mmHg; 95%CI, −2.28 to −1.70) as well as marginal decreases in total cholesterol and low-density lipoprotein cholesterol. While improvements were observed in the triglyceride and high-density lipoprotein cholesterol response following the incorporation of other healthy dietary changes, no additional cardiovascular benefits were observed when FV intake was increased from > 3 to > 5 servings daily.

Conclusion

Increasing FV intake to > 3 servings daily improves CVD risk factors, most distinctly triglyceride, especially when complemented with other healthy dietary changes.
Predicting Carbapenem-Resistant Enterobacteriaceae Carriage at the Time of Admission Using a State-Wide Hospital Discharge Database
Authors: Lin Michael Y , Ray Michael J , Rezny Serena , Runningdeer Erica , Weinstein Robert A , Trick William E ,   CDC Prevention Epicenters Program
Published: November 2019

Background

Timely identification of patients likely to harbor carbapenem-resistant Enterobacteriaceae (CRE) can help healthcare facilities provide effective infection control and treatment. We evaluated whether a model utilizing prior healthcare information from a state hospital discharge database could predict a patient’s probability of CRE colonization at the time of hospital admission.

Methods

We performed a case-control study using the Illinois hospital discharge database. From a 2014-2015 patient cohort, we defined cases as index adult patient hospital encounters with a positive CRE culture collected within the first three days of hospitalization, as reported to the Illinois XDRO registry; controls were all patient admissions from the same hospital and month. We split the data into training (~60%) and validation (~40%) sets, and developed a logistic regression model to estimate coefficients for predictors of interest.

Results

We identified 486 index cases and 340,005 controls. Independent risk factors for CRE at time of admission were: age, number of short term acute care hospital (STACH) hospitalizations in the prior 365 days, mean STACH length of stay, number of long-term acute care hospital (LTACH) hospitalizations in the prior 365 days, mean LTACH length of stay, current admission to LTACH, and prior hospital admission with an infection diagnosis code. When applying the model to the validation dataset, the area under the receiver operating characteristic curve was 0.84.

Conclusions

A prediction model utilizing prior healthcare exposure information could discriminate patients who were likely to harbor CRE at the time of hospital admission.
Deceptive Sexual Relations: A Theory of Criminal Liability
Authors: Gibson Matthew
Published: November 2019

Many common law jurisdictions criminalise penetrative and non-penetrative deceptive sexual relations. Often, they prohibit that conduct under their principal sexual offences, namely rape, sexual/indecent assault etc. This article challenges that practice via two linked processes: criminalisation and fair labelling, respectively. First, it argues that, whilst deceptive sexual relations (with one exception) are equally harmful to a victim’s right to sexual autonomy as the relations proscribed by the principal sexual offences, they represent a different wrong. Secondly, it contends that this view entails the creation of separate sexual offences targeting penetrative and non-penetrative deceptive sexual relations. This would better signal to the criminal law’s audiences the distinct wrongdoing inherent in these relations. Such labelling becomes critical at the point of conviction given its effects on defendants and other parties.
Heavy quark spin multiplet structure of Pc-like pentaquarks as a P-wave hadronic molecular state
Authors: Shimizu Yuki , Yamaguchi Yasuhiro , Harada Masayasu
Published: November 2019

We study the heavy quark spin (HQS) multiplet structure of P-wave $Q\bar{Q}qqq$-type pentaquarks treated as molecules of a heavy meson and a heavy baryon. We define the light-cloud spin (LCS) basis decomposing the meson–baryon spin wave function into LCS and HQS parts. Introducing the LCS basis, we find HQS multiplets classified by the LCS: five HQS singlets, two HQS doublets, and three HQS triplets. We construct the one-pion exchange potential respecting the heavy quark spin and chiral symmetries to demonstrate which HQS multiplets are realized as a bound state. By solving the coupled channel Schrödinger equations, we study the heavy meson–baryon systems with $I=1/2$ and $J^P=(1/2^+, 3/2^+, 5/2^+, 7/2^+)$. The bound states which have the same LCS structure are degenerate at the heavy quark limit, and the degeneracy is resolved for finite mass. This HQS multiplet structure will be measured in future experiments.
Doing Casual Sex: A Sexual Fields Approach to the Emotional Force of Hookup Culture
Authors: Wade Lisa
Published: November 2019

Sex on college campuses has emerged as a source of emotional distress for students. This paper adopts a sexual fields approach to offer a gendered analysis of hookup culture’s central emotional imperative: to be casual about sex. Based on 101 first-person accounts of sex and relationships in college, the findings reveal how students enact sexual casualness by hooking up only when drunk, refraining from tenderness, being unfriendly afterward, and avoiding “repeat” hookups. Students both break and follow these rules. Breaking them is a primary way they form romantic relationships, but also a source of stigma, especially for women. This process helps explain some of the negative emotional consequences of hookup culture, as well as how hookup culture suppresses relationship formation and friends-with-benefits arrangements. The descriptive account of how students “do” casual sex adds much needed interactive detail to the literature on hooking up, while also contributing to sexual field theory. The findings add an emotional dimension to literature on the structure of desire, document a sexual field that fails to reflect the majority of its participants’ desires, and reveal that a sexual field can be resilient, and possibly even strengthen, even in the face of widespread dissatisfaction.
Identification of Genes Underlying the Resistance to Melampsora larici-populina in an R Gene Supercluster of the Populus deltoides Genome
Authors: Wei Suyun , Wu Huaitong , Li Xiaoping , Chen Yingnan , Yang Yonghua , Dai Meili , Yin Tongming
Published: November 2019

Identification of the particular genes in an R genes supercluster underlying resistance to the rust fungus Melampsora larici-populina in poplar genome remains challenging. Based on the de novo assembly of the Populus deltoides genome, all of the detected major genetic loci conferring resistance to M. larici-populina were confined to a 3.5-Mb region on chromosome 19. The transcriptomes of the resistant and susceptible genotypes were sequenced for a timespan from 0 to 168 hours postinoculation. By mapping the differentially expressed genes to the target genomic region, we identified two constitutive expression R genes and one inducible expression R gene that might confer resistance to M. larici-populina. Nucleotide variations were predicted based on the reconstructed haplotypes for each allele of the candidate genes. We also confirmed that salicylic acid was the phytohormone mediating signal transduction pathways, and PR-1 was identified as a key gene inhibiting rust reproduction. Finally, quantitative reverse transcription PCR assay revealed consistent expressions with the RNA-sequencing data for the detected key genes. This study presents an efficient approach for the identification of particular genes underlying phenotype of interest by the combination of genetic mapping, transcriptome profiling, and candidate gene sequences dissection. The identified key genes would be useful for host resistance diagnosis and for molecular breeding of elite poplar cultivars exhibiting resistance to M. larici-populina infection. The detected R genes are also valuable for testing whether the combination of individual R genes can induce durable quantitative resistance.
Cerebellar neurodynamics during motor planning predict decision timing and outcome on single-trial level
Authors: Lin Qian , Helmreich Magdalena , Schlumm Friederike , Li Jennifer M. , Robson Drew N. , Engert Florian , Schier Alexander , Nöbauer Tobias , Vaziri Alipasha
Published: November 2019

The neuronal basis of goal-directed behavior requires interaction of multiple separated brain regions. How subcortical regions and their interactions with brain-wide activity are involved in action selection is less understood. We have investigated this question by developing an assay based on whole-brain volumetric calcium imaging using light-field microscopy combined with an operant-conditioning task in larval zebrafish. We find global and recurring dynamics of brain states to exhibit pre-motor bifurcations towards mutually exclusive decision outcomes which arises from a spatially distributed network. Within this network the cerebellum shows a particularly strong pre-motor activity, predictive of both the timing and outcome of behavior up to ∼10 seconds before movement initiation. Furthermore, on the single-trial level, decision directions can be inferred from the difference neuroactivity between the ipsilateral and contralateral hemispheres, while the decision time can be quantitatively predicted by the rate of bi-hemispheric population ramping activity. Our results point towards a cognitive role of the cerebellum and its importance in motor planning.
Attentional Modulation of the Auditory Steady-State Response across the Cortex
Authors: Manting Cassia Low , Andersen Lau M. , Gulyas Balazs , Ullén Fredrik , Lundqvist Daniel
Published: November 2019

Selective auditory attention allows us to focus on relevant sounds within noisy or complex auditory environments, and is essential for the processing of speech and music. The auditory steady-state response (ASSR) has been proposed as a neural measure for tracking selective auditory attention, even within continuous and complex soundscapes. However, the current literature is inconsistent on how the ASSR is influenced by selective attention, with findings based primarily on attention being directed to either ear rather than to sound content. In this experiment, a mixture of melody streams was presented to both ears identically (diotically) as we examined if selective auditory attention to sound content influences the ASSR. Using magnetoencephalography (MEG), we assessed the stream-specific ASSRs from three frequency-tagged melody streams when attention was directed between each melody stream, based on their respective pitch and timing. Our main results showed that selective attention enhances the ASSR power of an attended melody stream by 15 % at a general sensor level. This ability to readily capture attentional changes in a stimuli-precise manner makes the ASSR a useful tool for studying selective auditory attention, especially in complex auditory environments. Furthermore, as a secondary aim, we explored the distribution of cortical ASSR sources and their respective attentional modulation. A novel finding using distributed source modelling revealed that the ASSR is modulated by attention in many areas across the cortex, with frontal regions experiencing the strongest enhancement of up to ~ 80 %. ASSRs in the temporal and parietal cortices were enhanced by approximately 20 - 25 %. For future studies, this work can serve as a template to narrow-down possible sites of ASSR attentional modulation for further investigation.
Shark: fishing in a sample to discard useless RNA-Seq reads
Authors: Bonizzoni Paola , Ceccato Tamara , Vedova Gianluca Della , Denti Luca , Pirola Yuri , Previtali Marco , Rizzi Raffaella
Published: November 2019

Recent advances in high throughput RNA-Seq technologies allow to produce massive datasets. When a study focuses only on a handful of genes, most reads are not relevant and degrade the performance of the tools used to analyze the data. Removing such useless reads from the input dataset leads to improved efficiency without compromising the results of the study.

To this aim, in this paper we introduce a novel computational problem, called gene assignment and we propose an efficient alignment-free approach to solve it. Given a RNA-Seq sample and a panel of genes, a gene assignment consists in extracting from the sample the reads that most probably were sequenced from those genes. The problem becomes more complicated when the sample exhibits evidence of novel alternative splicing events.

We implemented our approach in a tool called Shark and assessed its effectiveness in speeding up differential splicing analysis pipelines. This evaluation shows that Shark is able to significantly improve the performance of RNA-Seq analysis tools without having any impact on the final results.

The tool is distributed as a stand-alone module and the software is freely available at https://github.com/AlgoLab/shark.
Hierarchically-structured metalloprotein composite coatings biofabricated from co-existing condensed liquid phases
Authors: Jehle Franziska , Macías-Sánchez Elena , Fratzl Peter , Bertinetti Luca , Harrington Matthew J.
Published: November 2019

Complex hierarchical structure governs emergent properties in soft biopolymeric materials; yet, the material processing involved remains poorly understood. Here, we investigated the multiscale structure and composition of the mussel byssus cuticle before, during and after formation to gain further insight into the processing of this hard, yet extensible metal cross-linked protein composite. Our findings reveal that the granular substructure crucial to the cuticle’s function as a wear-resistant coating of an extensible polymer fiber is pre-organized in condensed liquid phase secretory vesicles. These are separated into catechol-rich proto-granules enveloped in a sulfur-rich proto-matrix which fuses during secretion, forming the sub-structure of the cuticle. Metal ions are added subsequently in a site-specific way, with Fe contained in the sulfur-rich matrix and V being relegated to the granules, coordinated by catechol. We posit that this hierarchical structure self-organizes via phase separation of specific amphiphilic protein components within secretory vesicles, resulting in a meso-scale structuring, critical to the cuticle’s advanced function.
Sleep time, social jetlag and intelligence: biology or work timing?
Authors: Ujma Péter P. , Baudson Tanja G. , Bódizs Róbert , Dresler Martin
Published: November 2019

Sleep-wake patterns show substantial biological determination, but they are also subject to individual choice and societal pressure. Some evidence suggests that high IQ is associated with later sleep patterns. However, t is therefore unclear whether the relationship between IQ and later sleep is due to biological or social effects, such as timing and flexibility of working hours. We investigated the association between habitual sleep timing during work days and work-free days, working time and intelligence in a sample of 1,172 adults. We found no difference in chronotype, and the later sleep timing of high-IQ individuals on work days was fully accounted for by later work start times.

Our results indicate that later sleep timing in those with higher IQs is not due to physiological differences, but rather due to later or more flexible work schedules. Later working times and the resulting lower social jetlag may be one of the reasons why higher IQ is associated with lower prospective morbidity and mortality.

Statement of significance

Some evidence shows that higher intelligence is associated with sleep characteristics, but it is unclear if this is because of biological or social mechanisms. We provide evidence for a social mechanism. We found that high IQ individuals indeed sleep later, but only on working days, and this difference is fully accounted for by later work timing. Our evidence is consistent with a view that highly intelligent individuals sleep later because they can afford to, consequently experience lower social jetlag, and this may partially account for better health outcomes.
Response learning confounds assays of inhibitory control on detour tasks
Authors: van Horik Jayden O. , Beardsworth Christine E. , Laker Philippa R. , Whiteside Mark A. , Madden Joah R.
Published: November 2019

The ability to inhibit prepotent actions towards rewards that are made inaccessible by transparent barriers has been considered to reflect capacities for inhibitory control (IC). Typically, subjects initially reach directly, and incorrectly, for the reward. With experience, subjects may inhibit this action and instead detour around barriers to access the reward. However, assays of IC are often measured across multiple trials, with the location of the reward remaining constant. Consequently, other cognitive processes, such as response learning (acquisition of a motor routine), may confound accurate assays of IC. We measured baseline IC capacities in pheasant chicks, Phasianus colchicus, using a transparent cylinder task. Birds were then divided into two training treatments, where they learned to access a reward placed behind a transparent barrier, but experienced differential reinforcement of a particular motor response. In the Stationary-Barrier treatment, the location of the barrier remained constant across trials. We therefore reinforced a fixed motor response, such as always go left, which birds could learn to aid their performance. Conversely, we alternated the location of the barrier across trials for birds in the Moving-Barrier treatment, and hence provided less reinforcement of their response learning. All birds then experienced a second presentation of the transparent cylinder task to assess whether differences in the training treatments influenced their subsequent capacities for IC. Birds in the Stationary-Barrier treatment showed a greater improvement in their subsequent IC performance after training compared to birds in the Moving-Barrier treatment. We therefore suggest that response learning aids IC performance on detour tasks. Consequently, non-target cognitive processes associated with different neural substrates appear to underlie performances on detour tasks, which may confound accurate assays of IC. Our findings question the construct validity of a commonly used paradigm that is widely considered to assess capacities for IC in humans and other animals.
Spatial heterogeneity of an ecologically relevant environment accelerates diversification and adaptation
Authors: van Houte Stineke , Padfield Dan , Gomez Pedro , Lujan Adela M. , Brockhurst Michael A. , Paterson Steve , Buckling Angus
Published: November 2019

Spatial heterogeneity is a key driver for the evolution of resource specialists and has been shown to both promote and constrain the rate of adaptation. However, direct empirical support for these evolutionary consequences of spatial heterogeneity comes from simplified laboratory environments. Here we address how spatial structure, through its effect on resource heterogeneity, alters diversification and adaptive evolution of the soil bacteriumPseudomonas fluorescensin an ecologically relevant context: soil-based compost. Our data show that environmental heterogeneity can both promote phenotypic diversification and accelerate adaptation. These results suggest that environmental disturbance, which can decrease spatial heterogeneity, may limit diversification and adaptation of microbial populations.