tbuckley/cabot-search huggingface dataset:
P11.45 Synergistic growth inhibition mediated by dual PI3K/mTOR pathway targeting and genetic or direct pharmacological AKT inhibition in human glioblastoma models
Authors: C von Achenbach, M Weller, K Kaulich, D Gramatzki, A Zacher, D Fabbro, G Reifenberger, E Szabó
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Molecular genetic aberrations in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway are common in human cancers including glioblastoma, yet, novel therapeutic approaches targeting this pathway in glioblastoma have had limited success to date. MATERIAL AND METHODS Here we analyzed the molecular mechanisms determining sensitivity to PI3K/mTOR inhibition using gene silencing or pharmacological target inhibition, and effects on proliferation, and clonogenicity or spherogenicity as readouts, in an extended panel of human long-term glioma cell (LTC) lines and glioma-initiating cells (GIC). RESULTS Glioma cells, including GIC in particular, were universally sensitive to growth inhibition induced by PQR309, a novel, dual pan-PI3K/mTOR antagonist in vitro. Cells exhibited profound growth arrest, but little apoptotic or necrotic cell death as confirmed by electron microscopy; yet, there was evidence of senescence. In vivo studies confirmed the anti-glioma activity of PQR309 in the orthotopic LN-229 glioma model. Cell lines with high basal levels of phosphorylated (active) AKT, low levels of phosphorylated (inactive) protein translation repressor eukaryotic initiation factor (eIF) 4E-binding protein 1 (p4E-BP1), and high levels of Ser9-phosphorylated (inactive) glycogen synthase kinase 3 beta (pGSK3ß) were more sensitive to PQR309. Accordingly, the activity of PQR309 was synergistically enhanced by AKT gene silencing or direct pharmacological AKT inhibition. CONCLUSION These data justify to explore combined targeted therapy approaches in glioblastoma that aim at down-regulating AKT function to enhance the therapeutic potential of dual PI3K/mTOR inhibitors.
P14.110 Primary leptomeningeal melanocytic tumors - clinical course and molecular pathological aspects of an underestimated entity
Authors: H Dohmen, A Jensen, K Schoeller, E Uhl, T Acker, M Stein
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Primary leptomeningeal melanocytic tumors (PLMT) of the central nervous system are extremely rare, usually benign pigmented tumors. The aim of our study is to present two complex cases of PLMT with discussion of clinical and molecular aspects. MATERIAL AND METHODS Medical charts of two patients from our institution with PLMT were reviewed. Oncogenic common gene mutations in GNAQ (Q209, exon 5), GNA11 (Q209, exon 5), TERT promoter and BRAF (exon 11, 15) were analyzed and a genome-wide DNA methylation array (Infinium Human-MethylationEPIC BeadChip) was performed. Brain tumors were categorized according to their DNA methylation profile using the brain tumor classifier algorithm (https://www.molecularneuropathology.org/mnp). RESULTS Case1: A 15 year-old boy presented with a large tumor in the in the cerebellopontine angle with extension to the cavernous sinus and the middle fossa in June 2013. Consequently, partial resection of the PLMT was performed followed by photon radiation therapy. First recurrence developed after 12 months. Despite reradiation with proton therapy, reresection, and several chemotherapies the patient died 4 years and 3 month after initial diagnosis. Histopathological examination of the resected tumor sample revealed a pigmented neoplasm with epithelioid cells with strong expression of melanocytic markers Melan A and HMB 45. In the recurrent biopsy samples, an increase in the Ki-67/MIB index from 2 to 10 % was observed. Molecular analysis showed a characteristic GNA11 Q209L mutation that supports the diagnosis of PLMT. Case2: In April 2016 the resection of a PLMT in a 42 year-old female in the pinealis region was performed. First recurrence developed after 21 months and reresection followed by proton therapy was performed. A distant tumor developed 7 month later and after resection the patient received local proton therapy. Only 1 month later a new tentorial tumor was detected and treated by proton therapy. Tumor tissue of the local recurrence showed focal epitheloid cell morphology with brain invasion, tumor necrosis and increased mitotic activity. KI-67/MIB1 index was approximately 3% in the first and above 10 % in the second and third operation. The hotspot mutation in GNAQ Q209L was found in all tumor samples. In addition to histological signs of malignancy, an increase in chromosomal aberrations was seen at recurrence as a sign of malignant progression. To-date the patient is alive but new cranial metastases were detected. CONCLUSION Though PLMT is defined as benign lesion, the treatment is complicated by early local recurrence as well as intracranial and spinal metastases. For the first time malignant transformation during the clinical course of PLMT was confirmed by histology and DNA methylation array.
Racial/Ethnic Disparities in Pregnancy-Related Deaths — United States, 2007–2016
Authors: Emily E. Petersen, Nicole L. Davis, David Goodman, Shanna Cox, Carla Syverson, Kristi Seed, Carrie Shapiro-Mendoza, William M. Callaghan, Wanda Barfield
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Approximately 700 women die in the United States each year as a result of pregnancy or its complications, and significant racial/ethnic disparities in pregnancy-related mortality exist (1). Data from CDC's Pregnancy Mortality Surveillance System (PMSS) for 2007-2016 were analyzed. Pregnancy-related mortality ratios (PRMRs) (i.e., pregnancy-related deaths per 100,000 live births) were analyzed by demographic characteristics and state PRMR tertiles (i.e., states with lowest, middle, and highest PRMR); cause-specific proportionate mortality by race/ethnicity also was calculated. Over the period analyzed, the U.S. overall PRMR was 16.7 pregnancy-related deaths per 100,000 births. Non-Hispanic black (black) and non-Hispanic American Indian/Alaska Native (AI/AN) women experienced higher PRMRs (40.8 and 29.7, respectively) than did all other racial/ethnic groups. This disparity persisted over time and across age groups. The PRMR for black and AI/AN women aged ≥30 years was approximately four to five times that for their white counterparts. PRMRs for black and AI/AN women with at least some college education were higher than those for all other racial/ethnic groups with less than a high school diploma. Among state PRMR tertiles, the PRMRs for black and AI/AN women were 2.8-3.3 and 1.7-3.3 times as high, respectively, as those for non-Hispanic white (white) women. Significant differences in cause-specific proportionate mortality were observed among racial/ethnic populations. Strategies to address racial/ethnic disparities in pregnancy-related deaths, including improving women's health and access to quality care in the preconception, pregnancy, and postpartum periods, can be implemented through coordination at the community, health facility, patient, provider, and system levels.
P11.19 Glioblastoma cancer stem cells proliferation and cell cycle arrest under TTFields influence
Authors: M Mazzanti, I Verduci, G Cannavale, I Pyromali, R Poloni, D Rampini
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive and fastest growing-type among brain tumours. The current standard of care is a combination of surgery, radio- and chemotherapy. However, GBM is characterized by a poor prognosis and an average life expectancy of 15 months under current treatment. Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200kHz), which have been demonstrated to block cell division and interfere with organelle assembly. It has been evaluated in randomized phase 3 trials in GBM and demonstrated to prolong progression-free survival and overall survival when administered together with standard maintenance temozolomide (TMZ) chemotherapy in patients. This technology represents the biggest step forward against GBM in more than a decade. METHODS Primary cultures of human glioblastoma enriched in cancer stem cells (GSCs) were stimulated using the InovitroTM System (NOVOCURE) for 72 hours. Remaining cells were collected for further experiments. RESULTS Our investigation has targeted GSCs, a subset of cells that are considered responsible for tumour recurrence and confer resistance to chemotherapy and radiotherapy. Our data show that after 72 hours of TTFields exposure, more than 60% of the cellular population are dead. The residual GSCs were able to recover proliferation as soon as TTFields application had ended. We used different combinations of TTFields exposure times and pharmacological treatments with the main objective to impair cell proliferation relapse. Prolong TTF stimulation kills more cells but survivor cells are still able to resume proliferation. The addition of 10 mM TMX increase drastically the efficacy of the TTFields treatment even if the few cells left were able to slowly form colonies in a single cell cloning assay. CONCLUSION GCSs are sensitive to TTFields and to the combining pharmacological treatment with TMZ. The strategy to optimize the antiproliferative action on GCSs relapse will be to find a best combination of anticancer drugs concentration, together with TTFields exposure.
Misinterpretation of time-to-first event curves can lead to inappropriate treatment
Authors: Samy Suissa, Amnon Ariel
Journal: European Respiratory Journal (2019)

<b>The IMPACT trial of triple therapy in COPD confirms that benefit on exacerbations is only in first month with no benefit in following 11 months, likely due to inclusion of asthma-like patients, suggesting a precision medicine opportunity in COPD treatment</b>http://bit.ly/2YxQpH0
Obesity: raising price of sugary snacks may be more effective than soft drink tax
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Increasing the price of sugary snacks such as biscuits, cakes, and sweets could be more effective at cutting obesity levels than increasing the price of sugar sweetened drinks, says a study published in The BMJ .1

The modelling study estimated the potential effect on body mass index (BMI) and the prevalence of obesity from a 20% price increase for high sugar snacks. It found that the effect on prevalence (2.7 percentage points) was double the level from a similar price increase on sugar sweetened drinks (1.3 percentage points).

In April 2018 the UK’s soft drinks industry levy came into effect, with an 18p/L tax on drinks containing ≥5 g/mL of sugar and 24p/L on those with ≥8 g/mL. …
High numbers of activated helper T cells are associated with better clinical outcome in early stage vulvar cancer, irrespective of HPV or p53 status
Authors: Kim E. Kortekaas, Saskia J. Santegoets, Ziena Abdulrahman, Vanessa J. van Ham, Marij van der Tol, Ilina Ehsan, Helena C. van Doorn, Tjalling Bosse, Mariëtte I. E. van Poelgeest, Sjoerd H. van der Burg
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Vulvar squamous cell carcinoma (VSCC) has been suggested to consist of three subtypes; HPV-positive, HPV-negative mutated <i>TP53</i> or HPV-negative <i>TP53</i> wildtype, with different clinical courses. To analyze the immune infiltrate in these molecular subtypes and its impact on clinical outcome, an in-depth study of the tumor immune microenvironment was performed. <h3>Methods</h3> Sixty-five patients with invasive VSCC matched for age, FIGO stage and treatment modality, were grouped according to the presence of HPV and p53 protein expression status. Archived tissues were analyzed for intraepithelial and stromal expression of CD3, CD8, Foxp3, PD-1, and pan-keratin in randomly selected areas using immunofluorescence. Additional phenotyping of T cells was performed ex-vivo on VSCC (<i>n</i>&nbsp;= 14) and blood samples by flow cytometry. Healthy vulvar samples and blood served as controls. <h3>Results</h3> Based on T-cell infiltration patterns about half of the VSCC were classified as inflamed or altered-excluded while one-third was immune-deserted. High intraepithelial helper T cell infiltration was observed in 78% of the HPV-induced VSCC, 60% of the HPVnegVSCC/p53wildtype and 40% of the HPVnegVSCC with abnormal p53 expression. A high intraepithelial infiltration with activated (CD3<sup>+</sup>PD-1<sup>+</sup>), specifically helper T cells (CD3<sup>+</sup>CD8<sup>−</sup>Foxp3<sup>−</sup>), was associated with a longer recurrence-free period and overall survival, irrespective of HPV and p53 status. Flow cytometry confirmed the tumor-specific presence of activated (CD4<sup>+</sup>PD-1<sup>++</sup>CD161<sup>−</sup>CD38<sup>+</sup>HLA-DR<sup>+</sup> and CD8<sup>+</sup>CD103<sup>+</sup>CD161<sup>−</sup>NKG2A<sup>+/−</sup>PD1<sup>++</sup>CD38<sup>++</sup>HLA-DR<sup>+</sup>) effector memory T cells. <h3>Conclusion</h3> This is the first study demonstrating an association between intraepithelial T cells and clinical outcome in VSCC. Our data suggest that abnormal p53 expressing VSCCs mostly are cold tumors whereas HPV-driven VSCCs are strongly T-cell infiltrated.
David Oliver: Health policy advice in the new number 10
Authors: David Oliver
Journal: BMJ (2019)

Just before taking up his post in Boris Johnson’s new support team, health policy adviser William Warr made quite a splash in a Daily Telegraph column.12

Generally, special health advisers in number 10 or Whitehall fly under the radar. Few people outside the healthcare policy and communications bubble would know their names or hear what they think. But in that column, Warr set out his views for public consumption.

Early reports on the new administration indicate that it is being run with control and strategic focus. Although Warr was not yet in post, I can’t believe he was just sounding off. This was surely a tactical decision to get some ideas into the public domain, while keeping the new …
The role of Pirh2 C-terminal residues and ubiquitin lysine chains in ubiquitination mechanism.
Authors: Rami Mahmoud Abou Zeinab, Roger Leng
Journal: Journal of Clinical Oncology (2013)

11110 Background: Pirh2, a p53 inducible gene, is proposed to be a main regulator of p53 family proteins fine tuning the DNA damage response by acting as an E3 ligase. A negative feedback loop between Pirh2 and p53 exists where under unstressed conditions, Pirh2 induces p53 ubiquitination followed by proteosomal degradation. In case of cellular stress when the activity of tumor suppressors is essential, Pirh2 is self-ubiquitinated releasing p53 continuous repression. Interestingly among all E3 ligases, Pirh2 is the only one to be over-expressed in a wide range of human tumors. This over-expression indicates a disruption in the self-ubiquitination mechanism or a defect in the degradation mechanism post ubiquitination. Based on that, we aimed to analyze Pirh2 ubiquitination mechanism through mapping Pirh2 domains to reveal the essential residues for this process and the ubiquitin chains utilized. Methods: Pirh2 constructs deleting major residues in the three domains were designed, and also ubiquitin mutant constructs were designed through single/multiple mutations at specific positions where lysine residues are mutated to arginine. Using these constructs and in comparison to WT proteins, we tested Pirh2 in-vitro self and p53 ubiquitination activity. Results: Regarding Pirh2, we were able to reveal that residues 240-250 of the c-terminal along with the ring domain are essential for self-ubiquitination.K63R and K48R ubiquitin did not affect Pirh2 self-ubiquitination minimizing the impact of ubiquitin mutations on Pirh2 self-ubiquitination. However, KO, which had all lysine residues mutated to arginine, showed total inhibition of Pirh2 self-ubiquitination confirming the importance of lysine residues. Interestingly, Pirh2 self-ubiquitination reaction showed no difference in the presence or absence of p53 proteins. Concerning Pirh2-p53 ubiquitination, K48 was found to be critical for E3 ubiquitin ligase activity because K48R and not K36R showed defective ubiquitination. All results were confirmed by quantifying ubiquitin. Conclusions: Our data added knowledge to the Pirh2 self-ubiquitination mechanism that can resolve the constant overexpression of Pirh2 proteins hence maximizing p53 response to DNA damage.
OS9.7 Telomere length, TERTp mutation and ALT status in adult diffuse gliomas
Authors: C Birzu, A Hillairet, M Giry, N Grandin, P Verrelle, K Mokhtari, Y Marie, K Hoang-Xuan, J Delattre, A Idbaih, M Charbonneau, M Sanson, A Alentorn
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The current classification of adult diffuse gliomas integrates two alternative telomere maintenance mechanisms: reactivation of telomerase activity by TERT promoter (TERTp) mutations or ATRX mutations associated with alternative length telomere (ALT). We investigated here the relation between these two mechanisms, telomere length, and outcome in a large series of diffuse gliomas. MATERIAL AND METHODS We performed C-circle assay (CCA) to determine ALT status, determined telomere length in tumor (RTLt) and leukocyte (RTLl) in a cohort of 354 adult diffuse gliomas, and sequenced ATRX gene. We calculated an age-adjusted telomere score considering tumor and leukocyte (blood) telomere length and corrected by age. This score was used in univariate and multivariate survival analyses to evaluate the potential impact of telomere length on the prognosis of gliomas. We used the TCGA LGG-GBM dataset to validate our findings in an independent cohort. RESULTS RTLl and RTLt were associated with ATRX mutation and ALT phenotype, and negatively associated with age and TERTp mutations. ATRX mutations (found in 52% (64/123) of samples) were mostly transitions (C&gt;T or T&gt;C), and were associated with ALT phenotype. None of 1p/19q co-deleted oligodendrogliomas harbored an ALT phenotype. No patients with TERTp mutations had ALT phenotype except for a very small subgroup of patients (3/87, 3.4%) suggesting that multiple ways of telomere maintenance, may co-exist in a single tumor, probably expressed in different clones. Telomere age-adjusted score was independently associated with better outcome (HR= 0.73 [95% CI 0.56–0.97], p-value 0.03 adjusted for age, TERTp mutation, IDH mutation, 1p/19q co-deletion and WHO grade). These results were validated using the LGG-GBM TCGA dataset. CONCLUSION We unravel the relation between RTLl and RTLt, TERTp mutation and ALT phenotype and describe a novel telomere age-adjusted score independently associated with better prognosis in adult diffuse gliomas.
Fighting infant infections with myeloid-derived suppressor cells
Authors: Rebekka Weber, Viktor Umansky
Journal: Journal of Clinical Investigation (2019)

Recent work demonstrated a role for myeloid-derived suppressor cells (MDSCs) in the antimicrobial response in newborns, but the signals guiding their differentiation remained unknown. In this issue of the JCI, Liu et al. demonstrate that lactoferrin (LF) converts newborn neutrophils and monocytes to MDSCs via the low-density lipoprotein receptor-related protein-2 (LRP2) receptor and NF-κB activation. Due to their strong antimicrobial activity, adoptive transfer of MDSCs generated by in vitro culture with LF prolonged the survival of newborn mice with necrotizing enterocolitis, a severe pathology in preterm infants. These findings indicate a surprising protective role of MDSCs in newborns and demonstrate the potential of MDSC therapy for the treatment of infants with diseases associated with deregulated inflammation.
P08.02 Israeli experience with Patient Reported Outcomes (PROs) in the field of neuro oncology - Quality of Life Assessment Metrics (QAM)
Authors: T Wagner, E Jan, S Bley, R Cohen, O Furman, A Talianski, L Zach
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND With the development of personalized medicine, it is necessary to take into consideration PROs, including quality of life (QOL) to adjust the treatment and follow up. Trends of QOL outcomes are of special interest for neuro oncologic patients in the setting of chemo-radiotherapy due to the high incidence of pseudo progression (worse MRI with no tumor progression). There are several QAM in the field of neuro oncology. We used the quality of life questionnaire (QLQ-30) for brain cancer with the QLQ-BN20 supplement, and Functional assessment of chronic illness therapy (FACIT) with the FACT-Br supplement (version 4). We looked at the level of agreement between the two assessment tools for QAM for Israeli patients with different brain tumors. MATERIAL AND METHODS Forty patients were recruited between September 2017 to May 2018 at Sheba Medical Center after local IRB approval. Patients fulfilled the two types of questionnaires at 4 time points: before radiotherapy, with radiotherapy completion, at three months follow up and before another intervention. The difference between the two metrics was measured by t-test and performed by Bland-Altman plot. The association between QAM and MRI after radiotherapy and doctor assessment was measured by Linear regression. RESULTS Forty patients completed 162 questionnaires overall (QLQ-30 and FACIT): 8 patients completed questionnaires at all 4 time points, 7 patients completed questionnaires - 3 times, 6 patients- twice, and 19 patients- once. Three patients didn’t answer FACIT questionnaires and 3 other patients didn’t answer QLQ questionnaires. Patients population included 40% (16/40) with astrocytoma [25% (4/16), 31.2% (5/16), 43.8% (7/16) of them with WHO Grade 2,3,4 respectively], 25% (10/40) with meningioma [60% (6/10), 20% (2/10), and 20% (2/10) of them with WHO Grade 1,2 and 3 respectively], 20% (8/40) with brain metastasis, and other tumors (6/40) consisted 15% of the patient population. We found a significant difference between QAM means of agreement of the two metrics used (p&lt;0.001). There was a significant correlation between QAM and MRI after radiotherapy (p=0.013; R2=0.369 and p=0.025; R2=0.292 for QLQ and FACIT questionnaire, respectively). There was no significant correlation between physician examination and QAM metrics (p=0.880; R2=0.002 and p=0.724; R2=0.009 for QLQ and FACIT questionnaires respectively). CONCLUSION Patients’ evaluation success depends on the appropriate assessment metrics. QLQ questionnaires were a more appropriate tool in our patient population confirmed by MRI assessment compared to physicians’ evaluation. Our study shows a significant difference between two well validated tools. Further research is needed to establish the source of this difference and adjust QAM for neuro oncologic patients accordingly.
Primary Sclerosing Cholangitis in Children With Inflammatory Bowel Diseases Is Associated With Milder Clinical Activity But More Frequent Subclinical Inflammation and Growth Impairment
Authors: Amanda Ricciuto, Bettina E. Hansen, Brian Ngo, Marina Aloi, Thomas D. Walters, Peter C. Church, Abigail Mazurek, Maryam Khan, Nicholas Carman, Iram Siddiqui, Geoffrey C. Nguyen, Binita M. Kamath, Anne M. Griffiths
Journal: Clinical Gastroenterology and Hepatology (2019)