tbuckley/cabot-search huggingface dataset:
Nutrition Therapy in Gestational Diabetes Mellitus: Time to Move Forward
Authors: Teri L. Hernandez, Jennie C. Brand-Miller
Journal: Diabetes Care (2018)

Nutrition therapy remains the conventional first-line approach to treatment of gestational diabetes mellitus (GDM). It will reach every woman with GDM across differing diagnostic criteria (1) and phenotypic heterogeneity (2). The goal of nutrition in pregnancy is to support maternal, placental, and fetal metabolic needs, and it may be the first introduction to a lifetime of healthy eating (3). In this way, nutrition therapy in GDM becomes an early-stage intervention in the vicious cycle of intergenerational obesity and diabetes (4). Importantly, because the prevalence of GDM has reached an alarming ≥20% of pregnancies (5), a cost-effective approach to management is urgently needed. While controlling fetal exposure to maternal hyperglycemia and overnutrition, effective nutrition can treat GDM in a way that is fiscally reasonable and culturally sensitive, ultimately reducing the need for medication and intensified health care resource use (1).

The importance of nutrition therapy in GDM is a premise unlikely to be contested. Yet, the widely accepted approach rooted in carbohydrate restriction was challenged more than a decade ago based on concerns related to higher fat intake and exacerbation of maternal insulin resistance by free fatty acids (6,7). The dietary management of diabetes in pregnancy has remained in limbo ever since, with no specific guidelines for nutrition therapy in GDM, a travesty that has resulted in non–evidence-based, fragmented, and inconsistent approaches globally (8–12). Action is necessary not only because of the powerful influence of nutrition on fetal programming and development (13,14) but also because of the ability to positively impact the health of millions of mother-infant dyads. Currently, nutrition therapy appears to have become our Achilles heel, such that despite our strength, we have limped forward in generating clinical evidence to substantiate …
MBRS-15. MELK INHIBITION AS A POTENTIAL THERAPEUTIC STRATEGY AGAINST ALL MOLECULAR SUBTYPES OF MEDULLOBLASTOMA
Authors: Jia-Min Ho, Zhi-Han Lim, Sekar Karthik, Jack M Su, Qi Lin, YuChen Du, Jianhe Shen, Wing-Yuk Chow, Ching C Lau, Adesina Adekunle, Angela Major, M Tarek Elghetany, Xiaonan Li, Kam-Man Hui, Wan-Yee Teo
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant embryonal brain tumors found among children. We found Maternal Embryonic Leucine Zipper Kinase (MELK), an oncogenic serine/threonine protein kinase, capable of disrupting critical cell cycle checkpoints leading to uncontrolled tumor growth, overexpressed among almost all patient tumors for MB. AIM: Our aim was to investigate the role of MELK in tumor biology in primary MB, to exploit its potential as a therapeutic target. We discovered consistently high expression of MELK across different molecular subtypes of patient embryonal MB, highlighting MELK inhibition as an attractive therapeutic strategy across all subtypes of MB. A panel of 5 MB cell lines tested demonstrated variation in MELK mRNA expression. MELK inhibition using a molecular inhibitor OTSSP167 at 50nM concentration in vitro effectively inhibited all except one patient-derived tumor cell lines tested. At 5nM OTSSP167 concentration, proliferation of high MELK-expressing tumor cell lines was effectively inhibited and demonstrated dose-dependent and time-dependent inhibition, but not low MELK-expressing tumor cell lines. We have developed a panel of patient-derived orthotopic xenograft models for MB comprising all 4 subtypes of MB. We demonstrated that MELK expression was retained and expressed on patient xenograft tumors. MELK inhibition is a potential therapeutic strategy against MB. Further, MELK is an attractive target because it is highly expressed across various molecular subtypes of MB. This study is ongoing to determine in vivo anti-tumor effects of MELK inhibition in MB.
Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial
Authors: Dipen J Parekh, Isildinha M Reis, Erik P Castle, Mark L Gonzalgo, Michael E Woods, Robert S Svatek, Alon Z Weizer, Badrinath R Konety, Mathew Tollefson, Tracey L Krupski, Norm D Smith, Ahmad Shabsigh, Daniel A Barocas, Marcus L Quek, Atreya Dash, Adam S Kibel, Lynn Shemanski, Raj S Pruthi, Jeffrey Scott Montgomery, Christopher J Weight, David S Sharp, Sam S Chang, Michael S Cookson, Gopal N Gupta, Alex Gorbonos, Edward M Uchio, Eila Skinner, Vivek Venkatramani, Nachiketh Soodana-Prakash, Kerri Kendrick, Joseph A Smith, Ian M Thompson
Journal: The Lancet (2018)
MBRS-60. MEDULLOBLASTOMA: APPLICATION OF GENOMIC MEDICINE FOR MOLECULAR CLASSIFICATION IN A TAIWANESE COHORT
Authors: Shih-Hung Yang, Meng-Fai Kuo, Yung-Li Yang, Hsin-Yi Huang, Shinn-Forng Peng, Hsuan-Yu Chen
Journal: Neuro-Oncology (2018)

One of the best models in pediatric brain tumor management is medulloblastoma. Maximal safe tumor resection followed by chemotherapy and radiotherapy results in long term survival from 50~80%. Breakthrough discovery of the genomic alterations in medulloblastoma has led to a new molecular classification of four subgroups with prognostic and therapeutic implications. To implement the new classification scheme, we retrospectively analyze a cohort of 37 medulloblastoma patients diagnosed between 1993 to 2015. There were 23 males and 14 females, aging from 0 to 42 years (mean = 8.46 years). Histopathological examination revealed 25 cases of classical type of tumor, 5 cases of desmoplastic/nodular type, 2 cases of large cell/anaplastic type, and 5 cases with no available tissue sample. We applied immunohistochemistry (IHC), multiplex ligand-dependent probe amplication (MLPA), and RNA sequencing (RNA-seq) for subgroup analysis in 17 patients with fresh frozen tissue. There were 3 cases of SHH group, no case of WNT group, and 14 cases of non-WNT/SHH group according to the result IHC and MLPA. The data from MLPA assay also revealed a trend of worse prognosis for patients having MYC gene amplification in tumor tissue. Further RNA sequencing confirmed the 3 cases of SHH subgroup, and segregated the remaining cases into group 3 (4 cases) and group 4 (10 cases). By integration of histology, IHC, MLPA and RNA sequencing data, we are able to classify medulloblastoma into major molecular subgroups for future patient care with a precision medicine approach.
Interim Futility Monitoring Assessing Immune Therapies With a Potentially Delayed Treatment Effect
Authors: Edward L. Korn, Boris Freidlin
Journal: Journal of Clinical Oncology (2018)

Purpose Introduction of new immune therapies that may have a delayed beneficial effect necessitates re-evaluation of traditional clinical trial designs in oncology. A key design feature of randomized trials is interim futility monitoring, which allows stopping early if the accruing data convincingly demonstrate that the experimental treatment is detrimental or is unlikely to be shown superior to the standard treatment. The appropriateness of futility monitoring is frequently questioned when the effect of the experimental treatment may be delayed (eg, in trials of many immune agents). We examine the advisability of using futility monitoring when there is potential for a delayed treatment effect and make recommendations concerning its use. Methods We evaluated the loss of statistical power when using some common futility interim monitoring rules and a new proposed conservative rule via simulation under varying amounts of treatment-effect delay and varying accrual periods. We also considered scenarios where the experimental treatment starts out being worse than the standard treatment but ends up being better, as may sometimes be the case when an immune therapy is compared with an active standard therapy. Results Some standard methods of futility monitoring can result in an unacceptable loss of power when there is a delayed treatment effect, especially if the accrual period is rapid or the experimental treatment is initially worse. The proposed conservative futility rule has a negligible loss of power in the situations considered. Conclusion Although care must be taken with the choice of futility monitoring when there is a delayed treatment effect, inclusion of appropriate rules can reduce the exposure of patients to ineffective therapies without reducing the probability of correctly identifying effective treatments.
Corrigendum re: “The Impact of Prostate Size, Median Lobe, and Prior Benign Prostatic Hyperplasia Intervention on Robot-Assisted Laparoscopic Prostatectomy: Technique and Outcomes” [Eur Urol 2011;59:595–603]
Authors: Andy C Huang, Keith J Kowalczyk, Nathanael D Hevelone, Stuart R Lipsitz, Hua-Yin Yu, Blakely A Plaster, Channa A Amarasekera, William D Ulmer, Yin Lei, Stephen B Williams, Jim C Hu
Journal: European Urology (2018)
Abstract 4361: Role of Rab GTPases and endosomal adaptor proteins in oncogenic RAS induced formation of perinuclear signaling complexes (PSCs)
Authors: Srikanta Basu, Sandip K. Basu, Jacqueline Salotti, Peter F. Johnson
Journal: Cancer Research (2018)

Abstract Oncogenic RAS signaling leads to neoplastic transformation in immortalized cells and oncogene induced senescence in primary cells. Our laboratory has found that in both primary and immortalized cells oncogenic RAS induces constitutive perinuclear re-localization of p-ERK, CK2, and the MAPK scaffolding protein, KSR1. KSR1 binds to p-ERK and CK2, forming assemblies that we call “perinuclear signaling complexes” (PSCs). We observe PSCs in all cancer cell lines tested and in KRasG12V-driven mouse lung tumors, indicating that PSC formation is an important and integral characteristic of tumor cells. Our results show that KSR1 is essential for PSCs, as RNAi-mediated depletion of KSR1 or knockout of KSR1 disrupted their formation. We also demonstrated a key role for endosomal trafficking in this localized RAS signaling, as pharmacological inhibition of endocytosis prevented PSC formation. Furthermore, Rab11A, a Rab GTPase involved in trafficking of recycling endosomes, is required for establishment of PSCs and co-localizes with a pool of cellular CK2 and KSR1, but not p-ERK. Moreover, Rab11A knockdown caused decreased proliferation and survival of A549 cells (human KRAS mutant non-small cell lung adenocarcinoma). Our results demonstrate that there may be at least two classes of PSC-containing endosomes, p-ERK bound endosomes and CK2 bound endosomes. We are currently attempting to identify Rab GTPases that may differentiate these two kinds of PSC containing endosomes. Jongsma et al. (Cell, 2016) have shown that endosomes associated with the ubiquitin adaptor proteins EPS15, Tollip or TAXBP1 localize to the perinuclear region via the signaling adaptor, SQSTM1 (p62), which is tethered to the ER. We found that Tollip knockdown in A549 cells disrupted the CK2 bound endosomes but not p-ERK bound endosomes. Tollip knockdown also decreased cell proliferation and cell survival, while increasing apoptosis and autophagy. Whether other adaptor proteins are involved in RAS-mediated PSC formation remains to be determined. Growth factors (GF) also transiently induced PSCs in normal cells with delayed kinetics (4-6 hr). Our findings indicate that transformed cells sustain this novel late phase of GF signaling, localizing RAS pathway kinases to a nuclear-proximal compartment to drive tumorigenesis. We propose that PSCs are hallmarks of cancer cells and may represent useful biomarkers for cancer diagnosis and therapeutic responses. Citation Format: Srikanta Basu, Sandip K. Basu, Jacqueline Salotti, Peter F. Johnson. Role of Rab GTPases and endosomal adaptor proteins in oncogenic RAS induced formation of perinuclear signaling complexes (PSCs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4361.
Moving Addiction Care to the Mainstream — Improving the Quality of Buprenorphine Treatment
Authors: Brendan Saloner, Kenneth B. Stoller, G. Caleb Alexander
Journal: New England Journal of Medicine (2018)

Moving Addiction Care to the Mainstream If treatment for opioid use disorder were moved to mainstream health care, more patients might recover. Buprenorphine currently presents the greatest opportunity for expanding treatment into the general medical system.
Two Weeks' Notice from Allogeneic Sources
Authors: Mark Anczurowski, Naoto Hirano
Journal: Clinical Cancer Research (2018)

A novel pipeline for neoantigen-specific T-cell receptor (TCR) identification has been validated in ovarian cancer, making use of HLA-matched allogeneic healthy donor T cells. This workflow allows for the identification of tumor-specific TCRs 2 weeks after antigen-specific stimulation and eliminates problematic patient-to-patient variation in the selection of neoantigen-specific TCRs. Clin Cancer Res; 24(21); 5195-7. ©2018 AACRSee related article by Matsuda et al., p. 5357.
Sickle-cell Rates in Kenya and the Southern Sudan
Authors: H. Foy, A. Kondi, G. L. Timms, W. Brass, F. Bushra
Journal: BMJ (1954)

CELL TRAIT AND MALARIA Africans without the sickle-cell trait, whereas in a comparable group of 15 Africans with the trait only 2 developed parasites.It is concluded that the abnormal erythrocytes of individuals with the sickle-cell trait are less easily parasitized by P. falciparum than are normal erythrocytes.Hence those who are heterozygous for the sickle-cell gene will have a selective advantage in regions where malaria is hyperendemic.This fact may explain why the sickle-cell gene remains common in these areas in spite of the elimination of genes in patients dying of sickle-cell anaemia.The implications of these observations in other branches of haematology are discussed.This investigation was made possible by a grant received from the Colonial Office at
Frequent PD-L1 Protein Expression and Molecular Correlates in Urinary Bladder Squamous Cell Carcinoma
Authors: Aaron M. Udager, Andrew S. McDaniel, Daniel H. Hovelson, Kristina Fields, Simpa S. Salami, Samuel D. Kaffenberger, Daniel E. Spratt, Jeffrey S. Montgomery, Alon Z. Weizer, Zachery R. Reichert, Ajjai S. Alva, Arul M. Chinnaiyan, Scott A. Tomlins, Rohit Mehra
Journal: European Urology (2018)
A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis
Authors: Brian A. Walker, Konstantinos Mavrommatis, Christopher P. Wardell, T. Cody Ashby, Michael Bauer, Faith Davies, Adam Rosenthal, Hongwei Wang, Pingping Qu, Antje Hoering, Mehmet Samur, Fadi Towfic, Maria Ortiz, Erin Flynt, Zhinuan Yu, Zhihong Yang, Dan Rozelle, John Obenauer, Matthew Trotter, Daniel Auclair, Jonathan Keats, Niccolo Bolli, Mariateresa Fulciniti, Raphael Szalat, Phillipe Moreau, Brian Durie, A. Keith Stewart, Hartmut Goldschmidt, Marc S. Raab, Hermann Einsele, Pieter Sonneveld, Jesus San Miguel, Sagar Lonial, Graham H. Jackson, Kenneth C. Anderson, Herve Avet-Loiseau, Nikhil Munshi, Anjan Thakurta, Gareth Morgan
Journal: Leukemia (2018)

Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.
Abstract 330: BRCA1 and BLM helicase compensate for replication fork defects in the absence of 53BP1 protein
Authors: Erin H. Sybouts, Sonal S. Tonapi, Alexander J. Bishop
Journal: Cancer Research (2018)

Abstract 53BP1 is well-known for its involvement in DNA double strand break (DSB) repair, binding DNA and influencing choice of DSB repair. In S/G2 phases of the cell cycle, 53BP1 accumulates at DSBs, but can be removed by BRCA1, allowing end-resection and homology-directed repair (HDR) to occur. Without BRCA1, HDR is defective unless 53BP1 is also lost, in which case HDR can proceed. Such secondary mutation is relevant as a mechanism of acquired chemoresistance in BRCA1 deficient tumors. BRCA1 is also important for maintaining replication fork stability, particular for blocking end resection by MRE11a at a collapsed fork. We therefore set out to ask whether 53BP1 also plays a role in maintenance of fork stability and how this role relates to the role of BRCA1 at a collapsed fork. 53BP1 has been indicated to co-localize with collapsed forks and indeed we find that in its absence fork stability is compromised in a DNA2, but not MRE11a, dependent manner. With decreased fork stability in the absence of 53BP1 we observe increased HDR, indicating a role for BRCA1 to compensate for the lack of 53BP1 by promoting HDR. However, if both 53BP1 and BRCA1 are both necessary for fork stability, then there must be additional compensating mechanisms providing fork stability when both are absent. In fact, absence of both 53BP1 and BRCA1 results in better replication progression than when either 53BP1 or BRCA1 alone are absent. A third mechanism of fork stabilization was identified involving BLM; a RecQ helicase involved in dissolving homologous recombination intermediates, can facilitate fork restart and reverse fork regression. Additionally, BLM has been shown to interact with both 53BP1 and BRCA1, is found at stalled replication forks, and promotes BRCA1 recruitment to sites of DNA damage. Targeting BLM in cells with impaired 53BP1 and BRCA1 increases chemosensitivity to DNA damaging agents, supporting the redundant nature of these three proteins at stalled replication forks. Our findings indicate that targeting BLM may be an effective treatment for HDR defective cancers that have developed chemoresistance; with applicability to BRCA1 and homologous recombination deficient cancers, such as breast, ovarian, and Ewing sarcoma. Citation Format: Erin H. Sybouts, Sonal S. Tonapi, Alexander J. Bishop. BRCA1 and BLM helicase compensate for replication fork defects in the absence of 53BP1 protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 330.
Professional Football Participation and Mortality
Authors: Gwen Sascha Fernandes, Michael Doherty, Weiya Zhang
Journal: JAMA (2018)

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An MDS-derived cell line and a series of its sublines serve as an in vitro model for the leukemic evolution of MDS
Authors: Jun-ichiro Kida, Takayuki Tsujioka, Shin-ichiro Suemori, Shuichiro Okamoto, Kanae Sakakibara, Takayuki Takahata, Takahiro Yamauchi, Akira Kitanaka, Yumi Tohyama, Kaoru Tohyama
Journal: Leukemia (2018)
The role of non-resolving inflammation in atherosclerosis
Authors: Canan Kasikara, Amanda C. Doran, Bishuang Cai, Ira Tabas
Journal: Journal of Clinical Investigation (2018)

Non-resolving inflammation drives the development of clinically dangerous atherosclerotic lesions by promoting sustained plaque inflammation, large necrotic cores, thin fibrous caps, and thrombosis. Resolution of inflammation is not merely a passive return to homeostasis, but rather an active process mediated by specific molecules, including fatty acid-derived specialized pro-resolving mediators (SPMs). In advanced atherosclerosis, there is an imbalance between levels of SPMs and proinflammatory lipid mediators, which results in sustained leukocyte influx into lesions, inflammatory macrophage polarization, and impaired efferocytosis. In animal models of advanced atherosclerosis, restoration of SPMs limits plaque progression by suppressing inflammation, enhancing efferocytosis, and promoting an increase in collagen cap thickness. This Review discusses the roles of non-resolving inflammation in atherosclerosis and highlights the unique therapeutic potential of SPMs in blocking the progression of clinically dangerous plaques.
Fatal Sepsis Associated with Bacterial Contamination of Platelets — Utah and California, August 2017
Authors: Roberta Z. Horth, Jefferson M. Jones, Janice J. Kim, Bert K. Lopansri, Sarah J. Ilstrup, Joy Fridey, Walter E. Kelley, Susan L. Stramer, Ashok Nambiar, Lynn Ramirez-Avila, Amy Nichols, Wendy Garcia, Kelly F. Oakeson, Nicholas Vlachos, Gillian McAllister, Robert Hunter, Allyn K. Nakashima, Sridhar V. Basavaraju
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

platelet unit at hospital Y and developed sepsis; blood cultures subsequently grew K. pneumoniae