tbuckley/cabot-search huggingface dataset:
P05.06 Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma
Authors: W. Lo, J. Chuang, C. Ko, S. Chou, R. Chen, K. Chang, J. Hung, W. Su, W. Chang, T. Hsu
Journal: Neuro-Oncology (2017)

Steroidogenesis-mediated production of neurosteroids is important for brain homeostasis. Cytochrome P450 17A1 (CYP17A1), which converts pregnenolone to dehydroepiandrosterone (DHEA) in endocrine organs and the brain, is required for prostate cancer progression and acquired chemotherapeutic resistance. However, whether CYP17A1-mediated DHEA synthesis is involved in brain tumor malignancy, especially in glioma, the most prevalent brain tumor, is unknown. To investigate the role of CYP17A1 in glioma, we determined that CYP17A1 expression is significantly increased in gliomas, which secrete more DHEA than normal astrocytes. We found that as gliomas became more malignant, both CYP17A1 and DHEA were significantly upregulated in temozolomide (TMZ)-resistant cells and highly invasive cells. In particular, the increase of CYP17A1 was caused by Sp1-mediated DNA demethylation, whereby Sp1 competed with DNMT3a for binding to the CYP17A1 promoter in TMZ-resistant glioma cells. CYP17A1 was required for the development of glioma-cell invasiveness and resistance to TMZ-induced cytotoxicity. Additionally, DHEA markedly attenuated TMZ-induced DNA damage and apoptosis. Together, our results suggest that components of the Sp1-CYP17A1-DHEA axis, which promotes the development of TMZ resistance, may serve as potential biomarkers and therapeutic targets in recurrent glioma.
OS11.2 Risk-adjusted survival outcomes for and features of 1p/19q codeletion oligodendrogliomas
Authors: B. Iorgulescu
Journal: Neuro-Oncology (2017)

Background: Oligodendrogliomas (OGs) are diffuse gliomas defined by IDH mutation and 1p/19q codeletion, in which response to treatment and survival are dictated not by histology, but by molecular subtypes. Methods: The US NCDB was queried for OG patients newly-diagnosed from 2004–2014. Patient and tumor factors were compared by Chi2 or t test. Overall survival (OS) was assessed by Cox proportional hazards and Kaplan-Meier methods, stratified by histology, grade, and codeletion status, and risk adjusted for age, sex, race, Charlson's comorbidity index, insurance, facility location, chemoradiotherapy, and tumor location, laterality, and size. Results: 14,948 patients with gliomas with OG histology remained after exclusion, 67% (n=10,075) were WHO gr2, 33% were WHO gr3 (i.e. anaplastic), and 36% displayed mixed oligoastrocytoma histology. Complete 1p/19q data were available in 20% (n=2,920). Compared to gr2 non-codeleted cases, codeleted OGs presented at an older median age of 43 yrs (IQR: 25–52; vs. 38 yrs, IQR: 25–51, p<0.0001). Notably, 67% were MGMT methylated (vs. 38%, p<0.001) and 75% arose in the frontal lobe (vs. 56%, p<0.001), and 12% in the temporal lobe (vs. 30%). For treatment, 41% of gr2 codeleted OGs received chemotherapy (vs. 36%, p<0.01), 28% received radiotherapy (vs. 41%, p<0.001), 86% underwent surgery, 55% of which were GTR. In risk-adjusted analysis of gr2 OGs, codeletion was associated with significantly improved OS (HR 0.44, 95%CI: 0.27–0.72, p=0.001), with 2-yr and 5-yr OS rates of 96% (95%CI; 94–97) and 87% (95%CI: 84–90), respectively; vs. 87% (95%CI: 84–90) and 70% (95%CI: 63–76) in non-codeleted OG. Mixed histology was not significant (HR 1.49, 95%CI; 0.92–2.44, p=0.11). Compared to gr3 non-codeleted cases, codeleted anaplastic OGs presented at a median age of 46 yrs (IQR: 37–56; vs. 43 yrs, IQR: 40–46, p=0.066). 75% were MGMT methylated (vs. 46%, p<0.001) and a majority arose in frontal lobes (78% vs. 62%, p<0.001); involving temporal lobes in 9% (vs. 23%). For treatment, 84% of gr3 codeleted OGs received chemotherapy, 70% received radiotherapy, and 96% underwent surgery, 52% of which were GTR. In risk-adjusted analysis of gr3 OGs, codeletion was associated with significantly improved OS (HR 0.36, 95%CI: 0.22–0.59, p<0.001), with 2-yr and 5-yr OS rates of 90% (95%CI; 87–93) and 72% (95%CI: 64–77), respectively; vs. non-codeleted OGs' 73% (95%CI: 68–78) and 47% (95%CI: 37–56). Mixed histology portends a worse OS (HR 1.72, 95%CI; 1.08–2.74, p=0.02). Conclusion: Although previously referred to as OGs, grade 2 and 3 diffuse gliomas without 1p/19q codeletion are markedly different from molecularly-defined OGs; particularly demonstrating reduced rates of MGMT methylation and significantly worse OS. In cases where a high grade OG is suspected histologically but 1p/19q are not codeleted, careful evaluation and management for IDH-wildtype GBM should be considered.
Identification of spinal circuits involved in touch-evoked dynamic mechanical pain
Authors: Longzhen Cheng, Bo Duan, Tianwen Huang, Yan Zhang, Yangyang Chen, Olivier Britz, Lidia Garcia-Campmany, Xiangyu Ren, Linh Vong, Bradford B Lowell, Martyn Goulding, Yun Wang, Qiufu Ma
Journal: Nature Neuroscience (2017)
P10.08 Resection of gliomas initially deemed to be inoperable
Authors: D. Southwell, M. Berger
Journal: Neuro-Oncology (2017)

Background: Maximal safe resection is a primary objective in the management of gliomas. Despite this, surgeons and referring physicians may, on the basis of radiologic studies alone, assume a glioma to be unresectable due to its proximity to areas of presumed functional eloquence. Because non-invasive studies, including functional MRI, may not localize brain functions, such language, with particularly high fidelity, this simplistic approach may exclude some patients from what could be a safe resection. Intraoperative direct electrical stimulation (DES) allows for the accurate localization of functional areas, thereby enabling maximal resection of tumors, including those that may appear inoperable based solely on radiologic studies. Here we describe the extent of resection and functional outcomes following resections of tumors deemed inoperable by referring physicians and neurosurgeons. Methods: We retrospectively examined the cases of 58 adult patients who underwent glioma resections within six months of undergoing brain biopsies of supposedly inoperable gliomas at outside hospitals. We characterized the extent of resection and six-month functional outcomes for this population. Results: Intraoperative DES mapping was performed on 96.6% of patients (56 of 58). Nearly half of patients (46.6%, 27 of 58) underwent an awake surgical procedure with DES. Overall, the mean extent of resection was 87.6% ± 13.6% (range, 39.0% to 100%). Gross total resection (resection of >99% of the pre-operative tumor volume) was achieved in 29.3% of patients (17 of 58). Sub-total resection (95-99% resection) and partial resection (<95% resection) were achieved in 12.1% (7 of 58) and 58.6% of patients (34 of 58), respectively. Of the cases that involved partial resection, the mean extent of resection was 79.4% ± 12.2%. Six months after surgery, no patient was found to have a new post-operative neurologic deficit. The majority of patients (87.9%, 51 of 58) were free of neurologic deficits both pre- and post-operatively. The remainder of patients exhibited either residual but stable deficits (5.2%, 3 of 58), or complete correction of pre-operative deficits (6.9%, 4 of 58). Conclusions: The use of DES enabled maximal safe resections of tumors that were deemed inoperable by referring physicians and neurosurgeons. With rare exceptions, the resectability of a glioma cannot be determined solely by radiologic studies.
EFFICACY OF A MOVEMENT CONTROL INJURY-PREVENTION PROGRAMME IN AN ADULT COMMUNITY RUGBY UNION POPULATION; A CLUSTER RANDOMISED CONTROLLED TRIAL
Authors: Matt Attwood, Simon Roberts, Grant Trewartha, Mike England, Keith Stokes
Journal: British Journal of Sports Medicine (2017)

Background Exercise programmes aimed at reducing injury have been shown to be efficacious for some non-collision sports, but evidence in collision sports such as rugby union is lacking. Objective To evaluate the efficacy of an evidence-informed injury prevention exercise programme in reducing match injuries in adult community rugby union players. Design Prospective cluster randomised (single-blind) controlled trial. Clubs were the unit of randomisation. Setting English adult community clubs (2015–2016 season) with a formally qualified medical professional to diagnose and report match-injuries. Participants 860 clubs were invited to participate of which 81 volunteered and were randomly assigned. Data was received from 41 clubs (control, 19; intervention, 22). Interventions A 42-week exercise programme comprising 6-week graduated exercise blocks was introduced during pre-season. The control programme reflected ‘normal practice’ exercises, whereas the intervention focused on proprioception, balance, cutting, landing, and resistance exercises. Main Outcome Measurements Match-injury incidence and burden for: all ≥8 days time-loss injuries and targeted (lower-limb, shoulder, head and neck, excluding fractures and lacerations) ≥8 days time-loss injuries. Results Poisson regression identified unclear differences between groups for overall injury incidence (rate ratio (RR), 90% confidence interval (CI)=0.9, 0.6–1.3) and injury burden (RR, 90% CI=0.8, 0.5–1.4). A likely beneficial difference in targeted injury incidence (RR, 90% CI=0.6, 0.4–1.0) was identified, with ∼40% lower lower-limb incidence (RR, 90% CI=0.6, 0.4–1.0) and ∼60% lower concussion incidence (RR, 90%CI=0.36, 0.18–0.70) in the intervention group. Completing the intervention at least once per week was associated with a likely beneficial difference between groups (intervention n=15, control n=13; RR, 90% CI=0.7, 0.4–1.0). Conclusions This movement-control injury-prevention programme appeared efficacious, with likely beneficial differences for lower-limb injuries and concussion for the treatment clubs. Targeted injury incidence was ∼30% lower when 1 or more intervention sessions were completed each week.
Screening for Preeclampsia
Authors: Kirsten Bibbins-Domingo, David C. Grossman, Susan J. Curry, Michael J. Barry, Karina W. Davidson, Chyke A. Doubeni, John W. Epling, Alex R. Kemper, Alex H. Krist, Ann E. Kurth, C. Seth Landefeld, Carol M. Mangione, William R. Phillips, Maureen G. Phipps, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng
Journal: JAMA (2017)

<h3>Importance</h3> Preeclampsia affects approximately 4% of pregnancies in the United States. It is the second leading cause of maternal mortality worldwide and may lead to serious maternal complications, including stroke, eclampsia, and organ failure. Adverse perinatal outcomes for the fetus and newborn include intrauterine growth restriction, low birth weight, and stillbirth. Many of the complications associated with preeclampsia lead to early induction of labor or cesarean delivery and subsequent preterm birth. <h3>Subpopulation Considerations</h3> Preeclampsia is more prevalent among African American women than among white women. Differences in prevalence may be, in part, due to African American women being disproportionally affected by risk factors for preeclampsia. African American women also have case fatality rates related to preeclampsia 3 times higher than rates among white women. Inequalities in access to adequate prenatal care may contribute to poor outcomes associated with preeclampsia in African American women. <h3>Objective</h3> To update the 1996 US Preventive Services Task Force (USPSTF) recommendation on screening for preeclampsia. <h3>Evidence Review</h3> The USPSTF reviewed the evidence on the accuracy of screening and diagnostic tests for preeclampsia, the potential benefits and harms of screening for preeclampsia, the effectiveness of risk prediction tools, and the benefits and harms of treatment of screen-detected preeclampsia. <h3>Findings</h3> Given the evidence that treatment can reduce maternal and perinatal morbidity and mortality, and the well-established accuracy of blood pressure measurements, the USPSTF found adequate evidence that screening for preeclampsia results in a substantial benefit for the mother and infant. In addition, there is adequate evidence to bound the harms of screening for and treatment of preeclampsia as no greater than small. Therefore, the USPSTF concludes with moderate certainty that there is a substantial net benefit of screening for preeclampsia in pregnant women. <h3>Conclusions and Recommendation</h3> The USPSTF recommends screening for preeclampsia in pregnant women with blood pressure measurements throughout pregnancy. (B recommendation)
Submucosal tunneling endoscopic resection of a gigantic esophageal leiomyoma
Authors: Saowanee Ngamruengphong, Yuri Hanada, Olaya Brewer Gutierrez, Majidah Bukhari, Yen-I Chen, Vivek Kumbhari, Mouen Khashab
Journal: Endoscopy (2017)

Submucosal tunneling endoscopic resection (STER) for removal of small upper gastrointestinal tumors arising from the muscularis propria has been demonstrated to be effective and safe [1] [2]. We demonstrated the submucosal tunneling technique for removal of a 10-cm esophageal leiomyoma, and subsequent management of a large mucosotomy.
Establishing Wiring Specificity in Visual System Circuits: From the Retina to the Brain
Authors: Chi Zhang, Alex L. Kolodkin, Rachel O. Wong, Rebecca E. James
Journal: Annual Review of Neuroscience (2017)

The retina is a tremendously complex image processor, containing numerous cell types that form microcircuits encoding different aspects of the visual scene. Each microcircuit exhibits a distinct pattern of synaptic connectivity. The developmental mechanisms responsible for this patterning are just beginning to be revealed. Furthermore, signals processed by different retinal circuits are relayed to specific, often distinct, brain regions. Thus, much work has focused on understanding the mechanisms that wire retinal axonal projections to their appropriate central targets. Here, we highlight recently discovered cellular and molecular mechanisms that together shape stereotypic wiring patterns along the visual pathway, from within the retina to the brain. Although some mechanisms are common across circuits, others play unconventional and circuit-specific roles. Indeed, the highly organized connectivity of the visual system has greatly facilitated the discovery of novel mechanisms that establish precise synaptic connections within the nervous system.
99m Technetium-Hydroxy-Diphosphate Tracer (99mTcHDP) Bone Scintigraphy: An Easily Accessible, Rapid, Non-Invasive Diagnostic Tool for Cardiac Amyloidosis
Authors: Simon DJ Gibbs, Caroline Wong, James Hare, Hendrik Zimmet, Jay Hocking, Anthony P Schwarer, Stephen B Ting
Journal: Blood (2016)
A laparoscopic approach is associated with a decreased incidence of SSI in patients undergoing palliative surgery for malignant bowel obstruction
Authors: Yoshiaki Maeda, Toshiki Shinohara, Tomonari Katayama, Nozomi Minagawa, Masao Sunahara, Akihisa Nagatsu, Noriaki Futakawa, Tomonori Hamada
Journal: International Journal of Surgery (2017)
Atrial Fibrillation
Authors: Laila Staerk, Jason A. Sherer, Darae Ko, Emelia J. Benjamin, Robert H. Helm
Journal: Circulation Research (2017)

The past 3 decades have been characterized by an exponential growth in knowledge and advances in the clinical treatment of atrial fibrillation (AF). It is now known that AF genesis requires a vulnerable atrial substrate and that the formation and composition of this substrate may vary depending on comorbid conditions, genetics, sex, and other factors. Population-based studies have identified numerous factors that modify the atrial substrate and increase AF susceptibility. To date, genetic studies have reported 17 independent signals for AF at 14 genomic regions. Studies have established that advanced age, male sex, and European ancestry are prominent AF risk factors. Other modifiable risk factors include sedentary lifestyle, smoking, obesity, diabetes mellitus, obstructive sleep apnea, and elevated blood pressure predispose to AF, and each factor has been shown to induce structural and electric remodeling of the atria. Both heart failure and myocardial infarction increase risk of AF and vice versa creating a feed-forward loop that increases mortality. Other cardiovascular outcomes attributed to AF, including stroke and thromboembolism, are well established, and epidemiology studies have championed therapeutics that mitigate these adverse outcomes. However, the role of anticoagulation for preventing dementia attributed to AF is less established. Our review is a comprehensive examination of the epidemiological data associating unmodifiable and modifiable risk factors for AF and of the pathophysiological evidence supporting the mechanistic link between each risk factor and AF genesis. Our review also critically examines the epidemiological data on clinical outcomes attributed to AF and summarizes current evidence linking each outcome with AF.
P08.53 CRISPR/Cas9 knockout of PI3K delta confirms its role in glioma cell migration and invasion
Authors: W. Shao, T. Ji, S. T. To
Journal: Neuro-Oncology (2017)

Introduction: The Class1A phosphatidylinositol-3-kinase (PI3K) catalytic isoforms p110α, p110β and p110δ, have been implicated to play vital roles in tumorigenesis. In the incurable malignant brain tumor, glioblastoma multiforme (GBM), their pathogenic roles have also been focused on. Although these three isoforms have overlapping roles in cellular processes, they also exhibit distinct functions in the malignant process of cancer cells. In 2012, our group found that p110δ is the only isoform involved in the migration and invasion process of GBM cells. Two years later, a report came out with results opposite to ours - p110α and p110β but not p110δ are involved in GBM cell migration and invasion. Though both studies used siRNA to knockdown these isoforms, there might be confounding factors such as off-target effects of the siRNA chosen. Materials and Methods: To clarify this discrepancy, we employed a cleaner gene silencing technology, CRISPR/Cas9, to completely knockout p110δ gene in the U87 GBM cell line. Modified cell clones were screened by Western blotting followed by DNA sequencing. The proliferation of modified cells was evaluated by the CCK-8 assay. Cell migration was assessed by the wound-healing assay. The invasiveness of modified cells was determined using the Boyden chamber method. Results: After screening for more than 80 clones, we have successfully isolated 3 clones with different gene modifications: (i) deletions: 2 bp and 12 bp, and (ii) insertion: 1 bp in exon 3 of the PIK3CD gene. The proliferation assay result showed that all of the three modified cell clones grew slower than the normal U87 parental cells. The wound healing migration assay and the Boyden chamber invasion assay showed that the migration and invasion capacity of modified cells is significantly weaker than the U87 parental cells. Conclusions: These data confirm our previous siRNA results on p110δ knockdown. Thus, the use of gene knockout technology on other PI3K isoforms may help to clarify some of the contradicting observations reported in glioblastoma multiforme. Dr. Shao is supported by the Hong Kong Scholars Program.
Transfusion independence in patients with myelodysplastic syndromes treated with azacitidine
Authors: L. R. Silverman, B. L. Peterson, J. F. Holland, R. M. Stone, B. L. Powell, R. A. Larson
Journal: Journal of Clinical Oncology (2006)

6576 Background: Patients (pts) receiving red blood cell (RBC) transfusions are exposed to various side-effects such as intolerance reactions, iron overload, and alloimmunization risks. Reduction in RBC transfusions plus improvement in quality of life was demonstrated in pts with MDS treated with azacitidine in the phase 3 randomized study (9221) conducted by the CALGB (JCO 2002;20:2429). Azacitidine also demonstrated beneficial effects on platelets and neutrophils. To further explore transfusion results in 9221, we compared RBC and platelet transfusion requirements in pts treated with azacitidine across 3 CALGB studies (phase 2 intravenous [IV] 8421, phase 2 subcutaneous [SC] 8921, and Phase 3 SC 9221). Methods: Baseline was defined as 90 days immediately prior to randomization or crossover, as appropriate. Transfusion independence was defined as maintaining independence for ≥56 days (IWG criteria). Duration of transfusion independence was defined as the date of last transfusion to the date of the next transfusion or date of censoring. Proportions of pts who became RBC or platelet independent during the study were compared, as were the median durations of independence. Results: Compared with pts treated with IV azacitidine, a greater percent of pts treated with SC azacitidine achieved independence ( Table ), but the IV study (8421) enrolled only pts with advanced MDS. Differences of 10% in proportions of pts registered or randomized to SC azacitidine who achieved transfusion independence were noted in the phase 2 and 3 studies for RBCs (8921: 35%; 9221: 45%) and for platelets (8921: 43%; 9221: 53%). Median duration of RBC independence in 8921 was 221 days, which was within 6% of that observed for pts randomized to azacitidine in 9221 (235 days). Conclusions: These results provide further support that azacitidine has beneficial effect on erythropoiesis and thrombopoiesis. Patients with MDS treated with azacitidine may develop RBC or platelet transfusion independence. [Table: see text] [Table: see text]
Contents, Vol. 7, Supplement 1, 1959
Authors: E.J. Anthony, G.W. Arendsen Hein, Dorothy W. Baruch, R. Battegay, Cornelius Beukenkamp, Åke Bjerstedt, Nathan Blackman, Curt Boenheim, Rachel B. Bross, Martha Brunner-Orne, José Angel Bustamante, Udo Derbolowsky, R.S. Drews, G. Egan, I. Frost, Henry Ezriel, C.M. Fleming, Hellmuth Freyberger, D. Fuchs-Kamp, H. Gastager, Henry Raphael Gold, Henry Greenbaum, S. Haddenbrock, Angela Hefferman, Thomas Hora, Asya L. Kadis, Berthold Kihn, F. Knobloch, D. Langen, Karl Hermann Lukas, Michael M. Miller, Theresa G. Muller, Jean Oury, Walter Zenner, Helmut Paul, Hertha Riese, Stefan de Schill, P.-B. Schneider, M. Barrelet, P. Jordi, R. Delaloye, Paul Senft, Gerdhild von Staabs, Mark Stern, Herbert Suchanek-Fröhlich, J. Wilder, Alexander Wolf, Emanuel K. Schwartz, Isidore Ziferstein, Manfred in der Beeck, Jack D. Krasner, G.A. Leutz, Margaret Naumburg, Janet Caldwell, Louis R. Ormont, G. Stürup, Ernst von Xylander
Journal: Psychotherapy and Psychosomatics (1959)
P08.25 Imaging scoring system for preoperative diagnoses of molecular status in gliomas
Authors: T. Kanazawa, H. Fujiwara, H. Takahashi, Y. Nishiyama, Y. Hirose, K. Yoshida, H. Sasaki
Journal: Neuro-Oncology (2017)

Gliomas are the most common primary brain tumors.There are no serum markers for the diagnosis of gliomas,and histopathological examination of surgically resected tissue is essential.Some recent studies have suggested that radiological examination may help to identify molecular signature of gliomas preoperatively.We intended to establish an imaging scoring system for preoperative diagnosis of molecular status in gliomas. We reviewed WHO grade 2 - 3 gliomas surgically treated at Keio University Hospital between April 2006 and March 2015.We analyzed an association between several radiological characteristics and genetic features of gliomas. The imaging findings were evaluated by two neurosurgeons and two radiologists independently, and the final judgement was made by consensus of more than 3 people. Calfication (CT),indistinct tumor border (T1),paramagnetic susceptibility effect (T1),inhomogenous tumor contents (FLAIR) and non temporal location were found to be more common in tumors with a -1p/19q codeletion.No imaging findings were associated with IDH mutation.Indistinct tumor border,surface localization (FLAIR),inhomogenous tumor contents were also found to be associated with promoter methylation of the MGMT gene. Based on these findings, an imaging scoring system for prediction of molecular status was designed,which was now under validation with another patient cohort.