tbuckley/cabot-search huggingface dataset:
P16.02 The effect fo pain reduction during frame fixation in the stereotactic radiosurgery by the pre-fixation time advanced local anesthesia under the needle cap guidance with marking of pin site
Authors: W. Cho
Journal: Neuro-Oncology (2017)

OBJECTIVES: With the introduction of gamma knife radiosurgery(GKRS), GKRS has been a major alternatives in the neurosurgical field. However, a lot of patients have complained of considerable discomfort during fixation of rigid frame. This study investigated whether this new procedure could be reduce the pain related with fixation. PATIENTS AND METHODS: 66 patients who underwent GKRS were enrolled in this study. Among them, 31 patients(Group A) were received usual subcutaneous infiltration technique. Another 35 patients (Group B) were received this new procedure. In the group A, with the stereotactic frame held in position by an assistant, local anesthetic solution was injected subcutaneously at each of the anticipated pin site with 23 gauge spinal needle. After 1 or 2 minute, the pins were applied according to measurement based on spinal needle depth. In the group B, with the stereotactic frame held in position by an assistant, targets of pin were marked with surgical pen at each of the anticipated pin site under the guidance of needle cap positioned through the pin hole in the frame bar. After the marking of the anticipated pin site, we remove the stereotactic frame from the patient’s head. And then, local anesthetic solution was injected subcutaneously at each marked pin sites with 26 gauge needle. After 5 minutes from the local infiltration, the stereotactic frame was held in position by an assistant under the same guidance with needle caps according to target marks. The pins were applied according to measurement based on spinal needle depth. To evaluate the severity of pain during procedure, VAS pain scores (scale: 0-10) were recorded as pain in local infiltration and pain during frame placement with pin. The pain scores of the 2 groups were statistically analyzed. Results: The group B revealed lower VAS pain scores during placement of frame (mean VAS score was 7.2 in group A and 3.6 in group B). Additionally, mean VAS pain scores in local infiltration also were lower in group B(mean VAS score was 4.7 in group A and 3.7 in group B). However, there was no significant difference in the VAS pain scores of IM injection between 2 groups. CONCLUSION: We found that group B revealed comparable pain reduction to group A during placement of pins. Additionally, use of 26 gauge needle resulted in less painful local infiltration. In conclusion, pre-fixation time advanced local anesthesia could be helpful to reduce the painful discomfort during stereotactic procedure.
Abstract 199: Dissecting the Shox2-nkx2-5 Antagonistic Mechanism in the Pulmonary Vein Myocardium and Sinoatrial Node
Authors: Wenduo Ye, Jun Wang, Yingnan Song, Diankun Yu, Cheng Sun, Chao Liu, Fading Chen, Yanding Zhang, Fen Wang, Richard Harvey, Laura Schrader, James Martin, YiPing Chen
Journal: Circulation Research (2015)

Atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. However, the genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. We have identified a Shox2-Nkx2-5 antagonistic mechanism that primes the pacemaking cell fate in the PV myocardium and SAN in the embryonic stage. Specifically, Shox2 deletion in the Nkx2-5+ domain of the SAN caused sick sinus syndrome, associated with the loss of pacemaker program. Nkx2-5 hypomorphism rescued the requirement for Shox2 for the expression of genes essential for SAN development in Shox2 mutants. Similarly, the pacemaker-like phenotype induced in PV myocardium in Nkx2-5 hypomorphs reverted back to a working myocardial phenotype when Shox2 was simultaneously deleted. Shox2 interacts with Nkx2-5 directly, and a substantial genome wide co-occupancy of Shox2, Nkx2-5, and Tbx5 suggest a balanced transcription output is essential for the pacemaker cell fate determination. Further characterization of mice carrying allelic series of Shox2 and Nkx2-5 revealed an essential role of both Shox2 and Nkx2-5 in maintain the normal development of pulmonary vein myocardium and the structures in the venous pole, suggesting the importance of transcriptional precision of Shox2 and Nkx2-5 and a role of Shox2-Nkx2-5 antagonistic mechanism in integrating the transcriptional accuracy of Shox2 or Nkx2-5.
OS03.3 Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis
Authors: A. Boire, Y. Zou
Journal: Neuro-Oncology (2017)

Leptomeningeal metastasis is an increasingly frequent and fatal complication of systemic cancer mediated by unknown mechanisms. To molecularly dissect leptomeningeal metastasis, we subjected lung and breast tumor cell lines to iterative in vivo selection for the ability to infiltrate and grow in the cerebrospinal fluid (CSF), an acellular, mitogen-poor microenvironment. Complement component 3 (C3) was upregulated in four leptomeningeal metastatic models, highly expressed in the CSF of patients harboring leptomeningeal metastasis, and predictive of clinical relapse to this site. C3 proved both necessary and sufficient for cancer cell growth within the leptomeningeal space. Cancer cell-derived C3 activates the C3a receptor in the choroid plexus to disrupt the blood-CSF barrier. This effect allows select plasma components including the mitogen amphiregulin to enter the CSF to promote cancer cell growth. We provide proof-of-principle that pharmacologic interference with C3 signaling is therapeutically beneficial to suppress leptomeningeal metastasis.
P01.21 The characteristics of molecular profile changes in recurrent lower grade gliomas and their implication for therapeutic strategy
Authors: A. Mukasa, K. Saito, S. Tanaka, S. Takayanagi, Y. Narita, M. Nagane, K. Ueki, R. Nishikawa, H. Aburatani, N. Saito
Journal: Neuro-Oncology (2017)

Introduction: Accumulating recent evidence demonstrated that even low-grade gliomas consist of heterogeneous cell populations and that recurrent tumors often demonstrated further complex clonal evolution, which lead to marked intratumoral heterogeneity. Due to such heterogeneity, the emergence of malignant clones resistant to therapy can occur easily. Therefore, understanding of the changes of the molecular profile during tumor progression is important to develop a proper treatment strategy. To this end, we performed comparative gene profile analysis between primary low-grade and recurrent gliomas. Methods: Multi “omics” analysis was performed in a large number of glioma samples that includes 26 paired samples of primary and recurrent astrocytic tumors. For “omics” analysis, we performed exome sequencing and RNA-sequencing using Illumina HiSeq, as well as epigenomic profile analysis using an Illumina Infinium 450K methylation chip. Results: By comparing somatic non-synonymous mutations of tumor samples, we observed that only a limited number of crucial driver mutations were retained in recurrent tumors in most cases, and that recurrent tumors gained many new mutations, indicating significant temporal heterogeneity. Interestingly, low-grade glioma treated by temozolomide - a common chemotherapeutic agent for glioma - acquired numerous de novo mutations accompanying mutations in mismatch repair genes and showed a “hypermutator phenotype”. Genome-wide DNA methylation analysis revealed characteristic DNA demethylation during malignant progression in a subset of IDH1/2 mutant astrocytic tumors, which initially showed the glioma CpG island methylator phenotype (G-CIMP). We labeled these tumors as “G-CIMP-demethylated”. Most demethylated loci were located outside of the CpG island. DNA demethylation accompanied the upregulation of mitosis related genes, which are considered to be related to the enhanced tumor growth of these G-CIMP-demethylated tumors. Integrated multi “omics” analysis demonstrated that G-CIMP-demethylated gliomas frequently harbor the RB pathway alterations. Conclusions: Recurrent tumors had a markedly different molecular profile from their primary tumor. The characteristic changes observed in the recurrent tumors are expected to be a future therapeutic target.
P06.07 Immune evasion mediated by PD-L1 on glioblastoma derived extracellular vesicles
Authors: F. L. Ricklefs, M. C. Speranza, J. Hayes, L. Balaj, X. O. Breakefield, A. Bronisz, B. Carter, G. Freeman, S. Lawler, E. A. Chiocca
Journal: Neuro-Oncology (2017)

Background: Extracellular Vesicles (EVs) shed by tumor cells have recently been demonstrated to act as a major conduit in cell-cell communication. Increasing knowledge of the effect of EVs on infiltrating lymphocytes within the tumor microenvironment shows the immune modulation capacity of EVs. In this study we investigated the potential role of PD-L1 on EVs in immune escape in heterogeneous glioblastoma (GBM). Methods: Peripheral blood mononuclear cells (PBMCs) (n=8) were stimulated by IL-2 or anti-CD3±anti-CD28±anti-PD1 treatment. Magnetic cell sorting was used to isolate CD3+ cells. Activation levels of CD3+CD4+, CD3+CD8+ and CD3-CD56+ were monitored by flow cytometry of the activation markers CD69, CD25, PD1 and TIM3. Concurrent eFluor staining was used to measure proliferation. EVs derived from four different glioblastoma stem-like cell lines (GSCs) from either the mesenchymal (M) or proneural (P) subtype were used in this study. PD-L1 expression was validated by immunoblotting and electron microscopy (EM). EV binding was visualized by PALM-tdTomato and PD-L1_RFP positive EVs and tested on plate-bound PD1. RNA-seq from TCGA and Immunohistochemistry (IHC) was used to correlate PD-L1 expression with CD3 infiltration. In addition, circulating EVs from GBM patients (n=22) and controls (n=5) were used to determine PD-L1 content via digital droplet-PCR. Results: PD-L1 was expressed on the surface of M GSC EVs. EVs were able to bind to the outer surface of CD3+ cells. In whole PBMCs EV treatment led to a significant, PD-L1 dependent, reduction of CD3+CD8+ and CD3+CD4+ T-cell activation as well as decreased proliferation in the M subtype. These effects were also observed in CD3+ sorted cells, indicating a direct effect of EVs on T cells. Furthermore PD-L1 on EVs was capable of binding directly to PD1. Using RNA-seq and IHC we show a correlation of CD3 infiltration and PD-L1 expression. In addition, circulating EVs from GBM patients show enriched PD-L1 DNA cargo that correlates with tumor volume. CONCLUSION: Our findings demonstrate the immunosuppressive potential of GSC-derived EVs in a PD-L1 dependent manner. Furthermore we show that PD-L1 on EVs can directly bind PD1 and is capable of hindering T cell activation locally and at distant sites and show how immune checkpoint blockade may systemically enhance immunity against GBM.
Abstract 351: Late-life Activation of GPR30 by G1 Reverses Diastolic Dysfunction in Senescent Fischer344 x Brown Norway Female Rats
Authors: Allan Alencar, Hao Wang, Jaqueline de Silva, Marina Lin, Xuming Sun, Leanne Groban
Journal: Circulation Research (2015)

Introduction: The aged heart is characterized by impaired lusitropy and increased stiffness, and no proven pharmacologic interventions exist that limit these manifestations of left ventricular diastolic dysfunction (LVDD). G1, a selective agonist to the estrogen receptor GPR30, attenuated the effects of estrogen (E2) loss on LVDD in a hypertensive model. To extend prior studies, we determined the cardioprotective potential of chronic GPR30 activation in the female Fischer344 x Brown Norway (F344BN) rat, a normotensive aging model. Methods and Results: Bilateral oophorectomy (OVX) or sham-operations were performed in middle- (Mid) (18 months) and Old-aged rats (27 months). At 28 months of age, Old rats were randomized to daily G1 (100 μg/kg/day, s.c.) or vehicle (VEH; soybean oil) injections (n=7 rats/group). Following 8 weeks of treatment, left ventricle (LV) mass was greater in Old vs. Mid-aged rats, independent of E2 or G1, while systolic function and LV wall thicknesses were similar among groups. Myocardial relaxation (e’) was reduced (P&lt;0.001) and LV filling pressure (E/e’) was increased (P&lt;0.01) in Old vs. Mid-aged rats, and this was exacerbated by OVX (P&lt;0.01) and reversed by late-life G1 treatment. Systolic blood pressure (SBP) increased by 20% after mid-life OVX, whereas late-life E2 loss had no effect on SBP, irrespective of G1. Cardiac chymase expression was increased in E2 deficient hearts determined by Western blot and G1 modestly limited this E2/age effect. Conclusion: Our data indicate that late-life G1 treatment reverses the detrimental effects of advanced age and E2 deficiency on diastolic function, possibly via interactions with the noncanonical cardiac renin angiotensin system.
Long-term outcome is better when a methotrexate-based treatment strategy is combined with 10 mg prednisone daily: follow-up after the second Computer-Assisted Management in Early Rheumatoid Arthritis trial
Authors: M Safy, JWG Jacobs, ND IJff, JWJ Bijlsma, JM van Laar, MJH de Hair
Journal: Annals of the Rheumatic Diseases (2017)

In the second Computer-Assisted Management in Early Rheumatoid Arthritis trial, patients had started with methotrexate and 10 mg prednisone (MTX+pred) or placebo (MTX+plac). After the trial, prednisone was tapered and stopped, if possible. The objective was to compare, during the post-trial follow-up between the two former strategy groups, initiation of the first biological disease-modifying antirheumatic drug (bDMARD), radiographic outcome and onset of glucocorticoid (GC)-related comorbidities.Data on prednisone and bDMARD use and onset of GC-related comorbidities were collected retrospectively. Sharp/van der Heijde scoring was performed. Data were analysed using Fisher's exact and Mann-Whitney U tests.Of 218 patients post-trial follow-up data were available. The maximum follow-up time was 11.8 years. Fewer patients initiated a first bDMARD in the former MTX+pred compared with the former MTX+plac strategy group: 31% vs 50%, p=0.003. At the 2 year post-trial follow-up, the median erosion score was significantly lower in the former MTX+pred versus former MTX+plac strategy group: 0 (range 0-0) versus 0 (0-2), p=0.002. No significant differences between the former strategy groups in the onset of GC-related comorbidities during the post-trial follow-up were found.Addition of 10 mg prednisone daily to an MTX-based treatment strategy in early rheumatoid arthritis results in a lower initiation rate of a first bDMARD and significantly better radiographic outcomes, yet does not result in more GC-related comorbidities.
P03.05 Nerve sheath tumours of cranial and spinal nerves - histomorphological spectrum: a tertiary cancer centre
Authors: P. Gupta, A. Sahay
Journal: Neuro-Oncology (2017)

Introduction: Histological spectrum of nerve sheath tumors (NST) include benign, malignant, some of uncertain malignant potential and few with heterologous differentiation (HD). This study is undertaken to evaluate the histological spectrum of these tumours involving cranial and spinal nerves. Materials and methods: Cases of cranial & spinal NSTs were retrieved from 2007 - October 2016 departmental archives. All were reviewed, detailed histological findings were recorded and clinical details were collected from the medical records. Results: Total 238 cases formed the study group; 140 of cranial nerve (with M:F=1:1) and 98 spinal (with M:F=1.3:1). Most common location for cranial nerves was vestibular (n:122;87.1%), others include trigeminal (n:6;4.2%), facial (n:4;2.8%), vagal (n:1;0.7%), hypoglossal (n:1;0.7%), lower cranial nerves-NOS (presenting as foramen magnum and jugular foramen SOL; n:3; 2.1%) and in the rest three site not specified. Most common location for the spinal was dorsal (n:30; 30.6%) followed by lumbar (n:22; 22.4%), cervical (n:21;21.4%), sacral (n:13;13.2%) and no specific site was known for rest 12. NF2 association was found in six out of 99 [5 vestibular and 1 cervical]. Histological spectrum included- benign (n:224; 94.1% - included conventional schwannoma and schwannoma with degenerative changes), malignant (MNST:5; 2.1%) and of uncertain malignant potential {n:9; 3.7% (cellular schwannoma [CS], tumours with <5 mitoses/10hpfs; n=8; 3.3%] & epithelioid change [EC =1; 0.4%]) and HD (1; 0.4%; in a case of vestibular MNST). No cases of perineuriomas and hybrid tumours identified. Conventional schwannoma (n:205; 86.4%) with M:F 1:1, 11 were pediatric (11–17 years; cranial n:3;27.2% & spinal n:8;72.7%) and 194 adults (19–86 years; cranial n:124; 63.9% & spinal n:70; 36%), Schwannoma with degenerative histomorphology (n:19; 7.9%; M:F- 1.7:1; age range 31–73 years), CS (n:8; 3.3%; M:F-1:1 & age range: 19–69 years) was commonest at spinal (n:4; 50%) followed by trigeminal (n:2; 25%), hypoglossal (n:1; 12.5%) and vestibular (n:1; 12.5%). Of 8 CS, 1 involving the trigeminal nerve recurred. NST with EC change (n:1; 0.4%) was seen in one of the cervical spinal tumour. MNST (n: 5; 2.1%) age range 16–60 years, commonest site was cervical (n:2; 40%). Lumbar and vestibular were one each (20%). Site was not known in one case. MNST with HD (n:1; 60/M) was from vestibular nerve. MIB labelling index in CS and MNST was overlapping ranged between 8–18%. Conclusions: as expected, the most common type of cranial and spinal NST is schwannoma. mnst of the cranial nerves is extremely rare but can occur and very rarely show HD. NSTs can rarely show uncommon histology in the form of ECs and few mitoses (cs), the latter appear to be more common in non-vestibular NSTs. however, the clinical significance of these uncommon histological findings needs to be ascertained in larger prospective studies
Granulocyte Colony-Stimulating Factor (GCSF) Use with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone +/- Rituximab (CHOP±R) Treatment for Aggressive Non-Hodgkin's Lymphoma (aNHL)
Authors: Tom Kouroukis, Winson Y. Cheung, Nizar Abdel-Samad, Sandeep Sehdev, Melanie Poulin-Costello, Brad Gillesby, Ewan J.D. Robson
Journal: Blood (2016)
Severe postpartum headache
Authors: Jeremy Chee, Thian Phey Lau
Journal: BMJ (2017)

A 35 year old primiparous woman presented four days postpartum with a two day history of severe bilateral parietal occipital headache extending from the top to the back, as well as blurring of vision and vomiting. She had had a normal vaginal delivery with epidural anaesthesia during labour. During pregnancy she was diagnosed with gestational diabetes mellitus. Her headache was better when lying down and worse when sitting up. She had no medical history except for occasional migraines and was not on any acute or chronic medications. Her blood pressure on arrival was 158/94 mm Hg, and her other vital signs were normal. She was afebrile. Clinical examination showed diplopia worse on the left gaze and which disappeared on covering the left eye. Funduscopic examination was normal. She had mild global hyper-reflexia; but pronator drift and Babinski responses were negative. The rest of her neurological examination was normal. Her white blood cell count and liver function tests were normal.

### Answers

### 1. What are the differential diagnoses and how are they investigated?

#### Short answer

Intracranial pathology—investigated through imaging of the brain.

Cerebral venous thrombosis—investigated through contrast imaging of the brain.

Pre-eclampsia—urine dipstick, full blood count, creatinine, liver function tests.

Post dural puncture headache—diagnosed on history and trial of treatment. …
Cytopenia, Predisposition to Myelodysplastic Syndrome, Immunodeficiency, and Neurological Disease Caused By Gain-of-Function SAMD9L Mutations Is Frequently Ameliorated By Hematopoietic Revertant Mosaicism
Authors: Bianca Tesi, Josef Davidsson, Matthias Voss, Timothy Holmes, Tim Ripperger, Samuel Chiang, Lars Nilsson, Magnus Nordenskjöld, Jan-Inge Henter, David Bryder, Thoas Fioretos, Johanna Uusimaa, Jonna Komulainen-Ebrahim, Merja Möttönen, Riitta Niinimäki, Jukka Moilanen, Elisa Rahikkala, Ulf Tedgård, Jörg Cammenga, Yenan Bryceson
Journal: Blood (2016)
OS03.1 The role of the immune system in facilitating the formation of brain metastasis of breast cancer
Authors: D. A. M. Mustafa, R. M. Pedrosa, A. Sieuwerts, M. Smid, V. de Weerd, T. Luider, R. Debets, J. Martens, J. Foekens, J. M. Kros
Journal: Neuro-Oncology (2017)

Brain metastases are clinically devastating and one of the most faired complications of cancer. They are the most common malignancy of the brain and 25–40% of cancer patients will develop brain metastases. The formation of cerebral metastases depends on the capacity of circulating tumor cells to successfully penetrate the blood-brain barrier (BBB). Elucidating the underlying mechanisms of crossing the BBB is crucial for the prevention of cerebral metastases. We compared the gene expression profiles of ER- primary breast cancer biopsy samples of women with metastasized disease, with and without brain involvement. We found genes related to T cell response as most prominently associated with the development of brain metastases. In functional studies using an in vitro BBB model breast cancer cells that were co-cultured with T cells passed the artificial BBB with a 300–600 fold acceleration. We identified 11 differentially expressed proteins in breast cancer cell lines that were co-cultured with T lymphocytes. After matching these proteins with RNA expression data of the original patient datasets, we found that the gene for guanylate binding protein 1 (GBP1) was upregulated in the samples that were associated with cerebral metastasis. Silencing of GBP1 in breast cancer cells resulted in a 30–70 fold decrease of the passage of the breast cancer cells through the BBB model. The results point to expressional imprinting of breast cancer cells by T lymphocytes, resulting in accelerated passage through the BBB. Proteins upregulated by the T cells like GBP1 are candidate biomarkers for estimating the risk of the formation of cerebral metastases.
Endoscopic ultrasound of gastroduodenal artery pseudoaneurysm
Authors: Malay Sharma, Piyush Somani
Journal: Endoscopy (2017)

A 28-year-old man was referred from a hospital with recurrent episodes of acute pancreatitis over a 7-month period. The last episode was 2 weeks before we saw him. Results of routine blood tests, and ultrasonography and computed tomography (CT) of the abdomen were normal. He was diagnosed with idiopathic recurrent acute pancreatitis. Linear endoscopic ultrasonography (EUS) was planned for the evaluation of the condition.
上腕内皮血管運動機能とcarotid plaque echolucencyの超音波評価の併用はメタボリックシンドロームにおける心血管疾患を予測する
Authors: Nakamura Takamitsu, Kitta Yoshinobu, Iwaoka Masahiko, Takano Hajime, Kodama Yasushi, Kawabata Kenichi, Obata Junei, Mende Akira, Abe Makoto, Kugiyama Kiyotaka
Journal: Circulation (2007)
Interaction between the gut microbiome and mucosal immune system
Authors: Na Shi, Na Li, Xinwang Duan, Haitao Niu
Journal: Military Medical Research (2017)

The gut microbiota, the largest symbiotic ecosystem with the host, has been shown to play important roles in maintaining intestinal homeostasis. Dysbiosis of the gut microbiome is caused by the imbalance between the commensal and pathogenic microbiomes. The commensal microbiome regulates the maturation of the mucosal immune system, while the pathogenic microbiome causes immunity dysfunction, resulting in disease development. The gut mucosal immune system, which consists of lymph nodes, lamina propria and epithelial cells, constitutes a protective barrier for the integrity of the intestinal tract. The composition of the gut microbiota is under the surveillance of the normal mucosal immune system. Inflammation, which is caused by abnormal immune responses, influences the balance of the gut microbiome, resulting in intestinal diseases. In this review, we briefly outlined the interaction between the gut microbiota and the immune system and provided a reference for future studies.