tbuckley/cabot-search huggingface dataset:
Structural and Functional Changes in Human Kidneys with Healthy Aging
Authors: Musab S. Hommos, Richard J. Glassock, Andrew D. Rule
Journal: Journal of the American Society of Nephrology (2017)

Aging is associated with significant changes in structure and function of the kidney, even in the absence of age-related comorbidities. On the macrostructural level, kidney cortical volume decreases, surface roughness increases, and the number and size of simple renal cysts increase with age. On the microstructural level, the histologic signs of nephrosclerosis (arteriosclerosis/arteriolosclerosis, global glomerulosclerosis, interstitial fibrosis, and tubular atrophy) all increase with age. The decline of nephron number is accompanied by a comparable reduction in measured whole-kidney GFR. However, single-nephron GFR remains relatively constant with healthy aging as does glomerular volume. Only when glomerulosclerosis and arteriosclerosis exceed that expected for age is there an increase in single-nephron GFR. In the absence of albuminuria, age-related reduction in GFR with the corresponding increase in CKD (defined by an eGFR<60 ml/min per 1.73 m2) has been shown to associate with a very modest to no increase in age-standardized mortality risk or ESRD. These findings raise the question of whether disease labeling of an age-related decline in GFR is appropriate. These findings also emphasize the need for a different management approach for many elderly individuals considered to have CKD by current criteria.
PTH-028 A preliminary report on the feasibility and efficacy of the novel eus guided shark core fine needle biopsy
Authors: M Kasi, J Ortiz Fernandez-Sordo, P Kaye, K Ragunath, M James, GP Aithal, SV Venkatachalapathy
Journal: Endoscopy (2017)

<h3>Introduction</h3> EUS guided Fine Needle aspiration (FNA) is the standard of care for diagnosing solid pancreatic lesions. However, with personalised approach to oncological treatment histology is required to improve diagnostic accuracy and molecular characterisation. In a recent meta-analysis, the pooled sensitivity and specificity for EUS Fine Needle Biopsy (FNB) needle for diagnosing solid tumours is 84% and 99% respectively <sup>(1)</sup>. A novel FNB needle has been introduced which has two sharp points of different lengths and it has a multifaceted bevel to capture additional tissue - Shark Core (SC). There has been limited data on this needle type. Our aim was to study the feasibility and efficacy of FNB-SC for diagnosing solid pancreatic and non-pancreatic lesions. <h3>Method</h3> We conducted a retrospective cohort study in which, all consecutive patients who had FNB-SC for solid tumours between July 2016 and January 2017, were identified through endoscopy database. The endoscopy reports, histology reports and Hepato-Pancreato-Biliary MDM outcomes were reviewed through hospital reporting systems. The histopathologist reviewed the tissue adequacy on all samples. We assessed the histological yield and diagnostic accuracy of the FNB-SC needle. <h3>Results</h3> 29 patients were included in study of which, 55% (n=16) males and 45% (n=13) females with median age of 65 years (range 33–84). 26 patients (86%) had pancreatic lesions and 3 were non pancreatic lesions (2 GIST, 1 Ampullary adenoma). Median size of the lesions was 30 mm (range 17 mm-70mm). Sample deemed adequate for histological analysis in 96.5% (n=28) and inadequate in 3.5% (n=1). 22gauge needle was used in 86% and 25gauge in 14% of the patients. The Median number of passes to obtain adequate sample are 3 (range 2–4). Among the adequate samples obtained histological diagnosis were matched with radiological diagnosis in 89.2% (25/28) and with clinical diagnosis in 83% (24/28) at three months follow up with no further cancer detected. There was only one patient who had surgery in whom the histology results from surgical specimen matched with FNB diagnosis. The sensitivity, specificity, positive predictive value and negative predictive value for diagnostic accuracy were 92.8% (95% CI 76.5%&gt;99.1%), 100% (95% CI 2.5%&gt;100%), 100%, 33.3% (95% CI 11.6%–65.5%) respectively. There were no complications in our cohort of patients. <h3>Conclusion</h3> EUS FNB-SC needle is feasible and effective in obtaining tissue for solid tumours. It has high sensitivity and specificity in diagnosing solid tumours. <h3>Reference</h3> . Yang, Yongtao, et al. "Endoscopic ultrasound-guided fine needle core biopsy for the diagnosis of pancreatic malignant lesions: a systematic review and Meta-Analysis."Scientific reports6 (2016). <h3>Disclosure of Interest</h3> None Declared
Tremelimumab, a fully human anti-CTLA-4 monoclonal antibody, optimal dosing regimen for patients with unresectable malignant mesothelioma (MM).
Authors: Rajesh Narwal, Alessandra DiPietro, Ramy Ibrahim, Luana Calabrò, Michele Maio, Paul B. Robbins, Lorin Roskos
Journal: Journal of Clinical Oncology (2015)

3042 Background: Tremelimumab (T) is a selective human IgG2 mAb inhibitor of CTLA-4 that promotes T-cell activity though CTLA-4 inhibition. The primary objective of this analysis was to project the optimal T dosing regimen for a Phase (Ph) 2b study in MM. Methods: Retrospective population PK (N = 654; Ph 1–3; 0.01 to 15 mg/kg single dose/Q90D/Q4W) and exposure-OS (N = 293; Ph3; 15 mg/kg Q90D) analyses were performed using data from metastatic melanoma studies (A3671001/NCT00086489/NCT00254579/NCT00257205). PK (N = 40) and efficacy (N = 58) data were collected from a Ph2 study of T (NCT01649024/NCT01655888) following 2 dosing regimens: 15 mg/kg Q90D and 10 mg/kg Q4W. Modeling and simulations were performed in NONMEM and CTS software. Results: PK profiles were adequately described in the population model, resulting in parameters similar to a typical mAb with modest variability and indicating no need for dose adjustments. The exposure-OS analysis of a Ph3 study in melanoma showed better OS in patients with higher exposure compared to lower exposure (mOS of 18.4 vs 9 months). T did show clinical benefit in the Ph3 melanoma study; however, the primary endpoint was not met. One potential reason could be the sub-optimal dose of 15 mg/kg Q90D. Following 15 mg/kg Q90D, exposure was below the target trough level of ~30 µg/mL for about half of the dosing interval, with almost all patients below the LLOQ at the end of dosing interval. PK simulations indicated more frequent dosing of 10 mg/kg Q4W could maintain exposure at or above the target trough level in > 90% patients over the entire dosing interval and could yield higher OS. Based on these evaluations, a 10 mg/kg Q4W regimen extension arm was added in an ongoing ISS study exploring 15 mg/kg Q90D. Data from this ISS study confirmed similar PK for both schedules in melanoma and MM. A 10 mg/kg Q4W dose yielded higher exposure and could be associated with better clinical outcome in MM. The dosing regimen of 10 mg/kg Q4W for 6 months followed by 10 mg/kg Q12W is currently being tested. Conclusions: An optimal dosing regimen of 10 mg/kg Q4W T was identified based on integrated data analysis. This dosing regimen is currently being evaluated in an ongoing Ph2b study in MM. Clinical trial information: A3671001/NCT00086489/NCT00254579/NCT00257205/NCT01649024/NCT01655888.
Adequacy of Intraoperative Nodal Staging during Surgical Resection of NSCLC: Influencing Factors and Its Relationship to Survival
Authors: Tim Edwards, Haval Balata, Mohamed Elshafi, Philip Foden, Paul Bishop, Eustace Fontaine, Mark Jones, Piotr Krysiak, Kandadai Rammohan, Rajesh Shah, Philip Crosbie, Richard Booton, Matthew Evison
Journal: Journal of Thoracic Oncology (2017)
Influenza Vaccine Effectiveness in the United States during the 2015–2016 Season
Authors: Michael L. Jackson, Jessie R. Chung, Lisa A. Jackson, C. Hallie Phillips, Joyce Benoit, Arnold S. Monto, Emily T. Martin, Edward A. Belongia, Huong Q. McLean, Manjusha Gaglani, Kempapura Murthy, Richard Zimmerman, Mary P. Nowalk, Alicia M. Fry, Brendan Flannery
Journal: New England Journal of Medicine (2017)

The A(H1N1)pdm09 virus strain used in the live attenuated influenza vaccine was changed for the 2015-2016 influenza season because of its lack of effectiveness in young children in 2013-2014. The Influenza Vaccine Effectiveness Network evaluated the effect of this change as part of its estimates of influenza vaccine effectiveness in 2015-2016.
AB1005 Hypothyroid and hyperthyroid status was strongly associated with musculoskeletal ultrasonographic abnormalities with arthralgia
Authors: BY Kim, SS Kim, JR Choi, H-S Kim
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Thyroid dysfunction can cause musculoskeletal symptoms and sign. Ultrasonography is a useful tool for the evaluation of synovitis and is more accurate than clinical examination. <h3>Objectives</h3> The purpose of the study was to determine whether musculoskeletal ultrasonographic (MSUS) abnormalities were observed according to the state of thyroid disease. <h3>Methods</h3> Patients with thyroid disease were categorized as euthyroid, hypothyroid, or hyperthyroid status according to thyroid hormone levels and evaluated the association with MSUS abnormalities. In addition, the association of the presence of thyroid autoantibodies with MSUS abnormalities was also studied. In MSUS, an experienced rheumatologist examined the presence of synovial fluid, synovial hypertrophy, and grade of power doppler in the knee joint. <h3>Results</h3> 109 consecutive patients who visited the endocrinology outpatient clinic and had thyroid disease with normal or abnormal thyroid function tests participated in the study. MSUS abnormalities were statistically significantly higher in hyperthyroid or hypothyroid status than in euthyroid status (p&lt;0.001). However, there was no statistically significant difference between hypothyroid status and hyperthyroid status. The presence of MSUS abnormalities with abnormal thyroid function was corrected according to the presence of radiological Knee osteoarthritis. Both hypothyroid and hyperthyroid status was still associated with MSUS abnormalities regardless of knee osteoarthritis. Visual analogue scale for knee pain was higher in patients with MSUS abnormalities (p&lt;0.001). But, there was no statistically difference of MGUS abnormalities with presence of thyroid autoantibodies. <h3>Conclusions</h3> Both hypothyroid and hyperthyroid status was significantly associated with MSUS abnormalities with knee arthralgia. MSUS is a useful tool to detect clinically early joint abnormalities. We suggest that patients with diagnosed thyroid dysfunction and who remain uncontrolled, should assess the MSUS examination in patients with arthralgia. Moreover a thyroid function test for unexplained arthritis maybe warranted. <h3>References</h3> Cakir M, Samanci N, Balci N, et al. Musculoskeletal manifestations in patients with thyroid disease. Clin Endocrinol 2003;59:162–7. Wakefield RJ, Green MJ, Marzo-Ortega H, et al. Should oligoarthritis be reclassified? Ultrasound reveals a high prevalence of subclinical disease. Ann Rheum Dis 2004;63:382–5. Magni-Manzoni S, Epis O, Ravelli A, et al. Comparison of clinical versus ultrasound-determined synovitis in juvenile idiopathic arthritis. Arthritis Rheum 2009;61:1497–504. Karim Z, Wakefield RJ, Quinn M, et al. Validation and reproducibility of ultrasonography in the detection of synovitis in the knee: a comparison with arthroscopy and clinical examination. Arthritis Rheum 2004:50:387–94. <h3>Disclosure of Interest</h3> None declared
02.22 Taking fly for understanding the molecular role of hla-b27/hb2m in spondyloarthritis
Authors: Nadège Jah, Benjamin Grandon, Aurore Rincheval-Arnold, Isabelle Guenal, Sébastien Gaumer, Claudine André, Maxime Breban, Gilles Chiocchia
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> After more than 40 years of research, the mechanisms underlying the association of HLA-B27 with spondyloarthritis (SpA) remain poorly understood. We hypothesised that <i>Drosophila</i> might be a relevant model to study HLA-B27 and particularly for deciphering the cellular cascade and the genetic pathways affected by HLA-B27 mutation. To do so, we developed HLA-B2705, HLA-B0702 (control) and human Beta-2-microglobulin (hB2m) transgenic <i>Drosophila</i>. <h3>Methods</h3> Gateway Technology and UAS-Gal4 system used for developing transgenic HLA-B/human hB2m <i>Drosophila. UAS-hB2m</i> transgene was inserted in the long arm of chromosome 3 and <i>UAS-HLA-B2705</i> and <i>UAS-HLA-B0702</i> were alternatively inserted at another position in the short arm of the same chromosome. For each construct, various transgenic lines were obtained and crossed with several tissue specific driver strains, to induce the expression of the sequence coding for <i>HLA-B0702</i> and <i>hB2m</i> or <i>HLA-B2705</i> and <i>hB2m</i> placed under the control of UAS sequences. <h3>Results</h3> HLA-B2705/hB2m transgenes were first expressed in <i>Drosophila</i> thanks to the vestigialGa4 driver line allowing to produce targeted proteins in the <i>Vestigial</i> domain (dorso-ventral frontier of the wing epithelia). We observed positive staining with HC10 antibodies (class I heavy chain) and W6/32 antibody (HLA-A, HLA-B and HLA-C conformation) for both tested HLA-B/hB2m but only HLA-B27/hB2m was labelled with ME1 (anti-HLA B/C) antibodies, suggesting a different conformation of HLA-B27 and HLA-B7 with hB2m in the wing epithelia. Furthermore, by mean of the nubbin or engrailed drivers which drive the expression in a larger part of the wing, we observed specific loss of the posterior cross-vein following HLA-B27/hB2m expression but not HLA-B7/hB2m. <h3>Conclusion</h3> <i>Drosophila</i> lines were established allowing tissue specific expression of different HLA-B alleles. Our data suggest that the expression of HLA-B/hB2m transgenes in epithelial cells leads to a plasma membrane localization for HLA-B2705/hB2m but not for HLA-B0702/hB2m. Furthermore, we observed that tissue specific expression of HLA-B27/hB2m but not HLA-B7/hB2m induced specific loss of cross-vein suggesting it interferes with developmental pathways involved in differentiation. This is the first time that differences in localization between HLA-B2705, a subtype associated with SpA, and HLA-B0702, which is not associated with the disease are reported. These results show that transgenic <i>Drosophila</i> might be a pertinent model to decipher molecular mechanisms involved in HLA-B27 trafficking and to better understand potential different behaviours of HLA-B subtypes.
The cell polarity determinant CDC42 controls division symmetry to block leukemia cell differentiation
Authors: Benjamin Mizukawa, Eric O’Brien, Daniel C. Moreira, Mark Wunderlich, Cindy L. Hochstetler, Xin Duan, Wei Liu, Emily Orr, H. Leighton Grimes, James C. Mulloy, Yi Zheng
Journal: Blood (2017)
カラシナ:異質倍数体カラシナ(Brassica juncea)のゲノム配列と選択に影響するホメオログの差異発現の解析
Authors: Yang Jinghua, HU Zhongyuan, MA Weiwei, Shopan Jannat, Zhang Mingfang, Liu Dongyuan, JI Changmian, Liu Baoning, JU Youhui, Yao Pu, LI Xuming, Xie Kun, Zhang Jianhui, Zheng Hongkun, Wang Xiaowu, Cheng Feng, Chen Sheng, Pental Deepak, Wang Jianlin, Liu Fan, Mackenzie Sally A
Journal: Nature Genetics (2016)
THE EFFECTS OF COGNITIVE MATURITY ON CONCUSSION ASSESSMENT IN LOW SOCIOECONOMIC URBAN HIGH SCHOOL ATHLETES
Authors: Tamerah Hunt, Jody Langdon
Journal: British Journal of Sports Medicine (2017)

Background Implementing concussion assessment programs for youth athletes are necessary to manage clinical care in sports. However, confounding factors such as cognitive maturity and socioeconomic status may complicate clinical interpretation of testing following concussion. Objective Determine the stability of test scores between low socioeconomic athletes and non-athletes. Design Prospective longitudinal between-groups cohort design. Setting Youth Sports. Participants High school students (n=783) were recruited either prior to their competitive season or during the academic year to establish baseline cognitive function. Interventions All participants were administered annual baseline testing on computerized neuropsychological test battery (ImPACT) to track the effect of cognitive maturity. Using SPSS, a one-way ANOVA with repeated measures (group×time) was run on ImPACT composite scores, using an alpha level of .05 for all tests. Main Outcome Measurements ImPACT composite scores. Results Significant interactions of group and time existed for composite visual motor (Wilks' λ=0.97, F(1,782)=20.53, p&lt;.001, η 2 =.03) and composite reaction time (Wilks' λ=0.99, F(1,782)=5.65, p&lt;0.05, η 2 =0.01.) between athletes and non-athletes. Significant main effects for time were seen in composite impulse control (Wilks' λ=0.99, F(1, 782)=4.05, p&lt;0.05, η 2 =0.01.) with lower scores during year one. Significant differences existed between 10th and 12th grade participants compared to 9th grade participants on composite visual motor (p=0.006), and total symptoms (p=0.043) with older participants performing better. Conclusions Cognitive maturity does not appear to affect composite ImPACT scores, however there is a break in composite visual motor scores between older and ninth grade participants. The need for annual baseline testing may not be warranted beyond tenth grade. Future research should examine test scores across a high school career to gain more understanding of changes related to cognitive maturity.
Phase I/Ib study of the PARP inhibitor olaparib (O) with carboplatin (C) in BRCA1/2 mutation carriers with breast or ovarian cancer (Br/OvCa) (NCT00647062).
Authors: Jung-min Lee, Christina M. Annunziata, John L. Hays, Anne M. Noonan, Lori M. Minasian, JoAnne Zujewski, Minshu Yu, Jiuping Jay Ji, Tristan Sissung, Nicole D. Houston, Elise C. Kohn
Journal: Journal of Clinical Oncology (2013)

2514 Background: O capsules have single agent activity against Br/OvCa in BRCA1/2 mut+ carriers. Our goals were to define safety and explore predictive biomarkers for an OC regimen in these pts. Methods: 3x3 dose escalation optimized daily oral O (100 or 200mg q12h; DL1&amp;2) with IV C/AUC3 on d8 and q21d, and on DL3-6, O d1-7 at 200 then 400mg q12h with C/AUC3-5 on d2. ≤ 8 OC cycles were given, followed by daily O until progression. Safety was assessed q cycle and response q2 cycles. PBMCs were collected for polymorphism analysis (PARP1; XRCC1), and serially for PAR incorporation by ELISA. Paired tumor biopsies (pre/postC1) were collected in phase Ib pts for protein microarray (RPPA) and TUNEL endpoints. Results: 45 women (37Ov/8Br) with BRCA1 (32), BRCA2 (11), 1 each BRCA1&amp;2 and BRCApro 68% received OC. All OvCa pts previously received C (6-55mo prior, median 14). DLT was thrombocytopenia (O 200mg q12h, C/AUC3 2/5 pts). MTD was not reached on the intermittent schedule. RP2D is O 400mg q12hx14, C/AUC5 (1/6: g4 thrombocytopenia). Gr 3/4 AEs included neutropenia (42%), thrombocytopenia (20%), anemia (13%), C hypersensitivity (9%), and fatigue (7%). 7 pts discontinued C early for hypersensitivity reaction (4) or myelosuppression (3). Responses included 1 CR (BrCa, 17mo), PR in 15/34 OvCa (44%; 3-28+mo) and 6/8 BrCa (5-24+ mo), and stabilization in 14/34 OvCa (41%; 3-25+ mo) and a BrCa pt (11mo) for a clinical benefit rate of 85% OvCa, 100% BrCa. RPPA (N=10) showed high FOXO3 and NFκB1 preC1 correlated with time on study (r=0.822, p=0.0035; r=-0.832, p=0.0028, respectively). The change post-preC1 correlated with time on study for the combination of eIF4E/G, caspase 7, pPI3K, FOXO3a, p62, E-cadherin, PCNA, Bim, and Bcl2 (r=-0.855, p=0.0068). Post-preC1 TUNEL results trended to correlate with response (p=0.07). PBMC PAR concentrations and PARP1/XRCC1 polymorphisms did not correlate with response. Conclusions: O 400mg q12h x14 with C/AUC5 q21d is active and tolerable in Br/OvCa BRCA mut+ pts despite interactive marrow suppression. Exploratory translational studies indicate FOXO3 and NFkB1 may be predictive for response to therapy, requiring a prospective validation. Clinical trial information: NCT00647062.
Factors Associated With Discordance Between Preoperative Parathyroid 4-Dimensional Computed Tomographic Scans and Intraoperative Findings During Parathyroidectomy
Authors: Shonan Sho, Alexander D. Yuen, Michael W. Yeh, Masha J. Livhits, Ali R. Sepahdari
Journal: JAMA Surgery (2017)

Parathyroid 4-dimensional computed tomographic scans (4D-CTs) have emerged as an accurate and cost-effective initial localization study for patients with primary hyperparathyroidism. However, potential limitations and factors affecting the accuracy of preoperative 4D-CTs remain poorly defined.To characterize factors associated with missed parathyroid lesions on preoperative 4D-CTs and to investigate patterns of commonly observed errors.A prospectively accrued patient database was analyzed from September 1, 2011, through October 31, 2016. The study was performed in a tertiary referral center. Consecutive patients with primary hyperparathyroidism undergoing preoperative 4D-CTs and subsequent parathyroidectomy were included in the study.Discordance between preoperative 4D-CTs and intraoperative findings in the number and location of abnormal parathyroid lesions.Of 411 patients studied (mean [SD] age, 59 [14] years; 325 [79.1%] female), 123 (29.9%) had discordance between preoperative 4D-CTs and intraoperative findings. Among the 411 patients, 75 (18.2%) had major discordance, including incorrectly localized adenoma on the contralateral side of the neck, missed double adenoma, and absence of any abnormal lesion detected on 4D-CTs. Compared with concordant cases, discordant cases had higher frequencies of multigland disease (66.7% [82 of 123] vs 24.3% [70 of 288], P < .001) and multinodular goiter or thyroid nodule (40.7% [50 of 123] vs 29.2% [84 of 288], P = .02). Missed parathyroid lesions were smaller (mean [SD], 0.86 [0.29] vs 1.24 [0.50] cm; P < .001) and were more likely to be in the inferior position (65.4% [87 of 133] vs 38.1% [177 of 465], P < .001). Parathyroid lesion size of 10 mm or less (odds ratio [OR], 4.37; 95% CI, 2.24-8.54), multigland disease (OR, 7.63; 95% CI, 3.49-16.69), multinodular goiter or thyroid nodule (OR, 1.82; 95% CI, 1.01-3.28), and parathyroid lesion in the inferior position (OR, 6.82; 95% CI, 3.10-14.99) were independently associated with discordant 4D-CT results.Multigland disease was most strongly associated with discordance between preoperative 4D-CTs and intraoperative findings, followed by parathyroid lesion in the inferior position and parathyroid lesion size of 10 mm or less. Awareness of these potential pitfalls may allow surgeons to better leverage this new localization technique in preoperative planning and intraoperative troubleshooting.
PFKFB3 Is a Crucial Target in the Treatment of Tyrosine Kinase Inhibitor Resistant Chronic Myelogenous Leukemia
Authors: Yu Zhu, Jianyong Li, Chun Qiao, Yi Shan, Sixuan Qian, Yaoyu Chen, Ming Hong, Huihui Zhao, Huapeng LI, Xuejun Zhu, Yang Zhongfa
Journal: Blood (2016)