tbuckley/cabot-search huggingface dataset:
Abstract P114: Genetic Polymorphisms of <i>CD36</i> Associated With Metabolic Syndrome in Chinese Han Population: A Nested Case-Control Study
Authors: Ruiyuan Zhang, Dongdong Zhang, Yu Liu, Xizhuo Sun, Zhaoxia Yin, Yang Zhao, Bingyuan Wang, Yongcheng Ren, Xuejiao Liu, Dechen Liu, Feiyan Liu, Xu Chen, Leilei Liu, Cheng Cheng, Qionggui Zhou, Changwei Li, Dongsheng Hu, Ming Zhang
Journal: Circulation (2019)

Aims: CD36 , an important gene involved in cholesterol and fatty acid metabolism,, has been associated with many metabolic-related traits, including diabetes, hypertension, and obesity in different populations. However, the association of this gene with metabolic syndrome (MS) has not been well-studied. We aimed to investigate the association of CD36 with the risk of MS and longitudinal changes of its components in among participants of the Rural Chinese Cohort Study (RCCS). Materials and Methods: The RCCS enrolled 20,194 participants aged 2 18 years old between July of 2007 and August of 2008. A total of 17,265 participants (response rate 85.5%) were examined in the follow-up survey between July of 2013 and October of 2014. During the six years, 729 new incident cases of MS were ascertained. We conducted a nested case-control study within the RCCS. Specifically, 408 MS randomly cases and 408 one-to-one matched controls were included in the current study. In addition to follow-up time, non-MS controls were matched to MS cases on age, gender, marital status, and residence village. Human genomic DNA was extracted using a standard method from blood samples collected at the baseline. After quality control, 4 single nucleotide polymorphisms (SNPs) within the CD36 were successfully genotyped. MS was defined according to the 2009 criteria proposed by IDF and AHA/NHLBI. Multivariate conditional logistic regression was used to determine additive associations of SNPs and SNP-haplotype with MS adjusting for body mass index (BMI), smoking, drinking, and physical activity at baseline. Multivariate linear regression models were conducted among the control group to examine association of SNPs and SNP-haplotypes with MS components, controlling for age, gender, BMI, smoking, drinking and physical activity. Multiple testing was corrected by false positive discovery rate (FDR) method. Results: Two SNPs, rs7755 and rs1049673, were associated with risk for MS. Per minor allele increase in rs7755 and rs1049673 was associated with 2.29 (95% confidence interval [CI]: 1.24-4.24, p =0.008) and 2.30 (95% CI: 1.24-4.26, p =0.008) times higher odds of MS, respectively. In addition, rs1194197 was associated with changes of triglycerides level (β=0.151, p =0.014), and rs7755 (β=-0.065, p =0.028) and rs1049673 (β=-0.067, p =0.025) were associated with changes of high density lipoprotein cholesterol in the control group. One haplotype of the four SNPs, AGAG, was associated with the change of waist circumference (β=-1.773, p =0.048). Conclusions: We identified important SNPs and SNP-haplotypes of the CD36 associated with MS and changes of MS components in a Han Chinese population.
Intraoperative and early postoperative outcomes in post-chemotherapy retroperitoneal lymphadenectomy using validated grading classifications.
Authors: Eric Umbreit, Andrew G. McIntosh, Chalariat Suk-ouichai, Luis Segarra, Levi Holland, Bryan M. Fellman, Shi-Ming Tu, Curtis Alvin Pettaway, Louis L. Pisters, John Francis Ward, Christopher G. Wood, Jose A. Karam
Journal: Journal of Clinical Oncology (2019)

535 Background: Post-chemotherapy retroperitoneal lymphadenectomy (PC-RPLND) is an integral treatment modality in the management of advanced germ cell tumors. We sought to define the complication profile of PC-RPLND using validated grading systems for intraoperative adverse events (iAE) and early postoperative complications. Methods: After IRB approval, we analyzed perioperative outcomes of 453 patients (pts) who underwent PC-RPLND between 2000 and June 2018. iAE and early postoperative complications (within 90 days) were graded using Kaafarani and Clavien-Dindo classification, respectively. Logistic regression models were conducted to assess patient and tumor factors associated with iAEs and postoperative complications. Results: Of the 453 pts, 287 (63%) were clinical stage III and had a median post-chemotherapy retroperitoneal mass size of 4.1 cm (IQR 2.4-7.4 cm). There were 132 iAE, which occurred in 115 (25%) pts. Early postoperative complications occurred in 255 (56%) pts. Major iAE (grade ≥ 3) was observed in 15 (3%) pts and major postoperative complications (grade ≥ 3) were noted in 83 (18%) pts. The most common iAE was vascular injury (112 of 132 events, 85%), which occurred in 92 (20%) pts. The most common postoperative complication was ileus, occurring in 121 (27%) pts. Residual retroperitoneal mass size (OR = 1.14; 95% CI: 1.09–1.20, p&lt;0.001), non-pulmonary metastases (OR = 3.18; 95% CI: 1.68–6.00, p&lt;0.001), previous laparotomy (OR = 1.92; 95% CI: 1.01–3.66, p=0.047), previous RPLND (OR = 1.14; 95% CI: 1.01–5.59, p=0.046), and adjuvant surgical procedures (OR = 13.54; 95% CI: 7.01–26.14, p&lt;0.001) increased the risk of iAE and postoperative complications. Postoperative complications were more likely for patients that experienced an iAE (OR = 2.50; 95% CI: 1.58–3.97, p&lt;0.001). Conclusions: This is the first analysis of PC-RPLND defining morbidity using validated classifications of severity for iAE and postoperative complications. Larger retroperitoneal mass, non-pulmonary metastases, previous surgery and adjuvant surgical procedures increased the risk of perioperative complications. iAE increased the risk of postoperative complications.
Dural lymphatics regulate clearance of extracellular tau from the CNS
Authors: Tirth K. Patel, LeMoyne Habimana-Griffin, Xuefeng Gao, Baogang Xu, Samuel Achilefu, Kari Alitalo, Celia A. McKee, Patrick W. Sheehan, Erik S. Musiek, Chengjie Xiong, Dean Coble, David M. Holtzman
Journal: Molecular Neurodegeneration (2019)

Alzheimer's disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid-β (Aβ) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), some forms of frontotemporal dementia, and argyrophilic grain disease (AGD). The prion hypothesis suggests that after an initial trigger event, misfolded forms of tau are released into the extracellular space, where they spread through different brain regions, enter cells, and seeding previously normal forms. Thus understanding mechanisms regulating the clearance of extracellular tau from the CNS is important. The discovery of a true lymphatic system in the dura and its potential role in mediating Aβ pathology prompted us to investigate its role in regulating extracellular tau clearance.To study clearance of extracellular tau from the brain, we conjugated monomeric human tau with a near-infrared dye cypate, and injected this labeled tau in the parenchyma of both wild-type and K14-VEGFR3-Ig transgenic mice, which lack a functional CNS lymphatic system. Following injection we performed longitudinal imaging using fluorescence molecular tomography (FMT) and quantified fluorescence to calculate clearance of tau from the brain. To complement this, we also measured tau clearance to the periphery by measuring plasma tau in both groups of mice.Our results show that a significantly higher amount of tau is retained in the brains of K14-VEGFR3-Ig vs. wild type mice at 48 and 72 h post-injection and its subsequent clearance to the periphery is delayed. We found that clearance of reference tracer human serum albumin (HSA) was also significantly delayed in the K14-VEGFR3-Ig mice.The dural lymphatic system appears to play an important role in clearance of extracellular tau, since tau clearance is impaired in the absence of functional lymphatics. Based on our baseline characterization of extracellular tau clearance, future studies are warranted to look at the interaction between tau pathology and efficiency of lymphatic function.
Improving the definition of high-risk patients for tumor recurrence from clear cell renal cell carcinoma: The U-CISS classification.
Authors: Cedric Michel Lebacle, Nils Kroeger, Aydin Pooli, Sandy Liu, Karim Chamie, Arie S. Belldegrun, Brian Shuch, Alexandra Drakaki, Allan J. Pantuck
Journal: Journal of Clinical Oncology (2019)

629 Background: Thirty percent of patients with localized clear cell renal cell carcinoma (ccRCC) will ultimately develop recurrence (local or metastatic) after nephrectomy. Current risk stratification systems still misclassify patients. A better stratification is needed to select high-risk patients who may benefit from adjuvant therapy. We sought to improve the existing UISS by the addition of genetic information in a new UCLA cytogenetic integrated staging system (U-CISS). Methods: A total of 240 patients from UCLA with localized ccRCC and cytogenetic analysis on tumor specimen were included in the study. In a continuation of our previous research, cytogenetic (combined loss 3p-14q) and a pathological high-risk feature, microvascular invasion (MVI) were implemented in the UISS. Association with recurrence free survival (RFS) was analyzed in a uni- and multivariable fashion; prognostic accuracy was tested with the c-index. All tumors that had either MVI, combined loss 3p/14q or both in the UISS low-risk group were placed into the U-CISS intermediate group. Tumors with one or both risk factors in the UISS intermediate group were placed into the new U-CISS high-risk group. Results: Fifty patients developed tumor recurrence. On multivariate analysis, combined loss 3p-14q, and MVI were independent prognostic factors. The U-CISS placed significantly better prognosticated RFS in the high-risk group (7/50 (14%) with UISS vs. 23/50 (46%) with U-CISS) and thus, was more accurate in prognosticating RFS. The c-index for recurrence prognostication was improved in the U-CISS (0.70 vs. 0.65 for the UISS). Furthermore, the U-CISS was a better prognostication tool when the intermediate and high-risk group were combined (prognostication of 74% with U-CISS vs. 68% UISS). Conclusions: The use of U-CISS, which integrates genomic alterations with clinical and pathologic features, allowed a re-allocation of patients to create a better stratification of recurrence risk. This new definition of high-risk of recurrence could significantly improve selection of patients who are in greatest need of closer surveillance and/or adjuvant treatment. C.L. and N.K. contributed equally to first authorship.
Mitochondrial Genomics Reveals Shared Phylogeographic Patterns and Demographic History among Three Periodical Cicada Species Groups
Authors: Zhenyong Du, Hiroki Hasegawa, John R Cooley, Chris Simon, Jin Yoshimura, Wanzhi Cai, Teiji Sota, Hu Li
Journal: Molecular Biology and Evolution (2019)

The mass application of whole mitogenome (MG) sequencing has great potential for resolving complex phylogeographic patterns that cannot be resolved by partial mitogenomic sequences or nuclear markers. North American periodical cicadas (Magicicada) are well known for their periodical mass emergence at 17- and 13-year intervals in the north and south, respectively. Magicicada comprises three species groups, each containing one 17-year species and one or two 13-year species. Within each life cycle, single-aged cohorts, called broods, of periodical cicadas emerge in different years, and most broods contain members of all three species groups. There are 12 and three extant broods of 17- and 13-year cicadas, respectively. The phylogeographic relationships among the populations and broods within the species groups have not been clearly resolved. We analyzed 125 whole MG sequences from all broods and seven species within three species groups to ascertain the divergence history of the geographic and allochronic populations and their life cycles. Our mitogenomic phylogeny analysis clearly revealed that each of the three species groups had largely similar phylogeographic subdivisions (east, middle, and west) and demographic histories (rapid population expansion after the last glacial period). The mitogenomic phylogeny also partly resolved the brood diversification process, which could be explained by hypothetical temporary life cycle shifts, and showed that none of the 13- and 17-year species within the species groups was monophyletic, possibly due to gene flow between them. Our findings clearly reveal phylogeographic structures in the three Magicicada species groups, demonstrating the advantage of whole MG sequence data in phylogeographic studies.
Pharmacological Inhibition of Lck is Able to Revert Glucocorticoid Resistance in Pediatric T-ALL
Authors: Valentina Serafin, Giorgia Capuzzo, Gloria Milani, Silvia Bresolin, Marica Pinazza, Sonia Minuzzo, Stefano Indraccolo, Roberta Bortolozzi, Giuseppe Basso, Benedetta Accordi
Journal: Blood (2016)
Survival of patients with secondary acute myeloid leukemia (sAML) in Hodgkin Lymphoma (HL): A Surveillance Epidemiology and End Results (SEER) database study.
Authors: Sumit Dahal, Smith Giri, Vijaya Raj Bhatt, Binay Kumar Shah, Ranjan Pathak, Gregory Bociek, Julie Vose, James O. Armitage
Journal: Journal of Clinical Oncology (2015)

e18049 Background: Limited data exists on the prognosis of patients with sAML following HL. The aim of this study was to compare the survival of sAML with de novo cases using a large database. Methods: We utilized the SEER 9 database with appropriate histology codes to identify patients with HL diagnosed between 1973-2011. Microscopically confirmed cases of AML occurring at least 12 months after diagnosis of HL were categorized as sAML. Chemotherapy regimen and the prior use of autologous transplant could not be ascertained. OS of sAML was then compared to a propensity matched cohort (1:4) of de novo AML cases diagnosed during the same time period (1973-2011). Actuarial survival statistics and Kaplan Meier survival curves were computed for the unmatched and matched datasets and compared using log rank test and Z test. Multivariate analysis was done with 2 level hierarchical weighted cox regression methods. Results: A total of 118 cases of sAML and 29905 cases of de novo AML were identified. One-third of sAML cases were diagnosed after 2000. The median age of sAML (47.5 yrs; range 14-76) was significantly lower than de novo AML cases (66 yrs; 0-101 yrs). 82% of sAML were diagnosed in < 60 years. The unadjusted median OS (5 months vs. 4 months, p = 0.17) and 5 year OS (6% vs. 12%, p = 0.06) were comparable in the two groups. However, after matching for age, gender, race and year of diagnosis, the patients with sAML had a worse median OS (5 months vs. 10 months; p < 0.01) and 5 year OS (6% versus 20%; p < 0.01). On multivariate analysis, sAML was an independent predictor of worse OS (HR 1.73; 95% CI 1.37-2.20; p < 0.01) after adjusting for age, sex, race and year of diagnosis. Conclusions: This study uses real world data and is the largest study of sAML developing after HL.sAML developing after HL has a worse prognosis than de novo AML. However, 82% of sAML patients are diagnosed in younger patients, who may tolerate therapy intensification and allogeneic transplant. Such strategy and trials on novel therapies may provide an opportunity to improve OS.
BREAKFAST ASSOCIATION WITH ARTERIAL STIFFNESS AND CAROTID ATHEROSCLEROTIC BURDEN: INSIGHTS FROM THE CORINTHIA STUDY
Authors: Sotirios Tsalamandris, Evangelos Oikonomou, Tzortzina Vavuranaki, George Lazaros, Georgia Vogiatzi, Christos Chasikidis, Evangelia Christoforatou, George-Angelo Papamikroulis, Konstantinos Mourouzis, Vasiliki Mystakidou, Margienti Papakonstantinou, Panagiotis Theofilis, Savvas Mazaris, Nikolaos Galiatsatos, Dimitris Tousoulis
Journal: Journal of the American College of Cardiology (2019)
Efficacy of targeted therapy (TT) after checkpoint inhibitors (CPI) in metastatic renal cell carcinoma (mRCC): Results from the Canadian Kidney Cancer Information System (CKCis).
Authors: Austin Kalirai, Lori Wood, Aly-Khan A. Lalani, Daniel Yick Chin Heng, Sunita Ghosh, Marco Adelmo James Iafolla, Christian K. Kollmannsberger, Denis Soulieres, Vincent Castonguay, Dominick Bossé, Eric Winquist, Anil Kapoor, Naveen S. Basappa
Journal: Journal of Clinical Oncology (2019)

568 Background: While the use of CPI has demonstrated clinical benefit in patients with mRCC, data showing the efficacy of subsequent TT is limited. This real-world analysis evaluated the efficacy of TT post CPI in mRCC patients. Methods: Data was collected and analyzed from CKCis. Patients with mRCC who received TT after CPI were identified and analyzed based on line of therapy. Time to treatment failure (TTF – time from starting first subsequent TT to stopping TT) and overall survival (OS) were calculated. Hazard Ratio (HR) calculations were adjusted for IMDC group and age. Results: 102 patients were treated with TT post CPI (table). Those who received first-line ipilimumab + nivolumab (I/N) versus a vascular endothelial growth factor inhibitor (VEGFi) + CPI combination prior to second-line TT had a median TTF of 8.0 vs 5.2 months (m) (HR=0.43, 95% CI: 0.13-1.44) and median OS of 16.5 m vs not reached (HR=0.76, 95% CI: 0.11-5.24). Patients who received a VEGFi versus a mammalian target of rapamycin inhibitor (mTORi) as third-line TT had a median TTF of 7.6 vs 4.4 m (HR=0.52, 95% CI: 0.24-1.10) and median OS of 21.7 vs 16.2 m (HR=0.41, 95% CI: 0.16-1.08). All third-line TT patients received first-line VEGFi and second-line nivolumab. Of the third-line VEGFi TT patients, 24 received axitinib (TTF 7.1 m, OS 21.7 m) and 22 received cabozantinib (data immature). Conclusions: Activity of TT in mRCC patients after CPI is demonstrated in multiple lines. In second-line, VEGFi TT had numerically better outcomes after I/N than after VEGFi+CPI combination. Efficacy of third-line TT was seen with a trend favoring VEGFi over mTORi. Axitinib in the third-line has notable activity after CPI, while data on cabozantinib and fourth-line TT are maturing. These results support the use of VEGFi after CPI in mRCC patients. [Table: see text]
Investigating a novel recombinant antibody to attenuate prostate cancer progression by targeting cell surface GRP78.
Authors: Ali Al-Hashimi, Kevin Doyoon Won, Elizabeth Pham, Natalie Mariano, Julie Bailis, Richard Austin, Bobby Shayegan
Journal: Journal of Clinical Oncology (2019)

206 Background: Prostate cancer (PCa) is characterized by increased activation of the procoagulant protein, tissue factor (TF) that drive tumour progression. We now show that this process is modulated by GRP78 on the cell surface (cs). In PCa GRP78 is a endoplasmic reticulum-resident chaperone that localizes to the cell surface where it functions as a signaling molecule with antigenic properties. In response to csGRP78 presentation, PCa patients produce autoantibodies (AutoAbs) against the N-terminus of GRP78. AutoAbs:csGRP78 complex acts as a potent driver of tumor growth via upregulation of the unfolded protein response (UPR) and TF activity. We hypothesize that inhibiting the binding of anti-GRP78 AutoAbs to csGRP78 will supress UPR and TF activity. Here we describe a recombinant anti-GRP78 antibody (AEP8587) that competes with the binding of AutoAbs to csGRP78 and may act as a novel therapeutic antibody with antitumor activity. Methods: Changes in TF activity or UPR markers were evaluated in vitro in the PCa cell line DU145 following treatment with anti-GRP78 AutoAbs or co-treatment with either enoxaparin, a low molecular weight heparin (LMWH), or AEP8587. Protein expression of TF and UPR markers was determined using western blotting and qRT-PCR. TF activity was determined using a real-time continuous assay. AutoAbs were purified PCa patients (St. Joseph’s Healthcare Hamilton). Results: Pre-prostatectomy PCa patients display high levels of anti-GRP78 AutoAbs (~60µg/ml), compared to healthy controls (~5µg/ml). Here, we show that anti-GRP78 AutoAb increases TF activation in vitro and leads to increased tumor progression in a DU145 xenograft model. In contrast, we show a co-treatment of anti-GRP78 AutoAb with either enoxaparin or AEP8587 completely abolishes the AutoAb-mediated increase in TF activity in vitro. Enoxaparin or AEP8587 co-treatment reversed the AutoAb effect on increased UPR markers. Conclusions: We have identified anti-GRP78 AutoAb as a driver of PCa progression. Our results indicate that a recombinant antibody, AEP8587, can bind to csGRP78 and prevent the binding of anti-GRP78 AutoAbs. This represents a potential novel means to manage PCa progression.
HER2 Amplification and Anti-EGFR Sensitivity in Advanced Colorectal Cancer
Authors: Giacomo Bregni, Stefania Sciallero, Alberto Sobrero
Journal: JAMA Oncology (2019)

This Viewpoint questions a recently published treatment algorithm for patients with HER2-amplified metastatic colorectal cancer and proposes alternative timing for HER2 testing and HER2-directed therapies.
Influence of access on survival of renal cancer in a Brazilian center.
Authors: Luciana de Moura Leite, Aldo A. Dettino, José Augusto Rinck, Stenio Cassio Zequi, Simone Loose, Maria Nirvana Cruz Formiga
Journal: Journal of Clinical Oncology (2019)

644 Background: The introduction of tyrosine kinase inhibitors (TKI) and recently immunotherapy has brought major survival benefits for metastatic renal cancer (mRCC) patients (pts). In Brazil, there is no approved 2 nd line treatment for mRCC in the Public Health System (PHS). Our center is unique, because it provides care for both PHS and Private System (PrS) population, enabling us to make the comparison of overall survival (OS) of these pts. Methods: We retrospectively reviewed medical records of all mRCC pts treated with 1st line TKI at our service from 2007 to 2018. Categorial variables were compared by Fisher’s exact test and continuous by Mann–Whitney. Survival was estimated by Kaplan-Maier method, prognostic factors adjusted by Cox regression model. Results: 171 pts were eligible, 37 (21.6%) PHS and 134 (78.4%) PrS pts. Between the two groups, there was no differences in age, gender, number and sites of metastasis (mets). PHS pts had worst ECOG (≥2, in 35.1 vs 13.5%, p .007), a trend towards more poor IMDC risk (IMDC favorable 16.2 vs 26.6%, intermediate 51.4 vs 57%, poor 32.4 vs 16.4%, p.09), had less nephrectomies (73 vs 92.5%, p.008) and more non clear cell histology (32.4 vs 12.7%, p.01). Median lines of therapy were 1 for PHS vs 2 for PrS pts (p.03). Sunitinib was the 1 st line agent for 91.9 vs 67.2%, and pazopanib 8.1 vs 29.9%, of the PHS and PrS pts, respectively. Median time from diagnosis of mets to treatment start was 2.29 vs 1.79 m (p.59). Median OS was 16.5 vs 26.5 m (p.0002) and progression free survival, 8.4 vs 11 m (p.01), for the PHS vs PrS. On multivariate analysis, after adjusting for factors that were present before the beginning of treatment and were statistically significant for OS in the univariate model, PHS pts still had higher risk of death (HR 1.85, IC 95 1.2-2.9, p.01), probably due to having received fewer lines of therapy (≥2 lines of therapy vs 1, HR 0.51, IC95 0.4-0.7, p .001). Conclusions: Brazilian PHS pts had significant worse OS compared to PrS pts, in part due to less access to drugs. Access to cancer drugs is a challenge worldwide, and in Brazil effort has to be done to change this reality.