tbuckley/cabot-search huggingface dataset:
Abstract 103: Propofol Infusion in the Early Post-Cardiac Arrest Phase Improves Cerebral Perfusion and Confers Anti-Apoptotic Neuroprotection via Akt-eNOS-NO Signaling
Authors: Wei-Tien Chang, Min-Hsuan Hsu, Woan-Yi Wang, Chunpei Lee, Chih-Hung Wang, Min-Shan Tsai, Ming-Ju Hsieh, Hsiao-Ju Cheng, Chien-Hua Huang, Wen-Jone Chen
Journal: Circulation (2018)

Introduction: Neurological outcome after cardiac arrest (CA) and CPR is usually unsatisfactory even in this era of target temperature management (TTM). Propofol is not only a useful sedative drug for TTM but confers neuroprotective effect. We previously showed that propofol combined with TTM improves survival in patients resuscitated from CA. In this study we aimed to explore the underlying mechanism focusing on cerebrovascular circulation and anti-apoptosis signaling. Hypothesis: Infusion of propofol in the early post-CA phase improves cerebral perfusion and mitigates neuronal apoptosis via Akt-eNOS signaling. Methods: Using an established rat model of asphyxia cardiac arrest and CPR, propofol infusion (20 mg/kg/h) was instituted after return of spontaneous circulation (ROSC) and continued in the first 2 h. Hemodynamics were monitored and the cerebral perfusion was continuously recorded by OxyFLO probe. The arterial blood was regularly sampled for measurement of reactive oxygen species (ROS, chemiluminescence method) and NO (demonstrated by nitrate/nitrite). Two hours after ROSC, the brain was harvested for measurement of casepase-3, endothelial NO synthase (eNOS) and protein kinase B (Akt). Results: After CA and CPR, the cerebral perfusion was significantly reduced to ~0.5 folds that of baseline. With the infusion of propofol, the cerebral perfusion was significantly increased from the beginning after ROSC ( P &lt; 0.01 vs. CPR control). The plasma NO indicated by nitrate/nitrite 2 h post-CPR was significantly increased ( P &lt; 0.01) while ROS abrogated ( P &lt; 0.05). The cleaved caspase-3/caspase-3 of the brain was markedly reduced ( P &lt; 0.001), suggesting anti-apoptotic neuroprotection. When exploring the mechanism, the phosphorylated (p)-eNOS/eNOS and p-Akt/Akt were significantly increased (both P &lt; 0.001), indicating activation of Akt-eNOS-NO signaling. Conclusions: Infusion of propofol in the early post-CA phase reduces oxidative stress, improves cerebral perfusion, and ameliorates neuronal apoptosis. The protection is, at least in part, mediated via activation of Akt-eNOS-NO signaling.
Concordance between MRI fusion versus TRUS prostate biopsy and final pathology at radical prostatectomy: Data from the PURC.
Authors: Ruchika Talwar, Katharine Michel, Aseem Malhotra, Claudette Fonshell, John Danella, Serge Ginzburg, Thomas Lanchoney, Jay D. Raman, Adam Reese, Jeffrey Tomaszewski, Edouard John Trabulsi, Marc C. Smaldone, Robert Guy Uzzo, Daniel Lee, Thomas J. Guzzo
Journal: Journal of Clinical Oncology (2020)

354 Background: Studies suggest that MRI-fusion guided biopsies are superior to the transrectal ultrasound guided (TRUS) technique. Herein, we present the Pennsylvania Urologic Regional Collaborative (PURC) experience with MRI fusion biopsy. We aimed to calculate concordance rates between TRUS prostate needle biopsy versus MRI fusion biopsy and final pathology at the time of radical prostatectomy within our cohort. Methods: Within PURC, a prospective quality improvement collaborative of urology practices in Pennsylvania and New Jersey, we identified all men who underwent a TRUS or MRI fusion prostate needle biopsy followed by radical prostatectomy for the treatment of prostate cancer from 2015 to 2018. We analyzed International Society of Urological Pathology Grade Group (GG) scoring and calculated the concordance and upgrading rates at the time of biopsy versus final pathology at radical prostatectomy. To assess for differences between our rates, we performed a test of equal proportions and Pearson's chi-squared test (significance = p&lt;0.05). Results: We identified 1,437 men who underwent TRUS (n=1247) or MRI Fusion (n=196) biopsies followed by radical prostatectomy. Overall pathologic grading distribution at time of biopsy was: 35.8% (n=515) Grade Group (GG) 1, 28.5% (n=409) GG 2, 13.3% (n=191) GG 3, 11.5% (n=165) GG 4, and 10.9% (n=157) GG 5. Median number of cores at TRUS biopsy was 12 (IQR: 12,13). Median number of cores at MRI Fusion biopsy was 15 (IQR 13,18). Therefore, we inferred patients who underwent MRI Fusion biopsy also underwent standard TRUS biopsies at that time. On average, exact concordance rate between MRI Fusion biopsy and final pathology was 9.1% higher than concordance rate of TRUS biopsy (44.4% vs 35.3%, 95% CI: 1.6%-16.5%, p &lt; 0.01). The overall rate of upgrading on final pathology for MRI fusion biopsies was 5.7% lower than for TRUS biopsies, but this was not statistically significant (35.2% vs 40.9%, 95% CI: 1.5-13.0%, p=0.06). Conclusions: MRI fusion biopsies demonstrated higher concordance rates with final pathology at the time of radical prostatectomy than TRUS prostate biopsies alone.
Annals Graphic Medicine - Modern Medicine
Authors: Abey K. Thomas
Journal: Annals of Internal Medicine (2020)

Web Exclusives18 February 2020Annals Graphic Medicine - Modern MedicineFREEAbey K. Thomas, MDAbey K. Thomas, MDUT Southwestern Medical Center, Dallas, Texas (A.K.T.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G19-0022 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: UT Southwestern Medical Center, Dallas, Texas (A.K.T.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G19-0022.Author/Illustrator Information: Abey K. Thomas, MD, is an internal medicine hospitalist at University of Texas Southwestern Medical Center and a firm believer in the value of bedside medicine (e-mail: abeyk.[email protected]edu; twitter: @abeythomas). PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 18 February 2020Volume 172, Issue 4Page: W63KeywordsConflicts of interestDisclosureHealth careHospitalists ePublished: 18 February 2020 Issue Published: 18 February 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Erratum: Corrigendum: Adjuvanted influenza-H1N1 vaccination reveals lymphoid signatures of age-dependent early responses and of clinical adverse events
Authors: Olga Sobolev, Elisa Binda, Sean O'Farrell, Anna Lorenc, Joel Pradines, Yongqing Huang, Jay Duffner, Reiner Schulz, John Cason, Maria Zambon, Michael H Malim, Mark Peakman, Andrew Cope, Ishan Capila, Ganesh V Kaundinya, Adrian C Hayday
Journal: Nature Immunology (2016)
PSA status after neoadjuvant androgen deprivation therapy before high-dose-rate brachytherapy as biomarker for prediction of long-term outcome in high-risk prostate cancer patients.
Authors: Trude Wedde, Milada Cvancarova, Jonathan S. Hayman, Phuoc T. Tran, Gunnar Tafjord, Theodore L. DeWeese, Wolfgang Lilleby
Journal: Journal of Clinical Oncology (2020)

301 Background: The aim is to investigate the clinical significance of biochemical response after Androgen Deprivation Therapy (ADT) prior to high-dose-rate brachytherapy (HDR-BT) for early identification of patients at increased risk of recurrence. Measured outcomes included biochemical relapse free survival (bRFS), distant metastasis free survival (DMFS) and overall survival (OS). Methods: A total of 324 patients with high-risk Prostate Cancer (PCa) were identified in the Norwegian Radium Hospital brachytherapy database. Neo-adjuvant ADT was administered for 3-6 months, followed by two 10 Gy HDR-BT treatments to the prostate, each spaced by two weeks, followed by conformal external beam radiation to 50 Gy to the prostate gland and seminal vesicles. Total length of ADT ranged from 12 to 36 months. PSA (ng/mL) and testosterone values (T, nmol/L) after 3-6 months of neo-adjuvant ADT were measured. Kaplan Meier and Cox regression analyses were performed. Results: Median age at diagnosis was 66 years and median follow-up was 10 years. At last follow-up, 277 patients (85,2%) were alive, 10 patients (3.1%) had died of prostate cancer and 37 patients (11.4%) died of other causes. 24 patients (7.4%) had biochemical relapse and 9 patients (2.8%) had distant metastasis within the first 5 years. Patients with PSA &gt; 1 after neo-adjuvant therapy had 4.3 (95%CI 1.7 to 11.1) higher odds of biochemical relapse within 5 years compared to patients with PSA &lt; 1 (p = 0.002). ROC analysis confirmed that PSA &lt; 1 had a prediction accuracy of 0.76 (sensitivity 68% and specificity 67%). T &lt; 0.7 and PSA &lt; 1 after neo-adjuvant therapy were associated with improved bRFS, DMFS and OS (p &lt; 0.001). Neither the length of neo-adjuvant nor total ADT treatment impacted outcomes (p &gt; 0.05). Conclusions: Dose intensification with 2 HDR-BT boosts resulted in excellent survival in our cohort. PSA &gt; 1 after neo-adjuvant ADT may be able to predict patients at increased risk of relapse and worse OS and identify patients in whom increased monitoring and/or intervention is warranted. ADT &gt; 1 year did not improve outcome, indicating that shorter course of ADT may be used.
A novel multiplex score to predict outcomes of partial nephrectomy for multiple tumors.
Authors: Heather Chalfin, Nitin Yerram, Sandeep Gurram, W. Marston Linehan, Mark Wayne Ball
Journal: Journal of Clinical Oncology (2020)

656 Background: The RENAL nephrometry score (RNS) is widely used to describe renal mass complexity and inform patient counseling for partial nephrectomy (PN). However, in cases with multiple lesions (commonly seen in hereditary cancer syndromes) it is unknown which features drive postoperative complications. Here, we employed a novel scoring equation (Multiplex Score, MS) derived from RNS and assessed outcomes of multiplex PN at our institution. Methods: The MS was defined a priori as a weighted score (# low risk (LR) lesions) + 2*(# intermediate risk (IR)) + 4*(# high risk (HR)) based on published Clavien-Dindo III-V complication rates of 6.4%, 11.1%, and 21.9% for LR, IR, and HR RNS respectively. MS was dichotomized into favorable/unfavorable based on median score. Patient outcomes were maintained prospectively. Binary outcomes were evaluated with logistic regression and continuous outcomes were evaluated with linear regression. Results: From 10/2017-8/2019, 62 consecutive multiplex PN (median (range) # tumors = 4 (2-11), 65% robotic) were performed by a single surgeon. Median (range) MS was 6 (2-20). Of 13 complications, urine leak (N = 5, 8%) and bleed requiring embolization (N = 4, 6%) were the most common. Only 1 complication occurred in the favorable score group and MS was significantly associated with perioperative complication (OR 1.21, p = 0.018) and blood loss (242.42 mL, p &lt; 0.001). Hilar clamping was omitted in 32 (52%) cases with median 18.5 min when used. Every 1 additional HR or IR tumor was associated with a 2 minute increase in clamp time (2.01, p = 0.048). Median clamp time for favorable/unfavorable cases was 0 vs. 10 minutes. Change in renal function was negligible in our cohort (median ΔCr 0 mg/dL, IQR -0.61–0.1). There were no conversions from partial to radical nephrectomy and open conversion was only done in 3 (7.5%) cases, all assigned unfavorable MS. Conclusions: The novel Multiplex Score associated well with complications, blood loss, and open conversion. This tool may facilitate standardized reporting of complexity for multiplex series, with special relevance for hereditary cancer syndromes.
Factors associated with positive germline testing results in men with prostate cancer following NCCN guideline expansion.
Authors: Trevor Charles Hunt, Samantha Greenberg, Jacob P. Ambrose, Brock B. O'Neil, Jonathan David Tward
Journal: Journal of Clinical Oncology (2020)

230 Background: Pathogenic variants (PV) in genes associated with hereditary cancer risk account for over 10% of cases in men with metastatic prostate cancer (PCa). NCCN guidelines encouraging germline testing (GT) in metastatic PCa were recently expanded to include all men with high risk, very high risk, or regional PCa. Previously, we showed that the rate of PV findings did not significantly decrease after expansion of these criteria. In this study, we sought to identify factors associated with a PV finding. Methods: Men with PCa underwent multi-gene GT for PVs from April 2016 – December 2018 according to NCCN guidelines pre- (2016-17) and post-expansion (2018). The association of patient-level factors of interest with a positive GT result, where at least one PV was identified, was modeled with univariate logistic regression while overall model significance was validated with ANOVA. Results: Of 410 men undergoing GT, 44 (10.7%) positive and 366 (89.3%) negative tests resulted. Mean age at diagnosis was 62.2 years. Positive testing remained stable from 9.4% to 11.2% following guideline expansion (p=0.62). None of the patient-level factors of interest were significantly associated with increased odds of a positive GT result in any model generated. These factors included age at diagnosis, race, pretreatment PSA, Gleason grade group, NCCN risk group, and family history of cancer (breast and ovarian, prostate, any cancer). Model p-values ranged from 0.84 for Gleason grade group to 0.12 for family history of any cancer. Conclusions: Future work will need to further elucidate the role of patient-level factors in identifying men with PCa at increased risk for harboring a germline PV. Nonetheless, the lack of identification of other factors associated with positive GT results and a stable PV detection rate of roughly 10% support the recent expansion of NCCN testing guidelines. Given these findings, consideration of even broader NCCN criteria for GT may be justified.
Regulating rs2278414 (G/A) disease-associated SNP in ZNF350 3’UTR by miR-150-5p: A step towards personalised therapy in breast cancer
Authors: E.H. Fouad, R.A. Youness, R.A. Assal, M.Z. Gad
Journal: Annals of Oncology (2018)

Background: BRCA1/2 germline mutations accompanied by somatic mutations in p53 associated genes are associated with increased risk of developing breast cancer (BC). Genes acting upstream of p53, or participating in growth arrest following DNA damage such as the BRCA1-interacting protein, ZNF350, may modify the risk of BC in women with mutant BRCA1/2 through mediating BRCA1-induced transcriptional repression of several tumor suppressor genes. As a potential BC susceptibility gene, single nucleotide polymorphisms (SNPs) may influence transcriptional repression of ZNF350 target genes and individuals' BC risk. Moreover, rs2278414 (G/A) SNP in ZNF350 3'UTR was associated with BC onset in BRCA1/2 carriers ("A" allele hazard ratio= 2.47). We aimed at regulating rs2278414 SNP in ZNF350 by miRNAs in BC as it has never been investigated in such context. Methods: In-silico analysis predicted miRNAs targeting ZNF350. Wild-type constructs containing "A" allele or ancestral "G" allele of rs2278414 SNP in ZNF350 3′UTR were designed. miR-target binding regions were inserted downstream to luciferase reporter gene in pmirGLO Luciferase microRNA Target Expression Vector. MDA-MB-231 BC cells were transfected with empty pmiRGLO vector (control), or constructs with "A" or "G" SNP, or a construct with mutant target region (deleted binding region to ensure site-specific binding). After 24h, cells were co-transfected with miR-150-5p. Relative luciferase activity was measured after 48h by Steady-Glo Luciferase Reporter Assay. Wound-healing and colony forming assays were performed for miR-150-5p in MDA-MB-231. Results: Using bioinformatics software (http://www.bioguo.org/miRNASNP/ and http://mirdsnp.ccr.buffalo.edu/search.php), miR-150-5p was predicted to regulate rs2278414 "A" allele, but not "G" allele, in ZNF350 3'UTR with high score. Functionally, miR-150-5p downregulated the risk-associated "A" allele but failed to repress the ancestral protective "G" allele. Functional analysis of miRNA-150-5p showed a significant decrease in MDA-MB-231 cells' wound closure and clonogenicity. Conclusions: The novel tumor suppressor miR-150-5p downregulates rs2278414 "A" allele in ZNF350 3'UTR thus decreasing BC risk. Legal entity responsible for the study: German University in Cairo. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Efficacy of immune checkpoint inhibitors (ICI) treatment in special populations of metastatic renal cell carcinoma (mRCC).
Authors: Daniel Vilarim Araujo, Eoghan Ruadh Malone, Adrian G. Sacher, Nazanin Fallah-Rad, Srikala S. Sridhar, Aaron Richard Hansen
Journal: Journal of Clinical Oncology (2020)

673 Background: Immunotherapies involving a PD-1/PD-L1 immune-checkpoint inhibitor (ICI) are highly effective treatments for mRCC and are now standard of care. Nevertheless, special populations such as patients (pts) with renal impairment (RI) and elderly age were either excluded or underrepresented in registration trials. Here we investigate the efficacy of ICI in mRCC with RI and age above 70 years (yrs). Methods: We utilized the mRCC Princess Margaret database to select pts treated with an ICI agent from May 2005 to May 2018. Renal impairment (RI) was defined as a baseline creatinine &gt; 1.5 ULN or clearance of creatinine &lt; 40 mL/min. Pts were classified as elderly if their age was over 70yrs at the time of ICI initiation. Descriptive statistics and survival analysis were performed. Results: Of 387 pts, 74 received an ICI agent or combination. Mean age was 61yrs and median creatinine was 105 umol/L. Fifty-four pts (73%) were treated with single agent PD-1/PD-L1 ICI and 46 (62%) received treatment as 2nd line. Respectively, 19 (26%), 43 (58%) and 12 (16%) pts were classified as International Metastatic RCC Database Criteria (IMDC) prognostic groups good, intermediate and poor. Of 73 pts with available creatinine levels, 7 (9.5%) were classified as having RI. Ten pts (13.5%) were &gt; 70yrs. Despite not statistically different, pts with RI had worse median overall survival (OS) compared to pts without RI: 7.8 months (m) vs. 28.3m (p=.10). There was no OS difference between pts &gt; 70yrs compared to ≤ 70yrs: not reached (NR) vs. 28m (p=.65). Both RI and elderly patients had no differences in distribution of IMDC prognostic groups compared controls. Conclusions: RI was associated with a non-statistical detriment in OS of mRCC treated with ICI. RI may be a surrogate for comorbid factors that impact OS and needs further analysis in a larger patient sample. Age does not affect ICI efficacy in our cohort. Larger studies to confirm our findings in these special populations are necessary.
5-alpha reductase inhibitors (5-ARI) and prostate cancer mortality among men with regular access to screening and health care.
Authors: Lorelei A. Mucci, Claire Hampton Pernar, Emily Rencsok, Konrad H. Stopsack, Sydney Grob, Edward L. Giovannucci, Aria F Olumi, Adam S. Kibel, Mark A. Preston, Kathryn M. Wilson
Journal: Journal of Clinical Oncology (2020)

39 Background: The excess risk of high-grade prostate cancer in the Prostate Cancer Prevention Trial (PCPT) among men randomized to finasteride raised concerns that a chemoprevention benefit would be offset by increased mortality. Two 2019 publications had contrasting results whether 5-ARIs increased prostate cancer mortality. In PCPT, there was no excess prostate cancer mortality. In a VA study, 5-ARI use was associated with later stage at diagnosis and 39% higher prostate cancer mortality risk. We studied men with regular access to health care and screening to address this conflicting evidence. Methods: We performed two parallel analyses in the Health Professionals Follow-up Study. 5-ARI use was reported on biennial questionnaires starting in 1996. In line with PCPT, we studied 38,047 men for cancer incidence and mortality through 2016. In line with the VA study, we undertook a case-only study of 4,225 patients with localized/locally advanced cancers followed similarly. We estimated hazard ratios (HR) and 95% confidence intervals accounting for screening patterns, lifestyle factors, and concomitant medications. Results: 5-ARI ever-users (n = 4,101; 10.7%) were more likely to have had regular PSA screening (74% vs. 57% nonusers) and a negative prostate biopsy before diagnosis. Neither ever 5-ARI use (HR 1.08, 0.73-1.60, 445 events) nor long-term use ( &gt; 4 years, HR 1.03, 1.03-2.02) were associated with lethal prostate cancer. There was no difference in stage. Diagnostic PSA levels were lower in 5-ARIs users (10.0 vs. 16.0 ng/ml in never-users). Among nonmetastatic cases, 278 men died of prostate cancer; there was no association between 5-ARIs and prostate cancer survival (HR 0.85, 0.51-1.43). Conclusions: Our results align with PCPT and show no excess risk of lethal prostate cancer, no higher stage at diagnosis, and no excess mortality after diagnosis associated with 5-ARI. Men on 5-ARIs had more interactions with health care, which may have led to higher quality care. This contrasts with the VA study where men on 5-ARIs were diagnosed later due to suppressed PSA and had worse survival. These results show the importance of real-world data in framing the benefits and risks associated with 5-ARIs.
Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling
Authors: Austin Hsu, Qiming Duan, Sarah McMahon, Yu Huang, Sarah A.B. Wood, Nathanael S. Gray, Biao Wang, Benoit G. Bruneau, Saptarsi M. Haldar
Journal: Journal of Clinical Investigation (2020)

Salt-inducible kinases (SIKs) are key regulators of cellular metabolism and growth, but their role in cardiomyocyte plasticity and heart failure pathogenesis remains unknown. Here, we showed that loss of SIK1 kinase activity protected against adverse cardiac remodeling and heart failure pathogenesis in rodent models and cardiomyocytes derived from human induced pluripotent stem cells. We found that SIK1 phosphorylated and stabilized histone deacetylase 7 (HDAC7) protein during cardiac stress, an event that is required for pathologic cardiomyocyte remodeling. Gain- and loss-of-function studies of HDAC7 in cultured cardiomyocytes implicated HDAC7 as a prohypertrophic signaling effector that can induce c-Myc expression, indicating a functional departure from the canonical MEF2 corepressor function of class IIa HDACs. Taken together, our findings reveal what we believe to be a previously unrecognized role for a SIK1/HDAC7 axis in regulating cardiac stress responses and implicate this pathway as a potential target in human heart failure.
Safe nanoengineering and incorporation of transplant populations in a neurosurgical grade biomaterial, DuraGen PlusTM, for protected cell therapy applications
Authors: Louise Finch, Sarah Harris, Georgios Solomou, Jon Sen, Nikolaos Tzerakis, Richard D. Emes, Catherine S. Lane, Sarah R. Hart, Christopher F. Adams, Divya M. Chari
Journal: Journal of Controlled Release (2020)