tbuckley/cabot-search huggingface dataset:
A Variant of a Killer Cell Immunoglobulin-like Receptor Is Associated with Resistance to PD-1 Blockade in Lung Cancer
Authors: Marcel P. Trefny, Sacha I. Rothschild, Franziska Uhlenbrock, Dietmar Rieder, Benjamin Kasenda, Michal A. Stanczak, Fiamma Berner, Abhishek S. Kashyap, Monika Kaiser, Petra Herzig, Severin Poechtrager, Daniela S. Thommen, Florian Geier, Spasenija Savic, Philip Jermann, Ilaria Alborelli, Stefan Schaub, Frank Stenner, Martin Früh, Zlatko Trajanoski, Lukas Flatz, Kirsten D. Mertz, Alfred Zippelius, Heinz Läubli
Journal: Clinical Cancer Research (2019)

Abstract Purpose: PD-(L)1–blocking antibodies have clinical activity in metastatic non–small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade. Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. Experimental Design: Peripheral blood mononuclear cells were collected from 35 patients with NSCLC receiving nivolumab monotherapy. Cellular changes, cytokine levels, gene expression, and polymorphisms were compared between responders and nonresponders to treatment. Findings were confirmed in additional cohorts of patients with NSCLC receiving immune checkpoint blockade. Results: We identified a genetic variant of a killer cell immunoglobulin-like receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in patients with NSCLC. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients, the progression-free survival was significantly associated with presence of the KIR3DS1 allele (HR, 1.72; 95% confidence interval, 1.10–2.68; P = 0.017). No relationship was seen in cohorts of patients with NSCLC who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be due to NK-cell dysfunction. Conclusions: We identified an association of the KIR3DS1 allelic variant with response to PD-1–targeted immunotherapy in patients with NSCLC. This finding links NK cells with response to PD-1 therapy. Although the findings are interesting, a larger analysis in a randomized trial will be needed to confirm KIRs as predictive markers for response to PD-1–targeted immunotherapy.
Azacitidine and Ascorbate Inhibit the Competitive Outgrowth of Human TET2 Mutant HSPCs in a Xenograft Model of Pre-Leukemia
Authors: Yusuke Nakauchi, Daniel Thomas, Rajiv Sharma, M. Ryan Corces, Andreas Reinisch, David Cruz, Thomas Koehnke, Daiki Karigane, Amy Fan, Ravindra Majeti
Journal: Blood (2018)
A Novel Recombinant Human Thrombopoietin Therapy for Promoting Platelet Engraftment in Haematological Malignancies after Single Umbilical Cord Blood Transplantation: A Prospective Randomized Controlled Trial
Authors: Xiaoyu Zhu, Lulu Huang, Baolin Tang, Kaidi Song, Xuhan Zhang, Huilan Liu, Xiang Wan, Wen Yao, Juan Tong, Lei Zhang, Guangyu Sun, Zimin Sun
Journal: Blood (2018)
Pharmacogenomics-guided chemotherapy and supportive care for patients with metastatic colorectal cancer.
Authors: Pashtoon Murtaza Kasi, Tyler Koep, Candice Baldeo, Erica Schnettler, Saivaishnavi Kamatham, Faisal Shahjehan, Caren Hughes
Journal: Journal of Clinical Oncology (2019)

703 Background: In metastatic colorectal cancer (CRC), pharmacogenomics (PGx) testing presents a unique opportunity to improve outcomes since the genes DPYD &amp; UGT1A1 encoding the enzymes metabolizing the chemotherapy drugs, 5-fluorouracil and irinotecan, are already well known. In the TRIBE clinical trial, proportion of patients with serious adverse events (SAEs) was higher in those with DPYD/UGT1A1 aberrations and were dose dependent. Critical barrier has been integration into clinical practice. We aimed to report on the feasibility and results of incorporating PGx testing into clinical practice. Methods: As a quality improvement initiative, we integrated the use of OneOme RightMed comprehensive test through funding from our center of individualized medicine, which reports on 28 genes and over 350 medications of interest. Pharmacists provided dosage recommendations based on test results real-time. Results: 126 patients have had the PGx testing since November 2017. Results have been available within 3-5 days. The table outlines the analyzed results thus far of variants in UGT1A1 and the DPYD-genes alongside the CYP450 genes. Of these, 59% had a DPYD/UGT1A1 aberration and 100% had at least one actionable aberration related to supportive care medications from all possible medications listed on their PGx report. Conclusions: Preemptive comprehensive PGx testing can be integrated into clinical practice in real-time for cancer patients. This sets the stage for a prospective randomized clinical trial to demonstrate the amount of benefit this can result in these patients. [Table: see text]
Efficacy of Bortezomib Based Regimens and Disease Monitoring in Light Chain Multiple Myeloma: A Review of Literature
Authors: Mustafa Nadeem Malik, Abdul Rafae, Shehroz Aslam, Rida Riaz, Seren Durer, Ceren Durer, Muhammad Abu Zar, Zunairah Shah, Ahmad Kamal, Anum Qureshi, Jemin Aby Jose, Insija Ilyas Selene, Faiza Jamil, Madeeha Shafqat, Faiz Anwer
Journal: Blood (2018)
Use of Prescription Opioids and Initiation of Fatal 2-Vehicle Crashes
Authors: Stanford Chihuri, Guohua Li
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The prevalence of prescription opioids detected in fatally injured drivers has increased markedly in the past 2 decades in the United States. It is unclear whether driver use of prescription opioids plays a role in fatal crash causation. <h3>Objective</h3> To assess the association between driver use of prescription opioids and the risk of being culpable of crash initiation in fatal 2-vehicle crashes. <h3>Design, Setting, and Participants</h3> This pair-matched study was based on data from the Fatality Analysis Reporting System for drivers involved in fatal 2-vehicle crashes on US public roads between January 1, 1993, and December 31, 2016. Data analysis was conducted from December 8, 2017, to December 7, 2018. <h3>Exposures</h3> Testing positive for prescription opioids compared with testing negative, and blood alcohol concentrations (BACs) based on toxicological testing results. <h3>Main Outcomes and Measures</h3> Culpability of crash initiation and adjusted odds ratios and 95% CIs. <h3>Results</h3> A total of 36 642 drivers involved in 18 321 fatal 2-vehicle crashes were included. The most common driving error leading to fatal 2-vehicle crashes was failure to keep in lane (7535 [41%]). Drivers culpable of initiating the crashes were more likely than their nonculpable counterparts to test positive for prescription opioids (918 [5.0%] vs 549 [3.0%];<i>P</i> &lt; .001), alcohol (BAC ≥0.01 g/dL, 5258 [28.7%] vs 1815 [9.9%];<i>P</i> &lt; .001), and both substances (1.0% vs 0.3%,<i>P</i> &lt; .001). The adjusted odds ratio of crash initiation was 2.18 (95% CI, 1.91-2.48) for drivers testing positive for prescription opioids compared with drivers testing negative, and increased with BACs (BAC 0.01-0.07 g/dL: adjusted odds ratio, 1.97; 95% CI, 1.75-2.22; BAC ≥0.08 g/dL: adjusted odds ratio, 8.20; 95% CI, 7.42-9.07; compared with BAC &lt;0.01 g/dL). There was no significant interaction effect on crash initiation between prescription opioid use and alcohol use. <h3>Conclusions and Relevance</h3> Driver use of prescription opioids was associated with initiation of 2-vehicle crashes, independent of alcohol use. Clinicians should take into consideration the adverse effect of opioid analgesics on driving safety while prescribing these medications and counseling patients.
Inhibition of C3 with APL-2 Results in Normalisation of Markers of Intravascular and Extravascular Hemolysis in Patients with Autoimmune Hemolytic Anemia (AIHA)
Authors: Federico Grossi, Merrill Kingman Shum, Morie A. Gertz, Eloy Roman, Pascal Deschatelets, Mohamed Hamdani, Frank Stout, Cedric G Francois
Journal: Blood (2018)
New airway device as good as tracheal tube insertion for out-of-hospital resuscitation
Authors: Rob Cook, Vaughan Thomas, Rosie Martin
Journal: BMJ (2019)

The study Effect of a strategy of a supraglottic airway device versus tracheal intubation during out-of-hospital cardiac arrest on functional outcome: the AIRWAYS-2 randomised clinical trial Benger JR, Kirby K, Black S, Brett SJ, Clout M, Lazaroo MJ, Nolan JP, Reeves BC, Robinson M, Scott LJ, Smartt H, South A, Stokes EA, Taylor J, Thomas M, Voss S, Wordsworth S, Rogers CA Published on 28 August 2018 JAMA 2018;320:779-91 This study was funded by the National Institute for Health Research Health Technology Assessment Programme (project number 12/167/102). To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000686/new-airway-device-as-good-as-tracheal-tube-for-resuscitation-out-of-hospita
Abstract 12197: Increased Angiotensin II Sensitivity Contributes to Microvascular Endothelial Dysfunction in Women Who Have Had Preeclampsia
Authors: Anna E Stanhewicz, Lakshmi Santhanam, Lacy M Alexander
Journal: Circulation (2016)

Introduction: Women with a history of preeclampsia have increased cardiovascular disease risk, however the mechanisms responsible for this association remain unclear. Microvascular damage sustained during a preeclamptic pregnancy may persist post-partum. The putative mechanisms mediating this dysfunction include a reduction in nitric oxide (NO)-dependent dilation, and an increased sensitivity to angiotensin II (ang II). In this study, we evaluated endothelium-dependent dilation, ang II sensitivity, and the therapeutic effect of ang II receptor blockade (losartan) on endothelium-dependent dilation in vivo in the microvasculature of women with a history of preeclampsia (PrEC, n=7) and control women who had a healthy pregnancy (HC, n=9). We hypothesized that PrEC would have 1) reduced endothelium-dependent dilation, 2) reduced NO-mediated dilation, and 3) increased sensitivity to ang II. We further hypothesized that losartan would increase endothelium-dependent dilation in PrEC. Methods: We assessed microvascular function by measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (ACh; 10 -10 -10 -1 M) and ang II (10 -20 -10 -4 M); and during ACh co-infusion with 15mM L-NAME (NO-synthase inhibitor) or 43μM losartan. Results: ACh-induced vasodilation was attenuated in PrEC compared to HC (PrEC -3.3±0.2 vs. HC -4.7±0.1 logEC50; p&lt;0.05). There was no difference between PrEC and HC during ACh co-infusion with L-NAME (PrEC -4.4±0.2 vs. HC -4.6±0.2 logEC50; NS). NO-mediated dilation was attenuated in PrEC compared to HC (PrEC 10±4 vs. HC 35±4%; p&lt;0.01). PrEC had a greater vasoconstriction response to ang II (PrEC -11.8±0.2 vs. HC -9.7±0.2 logEC50; p&lt;0.05. Losartan co-infusion improved the vasodilation response to ACh in PrEC (losartan -4.6±0.2 vs. ACh alone -3.3±0.2 logEC50; NS). Conclusions: These findings suggest that women who have had preeclampsia have impaired endothelium-dependent vasodilation which is mediated, in part, by reductions in NO signaling and increased sensitivity to ang II. Furthermore, losartan improved endothelium-dependent dilation, suggesting that ang II receptor blockade may have therapeutic potential to treat microvascular dysfunction in women who have had preeclampsia.
Racial disparities and treatment outcomes among patients admitted with a diagnosis of colorectal cancer: Analysis of the 2014 national inpatient sample database.
Authors: Ikponmwosa Enofe, Manoj P. Rai, Osamuyimen Osaghae
Journal: Journal of Clinical Oncology (2019)

529 Background: Colorectal cancer is the fourth most common cancer in the United states and the second most common cause of death. Despite universal advocacy for screening colonoscopies and early diagnosis, racial disparities in screening and diagnosis of colorectal cancer exist and affect patients outcomes. In this analysis we determine racial disparities and treatment outcomes for colorectal cancer treatment in the United States. Methods: We performed a retrospective analysis of the National Inpatient Sample 2014 Database (HCUP_NIS) which contains records of all hospital discharges in the United States Patients 18 years and older with a diagnosis of colorectal cancer were identified by their ICD 9 codes along with treatment they had for colorectal cancer. We then used multivariable regression to identify the effect of race on receiving a therapeutic procedure (open surgical, laparoscopic or robotic) during hospitalization and outcomes as it relates to inpatient mortality. We adjusted for patients age, sex, number of comorbidities (elixhauser comorbidity score), insurance type, and hospital level charactertistics (i.e. size, teaching status) and location (urban and rural location). Results: There were 25,749 discharge diagnosis of colorectal cancer in the United States in 2014 of which 19,300 were associated with undergoing a procedure for colorectal cancer treatment. Whites accounted for the majority of colorectal cancer admissions (65%) while blacks 11.4 %, Hispanics 8.0%, Asian/Pacific Islanders 3.2 %, and Native Americans 0.4%. Blacks had the lowest frequency of procedure related admissions and were less likely to undergo a therapeutic procedure relating to colorectal cancer treatment (67.5 vs. 76.6 OR 0.84 CI 0.75 - 0.93) compared to whites. For specific procedures, blacks (OR 0.81, CI 0.72-0.91) and Hispanics (OR 0.85, CI 0.74-0.98) had a significantly lesser odds of undergoing open surgical procedures when compared to whites but were similarly likely (Blacks OR 0.93, CI 0.81-1.05, Hispanics OR 0.84, CI 0.61-1.14) to undergo laparoscopic/robotic surgical procedure. On multivariable analysis, Asian/Pacific Islanders had a significantly higher mortality (OR 1.61 CI 1.01-2.60) for non-procedure related colorectal cancer admissions. However, this increase mortality was not seen in procedure related colorectal cancer admissions. Overall, after adjusting for potential confounders and treatment, there was no significant variation amongst different races for colorectal cancer mortality in patients admitted to the hospital. Conclusions: Among patients with colorectal cancer there was no procedure related mortality differences between various races. However, for some reason Asian/Pacific Islanders had a significantly higher mortality for non-procedure related colorectal cancer admissions. Further studies are warranted to understand the above findings.
Antibiotics for Ceftriaxone-Resistant Gram-Negative Bacterial Bloodstream Infections
Authors: Jesús Rodríguez-Baño, Belén Gutiérrez-Gutiérrez, Gunnar Kahlmeter
Journal: JAMA (2019)

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Abstract 313: Sphingosine-1-Phosphate and RhoA Signaling Regulate Dynamin-Related Protein 1 and Cardiac Mitochondrial Fission
Authors: Cameron S Brand, Valerie P Tan, Joan H Brown, Shigeki Miyamoto
Journal: Circulation Research (2017)

In cardiomyocytes, signaling through RhoA is protective against ischemia/reperfusion injury. Cardioprotective receptor agonists such as sphingosine-1-phosphate (S1P) provide protection through RhoA activation. Mitochondrial fission has been suggested to play a role in cardioprotection, allowing for selective degradation of smaller damaged mitochondria. Our previous studies showed that RhoA signaling can protect cardiomyocytes against ischemia/reperfusion injury by blocking mitochondrial death pathways under oxidative stress, however it is not known if RhoA activation also regulates mitochondrial quality control. We tested the possibility that activated RhoA regulates cardiac mitochondrial fission. Adenoviral expression of constitutively active RhoA in cardiomyocytes caused an increase in small, fragmented mitochondria observed by both fluorescent confocal microscopy and electron microscopy. This mitochondrial fission phenotype was attenuated by inhibition of the downstream RhoA target Rho-associated Protein Kinase (ROCK), or by siRNA knockdown of the primary fission protein Dynamin-related Protein 1 (Drp1). Activated Drp1 causes mitochondrial fission when it translocates from the cytosol to the mitochondria, a process regulated by Drp1 phosphorylation. We determined that expression of active RhoA in cardiomyocytes stimulated phosphorylation of Drp1 at serine-616, and increased mitochondrial levels of Drp1. Both phosphorylation and mitochondrial translocation of Drp1 by active RhoA could be blocked by ROCK inhibition. Endogenous RhoA activation by S1P also increased Drp1 phosphorylation and mitochondrial translocation in a RhoA-dependent and ROCK-dependent mechanism. In conclusion, RhoA activation in cardiomyocytes can increase Drp1 phosphorylation and Drp1 mitochondrial localization, and induce mitochondrial fission. We propose that mitochondrial fission, elicited in response to increased availability of S1P and activation of RhoA in response to ischemia/reperfusion injury, represents a previously unknown pathway for cardioprotection.
Squamous cell carcinoma of the rectum: Practice trends and patient survival.
Authors: Sunil W Dutta, Clayton E Alonso, Mark Raymond Waddle, Shiv R. Khandelwal, Einsley-Marie Janowski, Daniel Michael Trifiletti
Journal: Journal of Clinical Oncology (2019)

625 Background: Leverage the National Cancer Database (NCDB) to evaluate trends in management of squamous cell cancer (SCC) of the rectum and their effect on survival for this uncommon tumor. Methods: Data was obtained from the NCDB for patients diagnosed with SCC of the rectum between 2004 and 2014, including cT1-4, cN0-2, cM0 (cohort A, n = 2,296) tumors. A subgroup analysis was performed on locally advanced tumors (cT1-T2, N+ or cT3, N any, subcohort B, n = 883), treated with chemoradiation (n = 706) or trimodality therapy (n = 177) including chemotherapy, radiation, and surgery. Pathological complete response rate following neoadjuvant therapy was obtained. Univariate and multivariate logistic regression analyses were performed to generate hazard ratios (HR) investigating factors associated with overall survival. Kaplan-Meier (K-M) method was used to estimate overall surviving proportion at 5 and 10 years. Results: The median age was 60 years with a strong female predilection (71% female). Among patients treated with neoadjuvant therapy, 36% achieved a complete pathological response at a median interval of 67 days from completion of radiation therapy to surgery. The K-M estimated 5 and 10 year overall survival for stage I disease was 71.3% and 57.8%, respectively; stage II disease was 57.0% and 38.9%, respectively; stage III disease was 57.8% and 41.5%, respectively. On multivariate analysis, increased age, male gender, more co-morbidities, and higher cT category ( P &lt; 0.001 for each) resulted in worse survival. For locally advanced tumors (subcohort B), there was no difference in survival between chemoradiation alone compared to trimodality therapy ( P = 0.909 on multivariate analysis). Conclusions: Most providers manage locally advanced SCC of the rectum similar to anal cancer, which results in equivalent overall survival and spares patients from the additional morbidity associated with surgical resection. [Table: see text]
Frailty and Changes in Cognitive Function after Kidney Transplantation
Authors: Nadia M. Chu, Alden L. Gross, Ashton A. Shaffer, Christine E. Haugen, Silas P. Norman, Qian-Li Xue, A. Richey Sharrett, Michelle C. Carlson, Karen Bandeen-Roche, Dorry L. Segev, Mara A. McAdams-DeMarco
Journal: Journal of the American Society of Nephrology (2019)

Background Restoration of kidney function after kidney transplant generally improves cognitive function. It is unclear whether frail recipients, with higher susceptibility to surgical stressors, achieve such post-transplant cognitive improvements or whether they experience subsequent cognitive decline as they age with a functioning graft. Methods In this two-center cohort study, we assessed pretransplant frailty (Fried physical frailty phenotype) and cognitive function (Modified Mini-Mental State Examination) in adult kidney transplant recipients. To investigate potential short- and medium-term effects of frailty on post-transplant cognitive trajectories, we measured cognitive function up to 4 years post-transplant. Using an adjusted mixed effects model with a random slope (time) and intercept (person), we characterized post-transplant cognitive trajectories by pretransplant frailty, accounting for nonlinear trajectories. Results Of 665 recipients (mean age 52.0 years) followed for a median of 1.5 years, 15.0% were frail. After adjustment, pretransplant cognitive scores were significantly lower among frail patients compared with nonfrail patients (89.0 versus 90.8 points). By 3 months post-transplant, cognitive performance improved for both frail (slope =0.22 points per week) and nonfrail (slope =0.14 points per week) recipients. Between 1 and 4 years post-transplant, improvements plateaued among nonfrail recipients (slope =0.005 points per week), whereas cognitive function declined among frail recipients (slope =−0.04 points per week). At 4 years post-transplant, cognitive scores were 5.8 points lower for frail recipients compared with nonfrail recipients. Conclusions On average, both frail and nonfrail recipients experience short-term cognitive improvement post-transplant. However, frailty is associated with medium-term cognitive decline post-transplant. Interventions to prevent cognitive decline among frail recipients should be identified.
Prognostic Impact of Blood <i>MN1</i> Copy Numbers Before Allogeneic Stem Cell Transplantation in Patients With Acute Myeloid Leukemia
Authors: Madlen Jentzsch, Marius Bill, Juliane Grimm, Julia Schulz, Stefanie Beinicke, Janine Häntschel, Karoline Goldmann, Wolfram Pönisch, Georg‐Nikolaus Franke, Vladan Vucinic, Michael Cross, Gerhard Behre, Thoralf Lange, Dietger Niederwieser, Sebastian Schwind
Journal: HemaSphere (2019)

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