tbuckley/cabot-search huggingface dataset:
Premature Mortality of 2050 High Bike Use Scenarios in 17 Countries
Authors: Julen Egiguren, M.J. Nieuwenhuijsen, David Rojas-Rueda
Journal: Environmental Health Perspectives (2021)

Biking plays a significant role in urban mobility and has been suggested as a tool to promote public health. A recent study has proposed 2050 global biking scenarios based on large shifts from motorized vehicles to bikes. No previous studies have estimated the health impacts of global cycling scenarios, either future car-bike shift substitutions.We aimed to quantify changes in premature mortality of 2050 global biking scenarios in urban populations from 17 countries.Through a quantitative Health Impact Assessment, the mortality risks and benefits of replacing car trips by bike (mechanica bike and electric bike) in urban populations from 17 countries were estimated. Multiple bike scenarios were created based on current transport trends or large shifts from car trips to bike trips. We quantified the estimated change in the number of premature deaths (reduced or increased) concerning road traffic fatalities, air pollution, and physical activity. This study focuses on urban populations between 20 and 64 y old.We found that, among the urban populations (20-64 y old) of 17 countries, 205,424 annual premature deaths could be prevented if high bike-use scenarios are achieved by 2050 (assuming that 100% of bike trips replace car trips). If only 8% of bike trips replace car trips in a more conservative scenario, 18,589 annual premature deaths could be prevented by 2050 in the same population. In all the countries and scenarios, the mortality benefits related to bike use (rather than car use) outweighed the mortality risks.We found that global biking policies may provide important mortality benefits in 2050. Current and future bike- vs. car-trip policies should be considered key public health interventions for a healthy urban design. https://doi.org/10.1289/EHP9073.
Humoral Responses Against SARS-CoV-2 and Variants of Concern After mRNA Vaccines in Patients With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia
Authors: Andres Chang, Akil Akhtar, Susanne L. Linderman, Lilin Lai, Victor M. Orellana-Noia, Rajesh Valanparambil, Hasan Ahmed, Veronika I. Zarnitsyna, Ashley A. McCook-Veal, Jeffrey M. Switchenko, Jean L. Koff, Kristie A. Blum, Amy A. Ayers, Colin B. O'Leary, Michael C. Churnetski, Shahana Sulaiman, Melissa Kives, Preston Sheng, Carl W. Davis, Ajay K. Nooka, Rustom Antia, Madhav V. Dhodapkar, Mehul S. Suthar, Jonathon B. Cohen, Rafi Ahmed
Journal: Journal of Clinical Oncology (2022)

Patients with non-Hodgkin lymphoma including chronic lymphocytic leukemia (NHL/CLL) are at higher risk of severe SARS-CoV-2 infection. We investigated vaccine-induced antibody responses in patients with NHL/CLL against the original SARS-CoV-2 strain and variants of concern including B.1.167.2 (Delta) and B.1.1.529 (Omicron).
HIP1R and vimentin immunohistochemistry predict 1p/19q status in IDH-mutant glioma
Authors: Marius Felix, Dennis Friedel, Ashok Kumar Jayavelu, Katharina Filipski, Annekathrin Reinhardt, Uwe Warnken, Damian Stichel, Daniel Schrimpf, Andrey Korshunov, Yueting Wang, Tobias Kessler, Nima Etminan, Andreas Unterberg, Christel Herold-Mende, Laura Heikaus, Felix Sahm, Wolfgang Wick, Patrick N Harter, Andreas von Deimling, David E Reuss
Journal: Neuro-Oncology (2022)

IDH-mutant gliomas are separate based on the codeletion of the chromosomal arms 1p and 19q into oligodendrogliomas IDH-mutant 1p/19q-codeleted and astrocytomas IDH-mutant. While nuclear loss of ATRX expression excludes 1p/19q codeletion, its limited sensitivity prohibits to conclude on 1p/19q status in tumors with retained nuclear ATRX expression.Employing mass spectrometry based proteomic analysis in a discovery series containing 35 fresh frozen and 72 formalin fixed and paraffin embedded tumors with established IDH and 1p/19q status, potential biomarkers were discovered. Subsequent validation immunohistochemistry was conducted on two independent series (together 77 oligodendrogliomas IDH-mutant 1p/19q-codeleted and 92 astrocytomas IDH-mutant).We detected highly specific protein patterns distinguishing oligodendroglioma and astrocytoma. In these patterns, high HIP1R and low vimentin levels were observed in oligodendroglioma while low HIP1R and high vimentin levels occurred in astrocytoma. Immunohistochemistry for HIP1R and vimentin expression in 35 cases from the FFPE discovery series confirmed these findings. Blinded evaluation of the validation cohorts predicted the 1p/19q status with a positive and negative predictive value as well as an accuracy of 100% in the first cohort and with a positive predictive value of 83%; negative predictive value of 100% and an accuracy of 92% in the second cohort. Nuclear ATRX loss as marker for astrocytoma increased the sensitivity to 96% and the specificity to 100%.We demonstrate that immunohistochemistry for HIP1R, vimentin, and ATRX predict 1p/19q status with 100% specificity and 95% sensitivity and therefore, constitutes a simple and inexpensive approach to the classification of IDH-mutant glioma.
Tailored immunotherapy approach with nivolumab in advanced transitional cell carcinoma (TITAN-TCC).
Authors: Marc-Oliver Grimm, Barbara Grün, Guenter Niegisch, Martin Pichler, Florian Roghmann, Bernd Schmitz-Dräger, Gustavo Bruno Baretton, Marc Schmitz, Susan Foller, Katharina Leucht, Ulrike Schumacher, Martin Schostak, Johannes Meran, Wolfgang C. Loidl, Friedemann Zengerling
Journal: Journal of Clinical Oncology (2022)

441 Background: Nivolumab (nivo) is an approved 2 nd line treatment after platinum-based chemotherapy in metastatic urothelial carcinoma (mUC). Recent studies suggest improved outcomes for dual checkpoint inhibition in mUC in particular with higher ipilimumab (ipi) doses (nivo 1mg/kg + ipi 3mg/kg). TITAN-TCC uses a response-based approach starting with 4 doses of nivo (8 weeks) followed by nivo+ipi boosts in non-responders. Here we report cohort 2 of TITAN-TCC applying nivo1/ipi3 boost doses in patients after prior platinum-based chemotherapy (2 nd /3 rd line). Methods: Between April 2019 and February 2021 83 patients with histologically confirmed mUC (TITAN-TCC cohort 2) started with nivo 240mg Q2W induction. After 4 doses and tumor assessment at week 8 (i) non-responders (stable (SD)/ progressive disease (PD)) received 2-4 doses nivo1+ipi3 while (ii) responders (complete (CR)/ partial response (PR)) continued with nivo maintenance but could receive nivo1+ipi3 for later PD. Primary endpoint was confirmed investigator-assessed ORR per RECIST1.1. Using a Fleming single-stage phase II design 77 evaluable patients would provide a 90% power to reject the null-hypothesis that ORR was ≤20% at a one-sided 5% type I error if the true ORR was ≥35%. Secondary endpoints included activity of nivo monotherapy at week 8, remission rate with nivo+ipi boosts, progression-free survival (PFS), overall survival (OS), and safety. Results: Median follow-up time was 5.6 months. Of the patients, 78 (94%) were 2 nd line. Median age was 68 years (range 37-84) and 57 patients (69%) were male. ORR with nivo monotherapy at first assessment (week 8) was 20.5%. Of the patients, 44 and 6 received nivo+ipi boosts after week 8 and for later PD, respectively. Confirmed objective response with nivo induction ± nivo+ipi boosts was achieved in 27/83 (32.5%) of the patients (significant &gt; 20%, p &lt; 0.01). Patients with PD-L1 expression in ≥1% of tumor cells had a numerically higher ORR (46% vs. 24% for PD-L1 negatives). Of the patients with initial SD after nivo induction, 4/13 (31%) achieved response upon boost. Of the patients boosted for PD, 9/37 (24%) improved. Median PFS was 1.9 months (95% CI 1.8-3.2), median OS was 7.6 months (95% CI 5.1-14.9). No new safety signals emerged. Conclusions: In patients after prior platinum-based chemotherapy treatment with nivo and nivo+ipi boosts in non-responders significantly improved ORR compared to the one reported for nivo as 2 nd line monotherapy. Patients with PD-L1 positive tumors appear to benefit most. Our study provides further evidence for the added value of high dose (3mg/kg) ipilimumab in mUC. Clinical trial information: NCT0321977.[Table: see text]
Single-Cell RNA Sequencing Unveils the Clonal and Transcriptional Landscape of Cutaneous T-Cell Lymphomas
Authors: Alyxzandria M. Gaydosik, Connor J. Stonesifer, Alexandra E. Khaleel, Larisa J. Geskin, Patrizia Fuschiotti
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Clonal malignant T lymphocytes constitute only a fraction of T cells in mycosis fungoides skin tumors and in the leukemic blood of Sézary syndrome, the classic types of cutaneous T-cell lymphomas. However, lack of markers specific for malignant lymphocytes prevents distinguishing them from benign T cells, thus delaying diagnosis and the development of targeted treatments. Here we applied single-cell methods to assess the transcriptional profiles of both malignant T-cell clones and reactive T lymphocytes directly in mycosis fungoides/Sézary syndrome patient samples. Experimental Design: Single-cell RNA sequencing was used to profile the T-cell immune repertoire simultaneously with gene expression in CD3+ lymphocytes from mycosis fungoides and healthy skin biopsies as well as from Sézary syndrome and control blood samples. Transcriptional data were validated in additional advanced-stage mycosis fungoides/Sézary syndrome skin and blood samples by immunofluorescence microscopy. Results: Several nonoverlapping clonotypes are expanded in the skin and blood of individual advanced-stage mycosis fungoides/Sézary syndrome patient samples, including a dominant malignant clone as well as additional minor malignant and reactive clones. While we detected upregulation of patient-specific as well as mycosis fungoides– and Sézary syndrome–specific oncogenic pathways within individual malignant clones, we also detected upregulation of several common pathways that included genes associated with cancer cell metabolism, cell-cycle regulation, de novo nucleotide biosynthesis, and invasion. Conclusions: Our analysis unveils new insights into mycosis fungoides/Sézary syndrome pathogenesis by providing an unprecedented report of the transcriptional profile of malignant T-cell clones in the skin and blood of individual patients and offers novel prospective targets for personalized therapy.
Abstract 11322: Role of Centhaquine (lyfaquin <sup>®</sup> ) in the Protection of Renal Tissues After Acute Kidney Injury
Authors: Amaresh Ranjan, Seema Briyal, Zhong Zhang, Anil Gulati
Journal: Circulation (2021)

Background: Acute Kidney Injury (AKI) is frequently associated with an in-hospital complication of sepsis, heart conditions, hemorrhagic shock, and surgery. However, at present, no specific drug to treat AKI is available. Centhaquine (Lyfaquin ® ) is a safe and effective first-in-class resuscitative agent for hypovolemic shock. We are investigating whether centhaquine could protect kidneys from acute injury during hypovolemic shock. Hypothesis: AKI is known to be associated with shock-related morbidity and mortality. We hypothesize that centhaquine would have a direct effect on alleviating the AKI and reducing shock-related mortality. Methods: Renal arteries of rats were clamped and de-clamped to induce AKI like ischemia/reperfusion model, and hemorrhage was carried out by withdrawing blood for 30 min from the femoral artery. Rats were resuscitated with centhaquine (0.02 mg/kg) for 10 min. Mean Arterial Pressure (MAP), heart rate (HR), and renal blood flow (RBF) were monitored for 120 min. Results: An improved RBF (p&lt;0.003) in centhaquine compared to vehicle rats was observed after resuscitation. While MAP and HR were similar in centhaquine and vehicle groups. At 120 min post-resuscitation, significantly reduced blood lactate level (p=0.0064) in centhaquine than the vehicle was seen. Higher damage in renal tissues in the vehicle than centhaquine was observed by histopathological analysis. Western blots showed higher HIF-1α (p=0.0152) and lower NGAL (p=0.01626) levels in centhaquine vs. vehicle. While significantly higher (p&lt;0.045) expression of HIF-1α and lower expression of Bax (p&lt;0.044) in kidney cortex and medulla of centhaquine rats were observed after immunofluorescence analysis. On the other hand, expression of PHD 3 (p&lt;0.0001) was higher, while the expression of Cytochrome C (p=0.01429) was lower in the cortex of centhaquine than the vehicle. Also, the in situ PCR data showed higher mitochondrial biogenesis in centhaquine than in the vehicle. Conclusions: Centhaquine (Lyfaquin ® ) increases renal blood flow and augments hypoxia response, which probably helps reduce tissue damage and apoptosis following hemorrhagic shock induced AKI, and hence the potential of centhaquine could be explored further to prevent/treat AKI.
Abstract 10881: Graph-Based Analysis of Cardiomyocyte Network Connectivity
Authors: Alexander J Wilson, Gregory Sands, Daniel Ennis
Journal: Circulation (2021)

Introduction: Cardiomyocytes branch and interconnect with one another, allowing for mechanical and electrochemical coupling. Despite being an essential structural feature enabling coordinated contraction, analysis of this branching structure has been limited. Herein, we use graph-based methods to analyze the cardiomyocyte network structure. Hypothesis: Cardiomyocytes are fully-connected, rather than being bundled into discrete, tract-bundles. We therefore expect that the size of connected graph components will increase with graph size, rather than tending towards a constant tract-bundle size. Methods: Rodent myocardium (n = 4) was stained for collagen and imaged using extended volume confocal microscopy. A sheetlet portion was segmented (~150 cells). The centerline of each cardiomyocyte was tracked. Vertices were identified where the cell bodies of adjacent cardiomyocytes merged. From the connected network (Fig 1A), an adjacency matrix was determined and the shortest-paths between all vertices calculated. The largest component was recorded as a function of graph size. Simulated fully-connected and tract-bundle networks (Fig 1B) were then compared to cardiomyocyte networks (Fig 1C). Results: For the simulated fully-connected network, the largest component increased with graph size, while the tract-bundle network levelled-off based on tract size (Fig 1B). In the cardiomyocyte networks (Fig 1C, red squares), the largest component continued to increase with graph size. Myocardial connectivity appears to lie between a tract-bundle and fully-connected simulated networks (Fig 1C). This suggests that the myocardium tends towards being a fully-connected network, although confirmation requires a larger image volume. Conclusion: Graph-based analysis of cardiomyocyte network structure distinguished between simulated fully-connected and tract-bundle networks. Cardiomyocyte networks are more similar to the fully-connected networks.
Treating Hypertension in Pregnancy
Authors: Michael F. Greene, Winfred W. Williams
Journal: New England Journal of Medicine (2022)

The latest data from the National Center for Health Statistics indicate that in 2019 more than 83,000 pregnant women in the United States had chronic hypertension that antedated their pregnancies.1 This number represents 2.2% of the more than 3.7 million births that were recorded that year. The rate of hypertension during pregnancy has been rising inexorably over five decades in parallel with the strongly associated covariates of a maternal age of more than 35 years and the presence of overweight or obesity, factors that were present in 55.9% of women who gave birth in 2019. In addition, hypertension is more . . .
100P Physician perceptions of testing practices in patients with early and advanced stage EGFR mutation-positive (EGFRm) NSCLC: A global survey
Authors: T. Bailey, F. Moiseenko, M.S. Paats, I. Demedts, M. Erman, D.A. Kahangire, V. Kozlov, M. Mark, J. Minatta, S. Rajappa, M. Zukin, M. Madondo, A. Taylor, J. Samol
Journal: Annals of Oncology (2022)
Increasing on-treatment hepatocellular carcinoma risk with decreasing baseline viral load in HBeAg-positive chronic hepatitis B
Authors: Won-Mook Choi, Gi-Ae Kim, Jonggi Choi, Seungbong Han, Young-Suk Lim
Journal: Journal of Clinical Investigation (2022)

BACKGROUND. It is unclear whether the level of serum hepatitis B virus (HBV) DNA at baseline affects the on-treatment risk of hepatocellular carcinoma (HCC) in hepatitis B e antigen–positive (HBeAg-positive), noncirrhotic patients with chronic hepatitis B (CHB).
Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 Variants
Authors: Jingyou Yu, Ai-Ris Y Collier, Marjorie Rowe, Fatima Mardas, John D Ventura, Huahua Wan, Jessica Miller, Olivia Powers, Benjamin Chung, Mazuba Siamatu, Nicole P Hachmann, Nehalee Surve, Felix Nampanya, Abishek Chandrashekar, Dan H Barouch
Journal: New England Journal of Medicine (2022)
Alpha Globin Gene Copy Number Is Associated with Prevalent Chronic Kidney Disease and Incident End-Stage Kidney Disease among Black Americans
Authors: A. Parker Ruhl, Neal Jeffries, Yu Yang, Rakhi P. Naik, Amit Patki, Lydia H. Pecker, Bryan T. Mott, Neil A. Zakai, Cheryl A. Winkler, Jeffrey B. Kopp, Leslie A. Lange, Marguerite R. Irvin, Orlando M. Gutierrez, Mary Cushman, Hans C. Ackerman
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Resistance artery endothelial cells express α -globin, which limits nitric oxide signaling and enhances α -adrenergic–mediated vasoconstriction—two signaling pathways involved in renal blood flow regulation and kidney disease pathogenesis. A common HBA gene deletion might therefore confer protection against kidney disease by increasing endothelial nitric oxide signaling and decreasing vasoconstriction in response to α -1–adrenergic stimuli. Among Black Americans, HBA copy number varied from 2 to 6; an increase by one HBA gene copy was associated with 14% greater risk of CKD and 32% greater hazard of incident ESKD. This study identifies HBA deletions as protective against CKD and ESKD and highlights the importance of understanding the role of α -globin in renovascular pathophysiology. Background α -Globin is expressed in endothelial cells of resistance arteries, where it limits endothelial nitric oxide signaling and enhances α -adrenergic–mediated vasoconstriction. α -Globin gene ( HBA) copy number is variable in people of African descent and other populations worldwide. Given the protective effect of nitric oxide in the kidney, we hypothesized that HBA copy number would be associated with kidney disease risk. Methods Community-dwelling Black Americans aged ≥45 years old were enrolled in a national longitudinal cohort from 2003 through 2007. HBA copy number was measured using droplet digital PCR. The prevalence ratio (PR) of CKD and the relative risk (RR) of incident reduced eGFR were calculated using modified Poisson multivariable regression. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression. Results Among 9908 participants, HBA copy number varied from 2 to 6. In analyses adjusted for demographic, clinical, and genetic risk factors, a one-copy increase in HBA was associated with 14% greater prevalence of CKD (PR, 1.14; 95% CI, 1.07 to 1.21; P &lt;0.0001). While HBA copy number was not associated with incident reduced eGFR (RR, 1.06; 95% CI, 0.94 to 1.19; P =0.38), the hazard of incident ESKD was 32% higher for each additional copy of HBA (HR, 1.32; 95% CI, 1.09 to 1.61; P =0.005). Conclusions Increasing HBA copy number was associated with a greater prevalence of CKD and incidence of ESKD in a national longitudinal cohort of Black Americans.
<i>Rlf–Mycl</i> Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer
Authors: Metamia Ciampricotti, Triantafyllia Karakousi, Allison L. Richards, Àlvaro Quintanal-Villalonga, Angeliki Karatza, Rebecca Caeser, Emily A. Costa, Viola Allaj, Parvathy Manoj, Kyle B. Spainhower, Faruk E. Kombak, Francisco J. Sanchez-Rivera, Janneke E. Jaspers, Anastasia-Maria Zavitsanou, Danilo Maddalo, Andrea Ventura, William M. Rideout, Elliot H. Akama-Garren, Tyler Jacks, Mark T.A. Donoghue, Triparna Sen, Trudy G. Oliver, John T. Poirier, Thales Papagiannakopoulos, Charles M. Rudin
Journal: Cancer Discovery (2021)

Abstract Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf–Mycl-driven mouse model of SCLC. RLF–MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF–MYCL genetically engineered mouse model displayed gene expression similarities with human RLF–MYCL SCLC. Together, our studies support RLF–MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC. Significance: The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF–MYCL gene fusion by developing a Rlf–Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis. This article is highlighted in the In This Issue feature, p. 2945
Abstract P117: Association Of Ambulatory Blood Pressure Monitoring Parameters With Left Ventricular Hypertrophy: Analysis Of Pooled Population- And Community-based Studies
Authors: Swati Sakhuja, Byron C Jaeger, Yuichiro Yano, Daichi Shimbo, Cora E Lewis, Donald Clark, James M Shikany, Joseph E Schwartz, Adolfo Correa, Paul Muntner
Journal: Circulation (2022)

Objectives: Ambulatory blood pressure (BP) monitoring (ABPM) parameters beyond mean BP may be useful for identifying individuals at high risk for cardiovascular end-organ damage. We examined the association between ABPM parameters, including 24-hour BP load, peak BP, peak increase in BP, and mean BP with left ventricular hypertrophy (LVH). Methods: Data were pooled from five US-based studies in which participants underwent ABPM for 24 hours (n=2,892). We defined systolic BP (SBP) load as the weighted average of the percent awake SBP readings ≥ 130 mm Hg and asleep SBP readings ≥ 110 mm Hg; peak SBP as the weighted average of awake and asleep 90 th percentile of SBP; peak increase as the difference between the peak SBP and mean SBP. These parameters were then categorized into quartiles. LVH was assessed by 2D-echocardiography. Analyses were stratified by mean 24-hour BP &lt; 130/80 and ≥ 130/80 mm Hg. Results: Among participants with mean 24-hour BP &lt; 130/80 mm Hg, the prevalence of LVH increased from the lowest to the highest quartile for SBP load, peak SBP, peak increase in SBP, and mean SBP ( Table ). The adjusted prevalence ratio (PR) for the association of the highest versus the lowest quartile with LVH was 1.82 (95%CI: 1.08-3.05) for SBP load, 2.00 (95%CI: 1.18-3.38) for peak SBP, 1.38 (95%CI: 0.85-2.23) for peak increase in SBP, and 1.51 (95%CI: 0.98-2.32) for mean SBP. Among participants with mean 24-hour BP ≥ 130/80 mm Hg, the prevalence of LVH increased for all ABPM parameters from the lowest to the highest quartile. The multivariable-adjusted PR for the association of the highest versus the lowest quartile with LVH was 1.39 (95%CI: 0.98-1.97) for SBP load, 1.66 (95%CI: 1.09-2.53) for peak SBP, 1.08 (95%CI: 0.76-1.53) for peak increase in SBP, and 1.88 (95%CI: 1.24-2.83) for mean SBP. Conclusion: The 24-hour SBP load and peak SBP were associated with a higher prevalence of LVH when mean 24-hour BP was &lt; 130/80 mm Hg. The 24-hour peak SBP and mean SBP were associated with a higher prevalence of LVH when mean 24-hour BP was ≥ 130/80 mm Hg.