tbuckley/cabot-search huggingface dataset:
163P Anti-tumor activity of cetuximab plus avelumab in non-small cell lung cancer patients involves innate immunity activation: Findings from the CAVE-lung trial
Authors: C.M. Della Corte, M. Fasano, V. Ciaramella, F. Cimmino, R. Cardnell, C.M. Gay, K. Ramkumar, L. Diao, R. Di Liello, G. Viscardi, V. Famiglietti, D. Ciardiello, G. Martini, S. Napolitano, T. Troiani, E. Martinelli, J. Wang, L. Byers, F. Morgillo, F. Ciardiello
Journal: Annals of Oncology (2022)
<i>TP53</i> Gain-of-Function and Non–Gain-of-Function Mutations Are Differentially Associated With Sidedness-Dependent Prognosis in Metastatic Colorectal Cancer
Authors: Minggui Pan, Chen Jiang, Pam Tse, Ninah Achacoso, Stacey Alexeeff, Aleyda V. Solorzano, Elaine Chung, Wenwei Hu, Thach-Giao Truong, Amit Arora, Tilak Sundaresan, Jennifer Marie Suga, Sachdev Thomas, Laurel A. Habel
Journal: Journal of Clinical Oncology (2021)

To examine the association of gain-of-function (GOF) and non-gain-of-function (non-GOF) TP53 mutations with prognosis of metastatic right-sided (RCC) versus left-sided colorectal cancer (LCC).This cohort study included patients with metastatic colorectal cancer (CRC) who had next-generation sequencing performed from November 2017 to January 2021. We defined R175H, R248W, R248Q, R249S, R273H, R273L, and R282W as GOF and all other mutp53 as non-GOF. We used Cox regression modeling to examine the association between GOF and non-GOF mutp53 and overall survival (OS), adjusting for age, sex, ethnicity, performance status, Charlson comorbidity index and receipt of chemotherapy.Of total 1,043 patients, 735 had tumors with mutp53 and 308 had wild-type p53 (wtp53). GOF was associated with worse OS than non-GOF mutp53 only in LCC (hazard ratio [HR] = 1.66 [95% CI, 1.20 to 2.29]), but not in RCC (HR = 0.79 [95% CI, 0.49 to 1.26]). Importantly, RCC was associated with worse OS than LCC only in the subset of patients whose CRC carried non-GOF (HR = 1.76 [95% CI, 1.30 to 2.39]), but not GOF mutp53 (HR = 0.92 [95% CI, 0.55 to 1.53]) or wtp53 (HR = 0.88 [95% CI, 0.60 to 1.28]). These associations were largely unchanged after also adjusting for RAS, BRAF, and PIK3CA mutations, and microsatellite instability-high.Poorer survival of patients with metastatic RCC versus LCC appeared to be restricted to the subset with non-GOF mutp53, whereas GOF versus non-GOF mutp53 was associated with poorer survival only among patients with LCC. This approach of collectively classifying mutp53 into GOF and non-GOF provides new insight for prognostic stratification and for understanding the mechanism of sidedness-dependent prognosis. If confirmed, future CRC clinical trials may benefit from incorporating this approach.
Abstract P165: Glycemic Response To Initial Treatment In Data-driven Diabetes Clusters In A Real-world Sample Of Adults With Newly Diagnosed Diabetes
Authors: Sridharan Raghavan, Wenhui Liu, Theodore Warsavage, Lawrence Phillips, Jane E Reusch, Liron Caplan
Journal: Circulation (2022)

Diabetes patient heterogeneity is well recognized. Statistical clustering methods are gaining popularity as a precision medicine tool for identifying diabetes subgroups. We evaluated data-driven clusters among individuals with newly diagnosed diabetes and examined associations with glycemic response to initial treatment in real-world care. We studied individuals in the US Veterans Affairs Health Care System with newly diagnosed diabetes based on diagnosis codes and medications who were initially treated with a single diabetes medication from 2005-2013. We performed k -means clustering as previously described based on age, body mass index (BMI), and hemoglobin A1c (HbA1c) at the time of diabetes diagnosis. We compared 5-year glycemic response by initial medication class (metformin, sulfonylurea, or insulin) in each cluster using linear mixed effects models, adjusted for age, race, sex, BMI, glomerular filtration rate, and HbA1c, and including a medication*time term to assess medication-specific HbA1c trends. Four clusters best fit the data for the 325,250 individuals studied (mean age 63.5 years, BMI 32.7 kg/m 2 , HbA1c 7.5%). Clusters corresponded to those identified previously in other studies with three characterized by extreme values of clustering variables: Cluster 1 with mean HbA1c 11.3% (N=35,071), Cluster 2 with mean BMI 41.1 kg/m 2 (N=70,909), Cluster 3 with mean age 76.8 years (N=92,363), and Cluster 4 with intermediate values for all the three variables (N=126,907). HbA1c trends differed by medication class in all four clusters (p&lt;0.0001 for all). However, differences in HbA1c trends by medication class were clinically small in all 4 clusters (Figure). Mean HbA1c trend was lowest among metformin users, intermediate among sulfonylurea users, and highest among insulin users in all clusters. Conclusion: Data-driven clustering of individuals with newly diagnosed diabetes using routinely collected clinical variables may not help guide initial diabetes treatment choice with regard to glycemic control.
TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis
Authors: Haifeng Yin, Xiaoyun Guo, Yi Chen, Yachang Zeng, Xiaoliang Mo, Siqi Hong, Hui He, Jing Li, Rachel Steinmetz, Qinghang Liu
Journal: Journal of Clinical Investigation (2022)

Mutations in TGF-β–activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α–induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency–induced dilated cardiomyopathy.
Author's correction for Euro Surveill. 2020;25(24)
Journal: Eurosurveillance (2022)

© This work is licensed under a Creative Commons Attribution 4.0 International License. Closure This is a corrected article applying to the following content: Prevalence of SARS-CoV-2 specific neutralising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at 06 April 2020
World Health Organization global air quality guideline recommendations: Executive summary
Authors: Anna Goshua, Cezmi A. Akdis, Kari C. Nadeau
Journal: Allergy (2022)

Air pollution is a leading cause of death globally and has resulted in the loss of millions of healthy years of life. Moreover, the health burden has fallen disproportionately upon people in many low- and middle-income countries, where air quality continues to deteriorate. To assist authorities and civil society in improving air quality, World Health Organization has published the first global update to its 2005 air quality guidelines based on a significantly improved body of evidence. To facilitate the implementation of the World Health Organization Global Air Quality Guideline recommendations, this article summarizes the purpose and rationale of the quantitative air quality guidelines and interim target levels for six key pollutants: particulate matter 2.5, particulate matter 10, sulfur dioxide, nitrogen dioxide, ozone, and carbon monoxide. In addition, good practice statements are established for the management of pollutants of concern that lack sufficient evidence to substantiate numerical targets.
High<i>FGFR1–4</i>mRNA Expression Levels Correlate with Response to Selective FGFR Inhibitors in Breast Cancer
Authors: Mònica Sánchez-Guixé, Cinta Hierro, José Jiménez, Cristina Viaplana, Guillermo Villacampa, Erika Monelli, Fara Brasó-Maristany, Zighereda Ogbah, Mireia Parés, Marta Guzmán, Judit Grueso, Olga Rodríguez, Mafalda Oliveira, Analía Azaro, Elena Garralda, Josep Tabernero, Oriol Casanovas, Maurizio Scaltriti, Aleix Prat, Rodrigo Dienstmann, Paolo Nuciforo, Cristina Saura, Mariona Graupera, Ana Vivancos, Jordi Rodon, Violeta Serra
Journal: Clinical Cancer Research (2021)

FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively.Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient-derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.High FGFR1-4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1-4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1-4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs.Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1-4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.
Abstract P155: Differential Incidence Trends In Non-traumatic Lower Limb Amputations In The Province Of Quebec, Canada: Does The Reduction Applies Equally In Both Sexes?
Authors: Sarah OConnor, Claudia Blais, Elhadji Anassour Laouan Sidi, Jacinthe Leclerc, Paul Poirier
Journal: Circulation (2022)

Introduction: Non-traumatic lower limb amputations (LLA) represent an important complication of diabetes (DM) and peripheral arterial disease (PAD). In Quebec, Canada, the latest data between 1996 to 2004 suggested a reduction in the incidence of LLA while other Canadian provinces observed a recent increase between 2010 and 2016. Our objective was to update the incidence trends of LLA in Quebec from fiscal years 2006 to 2019. Methods: Age-standardized incidence of LLA among individuals ≥40 years was assessed using the Quebec Integrated Chronic Disease Surveillance System (n=4,527,533 in 2019). The mean age of incident cases and the presence / duration of DM and/or PAD was collected. Estimations were presented for all, by sexes and by types of LLA (minor: below the knee; major: knee and above), with 99% confidence intervals (CI). Results: Between 2006 and 2019, incident cases of LLA increased from 818 to 1,099 but age-standardized incidence remained stable (Figure 1) for both sexes. Men had a higher age-standardized incidence of LLA then women (32.7 per 100,000 [99% CI: 29.7-35.9] vs 12.9 per 100,000 [11.2-14.9] in 2019). From 2006 to 2019, the age-standardized incidence of major LLA showed a relative decrease of 48% while minor LLA remained stable (Figure 1). Reduction in age-standardized incidence of major LLA was attributable to men (3.8 per 100,000 [2.7-5.3] to 1.7 per 100,000 [1.1-2.6]). The mean age of incident cases went from 68.2 to 69.5 years from 2006 to 2019 (72.4 for women and 68.3 for men in 2019). Ninety-eight percent of LLA had DM, while 95% had PAD and 95% had both in 2019. Between 2006 and 2019, the average time between the first LLA and DM diagnosis increased from 7.0 to 14.7 years and from 2.0 to 2.6 years for PAD. Conclusions: Although the age-standardized incidence of LLA is stable, men remain at higher risk then women. The portrait of incident cases is changing towards an older average age, longer DM duration and a reduction of major LLA. These results emphasize the importance to improve further preventive care of LLA in Quebec.
T-cell Receptor Therapy Targeting Mutant Capicua Transcriptional Repressor in Experimental Gliomas
Authors: Michael Kilian, Mirco Friedrich, Khwab Sanghvi, Edward Green, Stefan Pusch, Daisuke Kawauchi, Martin Löwer, Jana K. Sonner, Christopher Krämer, Julia Zaman, Stefanie Jung, Michael O. Breckwoldt, Gerald Willimsky, Stefan B. Eichmüller, Andreas von Deimling, Wolfgang Wick, Felix Sahm, Michael Platten, Lukas Bunse
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Gliomas are intrinsic brain tumors with a high degree of constitutive and acquired resistance to standard therapeutic modalities such as radiotherapy and alkylating chemotherapy. Glioma subtypes are recognized by characteristic mutations. Some of these characteristic mutations have shown to generate immunogenic neoepitopes suitable for targeted immunotherapy. Experimental Design: Using peptide-based ELISpot assays, we screened for potential recurrent glioma neoepitopes in MHC-humanized mice. Following vaccination, droplet-based single-cell T-cell receptor (TCR) sequencing from established T-cell lines was applied for neoepitope-specific TCR discovery. Efficacy of intraventricular TCR-transgenic T-cell therapy was assessed in a newly developed glioma model in MHC-humanized mice induced by CRISPR-based delivery of tumor suppressor–targeting guide RNAs. Results: We identify recurrent capicua transcriptional repressor (CIC) inactivating hotspot mutations at position 215 CICR215W/Q as immunogenic MHC class II (MHCII)-restricted neoepitopes. Vaccination of MHC-humanized mice resulted in the generation of robust MHCII-restricted mutation-specific T-cell responses against CICR215W/Q. Adoptive intraventricular transfer of CICR215W-specific TCR-transgenic T cells exert antitumor responses against CICR215W-expressing syngeneic gliomas. Conclusions: The integration of immunocompetent MHC-humanized orthotopic glioma models in the discovery of shared immunogenic glioma neoepitopes facilitates the identification and preclinical testing of human leukocyte antigen (HLA)-restricted neoepitope-specific TCRs for locoregional TCR-transgenic T-cell adoptive therapy.
Abstract MP08: Using Electronic Health Record Data To Link Families: The Pythonic Relationship Inference From The Electronic Health Record Algorithm
Authors: Amy E Krefman, Farhad Ghamsari, Daniel R Turner, Alice Lu, Martin Borsje, Daniel Schneider, Colby Witherup Wood, Faraz S Ahmad, Norrina Allen
Journal: Circulation (2022)

Introduction: Intergenerational patterns are an important part of understanding disease, but much of the family-based research can be costly or biased. Emergency contacts in electronic health records (EHR) can be used to link family members using a population that is more representative of a community than traditional family cohort studies. Hypothesis: Creating family trees using emergency contacts will result in robust data that can be used in intergenerational research. Methods: We revised a published algorithm: relationship inference from the electronic health record (RIFTEHR). Our version, pythonic RIFTEHR (P-RIFTEHR) was run on 8/5/21 in the Northwestern Medicine Electronic Data Warehouse (NMEDW) on approximately 3.7 million individuals and was validated using the existing link between children born at NM hospitals and their mothers as the gold-standard. As proof-of-concept, we modeled the association between parent and child obesity using logistic regression. Results: The P-RIFTEHR algorithm matched 1,427,622 individuals in 500,408 families. The median family size is 2, the largest family is approximately 300 persons, and 115 families span four generations or more. Of the EDW-linked mother-child pairs, all matching pairs in P-RIFTEHR were correctly identified as mother-child, resulting in 100% sensitivity. Children are two times more likely to be obese if a parent is obese (OR: 2.01; 95% CI: 1.94, 2.09). This association persists after adjustment (OR: 2.19; 95% CI: 2.10, 2.28) and in mixed models nesting children within parents (OR: 2.70; 95% CI: 2.56, 2.85). Conclusions: P-RIFTEHR works well in a large, diverse population in an integrated health system. Our obesity results are consistent with the literature, including a 2017 meta-analysis by Wang, et al, showing a strong parent-child obesity association (pooled OR: 2.22; 95% CI: 2.09, 2.36). While the information used in the EHR can be completely deidentified, privacy concerns will be addressed before these data are more widely available for research.
Streptococcus pneumoniae colonization associates with impaired adaptive immune responses against SARS-CoV-2
Authors: Elena Mitsi, Jesús Reiné, Britta C. Urban, Carla Solórzano, Elissavet Nikolaou, Angela D. Hyder-Wright, Sherin Pojar, Ashleigh Howard, Lisa Hitchins, Sharon Glynn, Madlen C. Farrar, Konstantinos Liatsikos, Andrea M. Collins, Naomi F. Walker, Helen C. Hill, Esther L. German, Katerina S. Cheliotis, Rachel L. Byrne, Christopher T. Williams, Ana I. Cubas-Atienzar, Tom E. Fletcher, Emily R. Adams, Simon J. Draper, David Pulido, Rohini Beavon, Christian Theilacker, Elizabeth Begier, Luis Jodar, Bradford D. Gessner, Daniela M. Ferreira
Journal: Journal of Clinical Investigation (2022)

BackgroundAlthough recent epidemiological data suggest that pneumococci may contribute to the risk of SARS-CoV-2 disease, cases of coinfection with Streptococcus pneumoniae in patients with coronavirus disease 2019 (COVID-19) during hospitalization have been reported infrequently. This apparent contradiction may be explained by interactions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and pneumococci in the upper airway, resulting in the escape of SARS-CoV-2 from protective host immune responses.MethodsHere, we investigated the relationship of these 2 respiratory pathogens in 2 distinct cohorts of health care workers with asymptomatic or mildly symptomatic SARS-CoV-2 infection identified by systematic screening and patients with moderate to severe disease who presented to the hospital. We assessed the effect of coinfection on host antibody, cellular, and inflammatory responses to the virus.ResultsIn both cohorts, pneumococcal colonization was associated with diminished antiviral immune responses, which primarily affected mucosal IgA levels among individuals with mild or asymptomatic infection and cellular memory responses in infected patients.ConclusionOur findings suggest that S. pneumoniae impair host immunity to SARS-CoV-2 and raise the question of whether pneumococcal carriage also enables immune escape of other respiratory viruses and facilitates reinfection.Trial registrationISRCTN89159899 (FASTER study) and ClinicalTrials.gov NCT03502291 (LAIV study).
Wound microenvironment-responsive glucose consumption and hydrogen peroxide generation synergistic with azithromycin for diabetic wounds healing
Authors: Minqi Shi, Zhen Du, Yuchen Qi, Wanlin Li, Huiqun Hu, Xiuhui Lin, Shoujie Wang, Zhe Tang, Min Zhou
Journal: Theranostics (2022)

Rationale: Chronic wounds are one of the common complications of diabetes. Due to the physiological conditions of diabetic patients, these wounds are more susceptible to bacterial infections and the formation of bacterial biofilms, leading to the inefficiency of conventional antibiotic treatment. Methods: Here, hollow mesoporous silica nanoparticles (HMSN) were used as the nanocarriers for co-delivery of azithromycin (AZM) and glucose oxidase (GOX), achieving a remarkable synergistic effect in chronic diabetic wounds. GOX possesses the catalytic ability to consume glucose and produce H2O2 in the diabetic wound area. The down-regulation of local glucose could effectively improve the chronic diabetic wound microenvironment. Meanwhile, the generated H2O2 effectively inhibits bacterial growth and eradicates bacterial biofilms with the synergism of antibiotics AZM. Results: In the bacteria-infected diabetic cutaneous wound models, the reduction of glucose, generation of H2O2, and release of AZM could effectively reduce the bacterial infection and promote the wounds healing. Moreover, there is no obvious toxicity behavior after the treatment. Conclusions: Therefore, the designed nanosystem could effectively accelerate the diabetic wound healing process by the amelioration of the hyperglycemia microenvironment and the eradication of bacterial biofilms around the wounds, making them promising candidates for clinical transformation.
Lung Cancer Diagnosed Through Screening, Lung Nodule, and Neither Program: A Prospective Observational Study of the Detecting Early Lung Cancer (DELUGE) in the Mississippi Delta Cohort
Authors: Raymond U. Osarogiagbon, Wei Liao, Nicholas R. Faris, Meghan Meadows-Taylor, Carrie Fehnel, Jordan Lane, Sara C. Williams, Anita A. Patel, Olawale A. Akinbobola, Alicia Pacheco, Amanda Epperson, Joy Luttrell, Denise McCoy, Laura McHugh, Raymond Signore, Anna M. Bishop, Keith Tonkin, Robert Optican, Jeffrey Wright, Todd Robbins, Meredith A. Ray, Matthew P. Smeltzer
Journal: Journal of Clinical Oncology (2022)

PURPOSE Lung cancer screening saves lives, but implementation is challenging. We evaluated two approaches to early lung cancer detection—low-dose computed tomography screening (LDCT) and program-based management of incidentally detected lung nodules. METHODS A prospective observational study enrolled patients in the early detection programs. For context, we compared them with patients managed in a Multidisciplinary Care Program. We compared clinical stage distribution, surgical resection rates, 3- and 5-year survival rates, and eligibility for LDCT screening of patients diagnosed with lung cancer. RESULTS From 2015 to May 2021, 22,886 patients were enrolled: 5,659 in LDCT, 15,461 in Lung Nodule, and 1,766 in Multidisciplinary Care. Of 150, 698, and 1,010 patients diagnosed with lung cancer in the respective programs, 61%, 60%, and 44% were diagnosed at clinical stage I or II, whereas 19%, 20%, and 29% were stage IV ( P = .0005); 47%, 42%, and 32% had curative-intent surgery ( P &lt; .0001); aggregate 3-year overall survival rates were 80% (95% CI, 73 to 88) versus 64% (60 to 68) versus 49% (46 to 53); 5-year overall survival rates were 76% (67 to 87) versus 60% (56 to 65) versus 44% (40 to 48), respectively. Only 46% of 1,858 patients with lung cancer would have been deemed eligible for LDCT by US Preventive Services Task Force (USPSTF) 2013 criteria, and 54% by 2021 criteria. Even if all eligible patients by USPSTF 2021 criteria had been enrolled into LDCT, the Nodule Program would have detected 20% of the stage I-II lung cancer in the entire cohort. CONCLUSION LDCT and Lung Nodule Programs are complementary, expanding access to early lung cancer detection and curative treatment to different-risk populations. Implementing Lung Nodule Programs may alleviate emerging disparities in access to early lung cancer detection.