tbuckley/cabot-search huggingface dataset:
Geriatric Emergency Care Reduces Health Care Costs—What Are the Next Steps?
Authors: Maura Kennedy, Kei Ouchi, Kevin Biese
Journal: JAMA Network Open (2021)

Ula Hwang, MD, MPH; Scott M. Dresden, MD, MS; Carmen Vargas-Torres, MA; Raymond Kang, MA; Melissa M. Garrido, PhD; George Loo, DrPh; Jeremy Sze, MA; Daniel Cruz, BS; Lynne D. Richardson, MD; James Adams, MD; Amer Aldeen, MD; Kevin M. Baumlin, MD; D. Mark Courtney, MD, MSc; Stephanie Gravenor, MBA; Corita R. Grudzen, MD, MSHS; Gloria Nimo, RN, NP; Carolyn W. Zhu, PhD; Geriatric Emergency Department Innovations in Care Through Workforce, Informatics, and Structural Enhancement (GEDI WISE) Investigators; Gallane Abraham; Cindy Amoko; Nicholas Genes; Barbara Morano; Denise Nassisi; Joanna M. Ortiz; Laura Rivera-Reyes; Martine Sanon; Jason Shapiro; Gary Winkel; Sanjeev Malik; Mark S. Rosenberg; Maria Christensen; Marianna Karounos; Richard Schultz; Debra Sumberg
Impact of angiotensin inhibitors on pathologic complete response with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC).
Authors: Jonathan Thomas, Gregory Russell Pond, Catherine Curran, Dory Freeman, Praful Ravi, Matthew Mossanen, Mark A. Preston, Graeme S. Steele, Charlene Mantia, Bradley Alexander McGregor, Rakesh K. Jain, Guru Sonpavde
Journal: Journal of Clinical Oncology (2021)

432 Background: The renin-angiotensin system (RAS) is involved in regulation of angiogenesis, cell proliferation, desmoplasia and immunosuppression. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) may have antitumor effects partly by inhibiting transforming growth factor (TGF)-β, a major resistance mechanism in bladder cancer. Methods: Patients (pts) with muscle invasive bladder cancer (MIBC) treated or not treated with ACEi/ARB while receiving preceding radical cystectomy (RC) were assessed for pathologic complete response (pCR) defined as pT0N0 and overall survival (OS). Pathologic features, performance status, clinical stage, type and number of cycles of NAC, and presence of grade ≥3 toxicities were collected retrospectively. The Kaplan-Meier method was used to estimate overall survival (OS). Logistic and Cox regression was used to explore factors potentially prognostic for pCR and OS respectively. Results: 187 patients received NAC followed by RC. The mean age at the time of NAC was 65. 71% were male and 29% were female. Of the 187 patients, 61% received Cisplatin/Gemcitabine and 28.3% received dose dense MVAC. Of patients receiving NAC, 53 (28%) had a pCR. The 5-year OS was 64%. There were 41 (21.9%) patients taking an ACEi and 24 (12.8%) patients taking an ARB at the start of NAC. Of the 41 patients who took an ACEi, 17 (41.5%) had a pCR; of the 146 patients who did not take an ACEi, 36 (24.7%) had a pCR. ACEi intake during NAC was the only factor associated with pCR on multivariable analysis (odds ratio of 2.17 [95% CI 1.05-4.48] p = 0.037). pCR was the only factor shown to be associated with significantly improved OS (Hazard Ratio 0.18 [95% CI 0.07-0.45] p = &lt; 0.001). After adjusting for pCR, ACEi was not significantly prognostic of OS (HR = 1.12, 95% CI = 0.60 to 2.09, p = 0.72). ARB intake while receiving NAC was not associated with pCR or OS. Conclusions: ACEi intake was associated with significantly increased pCR in patients with MIBC receiving NAC, and pCR was the only significant factor associated with OS. We hypothesize that ACEi may augment the activity of NAC and increase pCR, which translates to improved OS. ACEi intake was not associated with improvement in OS potentially due to competing causes of mortality in patients requiring ACEi. Our data requires validation.
Infant body mass index trajectories and asthma and lung function
Authors: Gulshan Bano Ali, Dinh Son Bui, Caroline Jane Lodge, Nilakshi T. Waidyatillake, Jennifer L. Perret, Cong Sun, Eugene Haydn Walters, Michael John Abramson, Adrian J. Lowe, Shyamali Chandrika Dharmage
Journal: Journal of Allergy and Clinical Immunology (2021)
Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias
Authors: Eleonora Mäkelä, Karolina Pavic, Taru Varila, Urpu Salmenniemi, Eliisa Löyttyniemi, Srikar G. Nagelli, Tea Ammunét, Veli-Matti Kähäri, Richard E. Clark, Laura L. Elo, Venkata Kumari Bachanaboyina, Claire M. Lucas, Maija Itälä-Remes, Jukka Westermarck
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56α. However, CIP2A mRNA variants remain uncharacterized. Here, we report the discovery of a CIP2A splicing variant, novel CIP2A variant (NOCIVA). Experimental Design: Characterization of CIP2A variants was performed by both 3′ and 5′ rapid amplification of cDNA ends from cancer cells. The function of NOCIVA was assessed by structural and molecular biology approaches. Its clinical relevance was studied in an acute myeloid leukemia (AML) patient cohort and two independent chronic myeloid leukemia (CML) cohorts. Results: NOCIVA contains CIP2A exons 1 to 13 fused to 349 nucleotides from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA-specific sequence are in the coding frame with exon 13 of CIP2A and code for a 13-amino acid peptide tail nonhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56α, but, whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, AML and CML patient samples overexpress NOCIVA, but not CIP2A mRNA. In AML, a high NOCIVA/CIP2A mRNA expression ratio is a marker for adverse overall survival. In CML, high NOCIVA expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib. Conclusions: We discovered a novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.
Effect of physicochemical properties on in vivo fate of nanoparticle-based cancer immunotherapies
Authors: Yongchao Wang, Jinjin Wang, Dandan Zhu, Yufei Wang, Guangchao Qing, Yuxuan Zhang, Xiaoxuan Liu, Xing-Jie Liang
Journal: Acta Pharmaceutica Sinica B (2021)

Current advances of immunotherapy have greatly changed the way of cancer treatment. At the same time, a great number of nanoparticle-based cancer immunotherapies (NBCIs) have also been explored to elicit potent immune responses against tumors. However, few NBCIs are nearly in the clinical trial which is mainly ascribed to a lack understanding of in vivo fate of nanoparticles (NPs) for cancer immunotherapy. NPs for cancer immunotherapy mainly target the immune organs or immune cells to enable efficient antitumor immune responses. The physicochemical properties of NPs including size, shape, elasticity and surface properties directly affect their interaction with immune systems as well as their in vivo fate and therapeutic effect. Hence, systematic analysis of the physicochemical properties and their effect on in vivo fate is urgently needed. In this review, we first recapitulate the fundamentals for the in vivo fate of NBCIs including physio-anatomical features of lymphatic system and strategies to modulate immune responses. Moreover, we highlight the effect of physicochemical properties on their in vivo fate including lymph nodes (LNs) drainage, cellular uptake and intracellular transfer. Challenges and opportunities for rational design of NPs for cancer immunotherapy are also discussed in detail.
Preclinical evaluation and pilot clinical study of [18F]AlF-labeled FAPI-tracer for PET imaging of cancer associated fibroblasts
Authors: Kongzhen Hu, Junqi Li, Lijuan Wang, Yong Huang, Li Li, Shimin Ye, Yanjiang Han, Shun Huang, Hubing Wu, Jin Su, Ganghua Tang
Journal: Acta Pharmaceutica Sinica B (2021)

In recent years, fibroblast activation protein (FAP) has emerged as an attractive target for the diagnosis and radiotherapy of cancers using FAP-specific radioligands. Herein, we aimed to design a novel 18F-labeled FAP tracer ([18F]AlF-P-FAPI) for FAP imaging and evaluated its potential for clinical application. The [18F]AlF-P-FAPI novel tracer was prepared in an automated manner within 42 min with a non-decay corrected radiochemical yield of 32 ± 6% (n = 8). Among A549-FAP cells, [18F]AlF-P-FAPI demonstrated specific uptake, rapid internalization, and low cellular efflux. Compared to the patent tracer [18F]FAPI-42, [18F]AlF-P-FAPI exhibited lower levels of cellular efflux in the A549-FAP cells and higher stability in vivo. Micro-PET imaging in the A549-FAP tumor model indicated higher specific tumor uptake of [18F]AlF-P-FAPI (7.0 ± 1.0% ID/g) compared to patent tracers [18F]FAPI-42 (3.2 ± 0.6% ID/g) and [68Ga]Ga-FAPI-04 (2.7 ± 0.5% ID/g). Furthermore, in an initial diagnostic application in a patient with nasopharyngeal cancer, [18F]AlF-P-FAPI and [18F]FDG PET/CT showed comparable results for both primary tumors and lymph node metastases. These results suggest that [18F]AlF-P-FAPI can be conveniently prepared, with promising characteristics in the preclinical evaluation. The feasibility of FAP imaging was demonstrated using PET studies.
First-dose mRNA vaccination is sufficient to reactivate immunological memory to SARS-CoV-2 in subjects who have recovered from COVID-19
Authors: Alessio Mazzoni, Nicoletta Di Lauria, Laura Maggi, Lorenzo Salvati, Anna Vanni, Manuela Capone, Giulia Lamacchia, Elisabetta Mantengoli, Michele Spinicci, Lorenzo Zammarchi, Seble Tekle Kiros, Arianna Rocca, Filippo Lagi, Maria Grazia Colao, Paola Parronchi, Cristina Scaletti, Lucia Turco, Francesco Liotta, Gian Maria Rossolini, Lorenzo Cosmi, Alessandro Bartoloni, Francesco Annunziato
Journal: Journal of Clinical Investigation (2021)

The characterization of the adaptive immune response to COVID-19 vaccination in individuals who recovered from SARS-CoV-2 infection may define current and future clinical practice. To determine the effect of the 2-dose BNT162b2 mRNA COVID-19 vaccination schedule in individuals who recovered from COVID-19 (COVID-19–recovered subjects) compared with naive subjects, we evaluated SARS-CoV-2 Spike–specific T and B cell responses, as well as specific IgA, IgG, IgM, and neutralizing antibodies titers in 22 individuals who received the BNT162b2 mRNA COVID-19 vaccine, 11 of whom had a previous history of SARS-CoV-2 infection. Evaluations were performed before vaccination and then weekly until 7 days after second injection. Data obtained clearly showed that one vaccine dose is sufficient to increase both cellular and humoral immune response in COVID-19–recovered subjects without any additional improvement after the second dose. On the contrary, the second dose proved mandatory in naive subjects to further enhance the immune response. These findings were further confirmed at the serological level in a larger cohort of naive (n = 68) and COVID-19–recovered (n = 29) subjects, tested up to 50 days after vaccination. These results question whether a second vaccine injection in COVID-19–recovered subjects is required, and indicate that millions of vaccine doses may be redirected to naive individuals, thus shortening the time to reach herd immunity.
Integrated gut virome and bacteriome dynamics in COVID-19 patients
Authors: Jiabao Cao, Cheng Wang, Yuqing Zhang, Guanglin Lei, Kun Xu, Na Zhao, Jingjing Lu, Fanping Meng, Linxiang Yu, Jin Yan, Changqing Bai, Shaogeng Zhang, Ning Zhang, Yuhuan Gong, Yuhai Bi, Yi Shi, Zhu Chen, Lianpan Dai, Jun Wang, Penghui Yang
Journal: Gut Microbes (2021)

SARS-CoV-2 is the cause of the current global pandemic of COVID-19; this virus infects multiple organs, such as the lungs and gastrointestinal tract. The microbiome in these organs, including the bacteriome and virome, responds to infection and might also influence disease progression and treatment outcome. In a cohort of 13 COVID-19 patients in Beijing, China, we observed that the gut virome and bacteriome in the COVID-19 patients were notably different from those of five healthy controls. We identified a bacterial dysbiosis signature by observing reduced diversity and viral shifts in patients, and among the patients, the bacterial/viral compositions were different between patients of different severities, although these differences are not entirely distinguishable from the effect of antibiotics. Severe cases of COVID-19 exhibited a greater abundance of opportunistic pathogens but were depleted for butyrate-producing groups of bacteria compared with mild to moderate cases. We replicated our findings in a mouse COVID-19 model, confirmed virome differences and bacteriome dysbiosis due to SARS-CoV-2 infection, and observed that immune/infection-related genes were differentially expressed in gut epithelial cells during infection, possibly explaining the virome and bacteriome dynamics. Our results suggest that the components of the microbiome, including the bacteriome and virome, are affected by SARS-CoV-2 infections, while their compositional signatures could reflect or even contribute to disease severity and recovery processes.
Dendritic Cell Regulation of T Helper Cells
Authors: Xiangyun Yin, Shuting Chen, Stephanie C. Eisenbarth
Journal: Annual Review of Immunology (2021)

As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs can induce both immune activation and immune tolerance according to the peripheral cues. Recent work has established that DCs comprise several phenotypically and functionally heterogeneous subsets that differentially regulate T lymphocyte differentiation. This review summarizes both mouse and human DC subset phenotypes, development, diversification, and function. We focus on advances in our understanding of how different DC subsets regulate distinct CD4+ T helper (Th) cell differentiation outcomes, including Th1, Th2, Th17, T follicular helper, and T regulatory cells. We review DC subset intrinsic properties, local tissue microenvironments, and other immune cells that together determine Th cell differentiation during homeostasis and inflammation.
The Impact of Detectable ADAMTS13 Inhibitor on the Clinical Presentation and Outcome of Patients with Immune Thrombotic Thrombocytopenic Purpura (iTTP): Analysis Using the United States Thrombotic Microangiopathy (USTMA) Clinical Registry
Authors: Meera Sridharan, Ana G Antun, Lisa Baumann Kreuziger, Spero R Cataland, Shruti Chaturvedi, Todd Clover, Elizabeth Davis, Andrew Johnson, Keith McCrae, Ming Yeong Lim, J. Evan Sadler, Marshall A. Mazepa, Ronald S Go
Journal: Blood (2017)
Genetic Ancestry Correlations with Driver Mutations Suggest Complex Interactions between Somatic and Germline Variation in Cancer
Authors: Felicia Gomez, Malachi Griffith, Obi L. Griffith
Journal: Cancer Discovery (2021)

Carrot-Zhang and colleagues describe associations between Native American ancestry and the somatic mutational landscape in lung cancer, including tumor mutation burden and specific driver mutations in EGFR, KRAS, and STK11. Local ancestry analysis suggests that specific germline loci, and not environment, underlie these associations.See related article by Carrot-Zhang et al., p. 591.
Persistent Nasal Inflammation 5 Months after Acute Anosmia in Patients with COVID-19
Authors: Thông Hua-Huy, Christine Lorut, Frédérique Aubourg, Caroline Morbieu, Jonathan Marey, Joëlle Texereau, Isabelle Fajac, Luc Mouthon, Nicolas Roche, Anh Tuan Dinh-Xuan
Journal: American Journal of Respiratory and Critical Care Medicine (2021)
Identification of characteristics associated with long-term survival in patients with metastatic urothelial carcinoma (mUC) who received durvalumab (D) with or without tremelimumab (T) in clinical studies.
Authors: Marie Alt, Carlos Stecca, Shaum Kabadi, Benga Kazeem, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2021)

441 Background: Immune checkpoint inhibitors (ICI) have changed the landscape of mUC, yet outcomes are variable as some patients (pts) do not respond to treatment while others have a durable response. To optimally select pts who may derive benefit from ICIs, predictive factors are required. This retrospective, post-hoc analysis evaluated pt characteristics to determine differences between short and long-term survivors among pts with mUC who received D (anti–PD-L1) with or without T (anti–CTLA-4) in two clinical studies. Methods: Pts with platinum-refractory mUC who received D monotherapy in the phase I/II study 1108 (10 mg/kg Q2W, up to 12 mo) or D+T in the phase I study 10 (D at 20 mg/kg + T at 1 mg/kg Q4W for 4 mo, then D at 10 mg/kg Q2W for 12 mo) were included. Pt characteristics, tumor characteristics, radiological assessments, and biological assessments were collected. The primary outcome measure was long-term overall survival (OS). Pts were categorized as OS ≥2 yrs (from 1st dose of study drug) or OS &lt;2 yrs. A univariate analysis was conducted on each baseline characteristic to assess independent associations with long-term OS; a multivariate logistic regression model was employed including each variable with a p-value ≤0.1 as factors or covariates. Results: A total of 367 pts with mUC were included in the analysis: 88 (24.0%) had OS ≥2 yrs (range: 2.09–4.99) and 279 (76.0%) had OS &lt;2 yrs (range: 0.03–1.98). Pts with OS ≥2 yrs had a significantly higher objective response rates than those with OS &lt;2 yrs (71.6% vs 5.7%; p&lt;0.0001) and a significantly longer duration of response (median 2.3 yrs vs 0.39 yrs; p&lt;0.0001). The characteristics included in the multivariate logistic regression model are listed in the Table. Long-term OS was significantly associated with ECOG PS, PD-L1 status, baseline hemoglobin level, and baseline absolute neutrophils count. Conclusions: Our analyses show that several characteristics, including tumor response to treatment, are associated with long-term OS for pts with mUC treated with D or D+T. Further investigation into these and other characteristics may provide additional insights into long-term survival outcomes with ICIs. [Table: see text]
The less‐known face of dupilumab: its role in mesenchymal stem cells by interleukin‐13 modulation
Authors: A. Campanati, M. Di Vincenzo, G. Radi, G. Rizzetto, G. Carnevale, S. Marchi, M. Orciani, A. Offidani
Journal: British Journal of Dermatology (2021)
Cardiovascular and Renal Disease Burden in Type 1 Compared With Type 2 Diabetes: A Two-Country Nationwide Observational Study
Authors: Robin Kristófi, Johan Bodegard, Anna Norhammar, Marcus Thuresson, David Nathanson, Thomas Nyström, Kåre I. Birkeland, Jan W. Eriksson
Journal: Diabetes Care (2021)

OBJECTIVE Type 1 diabetes (T1D) and type 2 diabetes (T2D) increase risks of cardiovascular (CV) and renal disease (CVRD) compared with diabetes-free populations. Direct comparisons between T1D and T2D are scarce. We examined this by pooling full-population cohorts in Sweden and Norway. RESEARCH DESIGN AND METHODS A total of 59,331 patients with T1D and 484,241 patients with T2D, aged 18–84 years, were followed over a mean period of 2.6 years from 31 December 2013. Patients were identified in nationwide prescribed drug and hospital registries in Norway and Sweden. Prevalence and event rates of myocardial infarction (MI), heart failure (HF), stroke, chronic kidney disease (CKD), all-cause death, and CV death were assessed following age stratification in 5-year intervals. Cox regression analyses were used to estimate risk. RESULTS The prevalence of CV disease was similar in T1D and T2D across age strata, whereas CKD was more common in T1D. Age-adjusted event rates comparing T1D versus T2D showed that HF risk was increased between ages 65 and 79 years, MI between 55 and 79 years, and stroke between 40 and 54 years (1.3–1.4-fold, 1.3–1.8-fold, and 1.4–1.7-fold, respectively). CKD risk was 1.4–3.0-fold higher in T1D at all ages. The all-cause death risk was 1.2–1.5-fold higher in T1D at age &amp;gt;50 years, with a similar trend for CV death. CONCLUSIONS Adult patients with T1D compared with those with T2D had an overall greater risk of cardiorenal disease (HF and CKD) across ages, MI and all-cause death at middle-older ages, and stroke at younger ages. The total age-adjusted CVRD burden and risks were greater among patients with T1D compared with those with T2D, highlighting their need for improved prevention strategies.
Validation of testicular germ cell tumor (GCT) staging in nationwide cancer registries.
Authors: Rohit R Badia, Daniel Wong, Rashed Ghandour, Nathan Chertack, Xiaosong Meng, Ryan C. Hutchinson, Vitaly Margulis, Yair Lotan, Alejandra Madrigales, Solomon L. Woldu, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2021)

383 Background: Nationwide cancer registries such as the National Cancer Database (NCDB) and Surveillance, Epidemiology, and End Results (SEER) rely on accurate data from institutional tumor registries to formulate hypotheses and report outcomes and treatment patterns for patients with cancer. We evaluated the accuracy of our institutional registry for testicular germ cell tumors (GCT) by comparing data abstracted by urologists with data abstracted by our tumor registry. Methods: We performed a retrospective review of patients receiving initial diagnosis and treatment for testicular cancer at our hospital system from 2005-2016. We reviewed registrar coding for American Joint Committee on Cancer clinical staging, overall composite stage grouping, and first-line treatment and compared it with urologist-reviewed staging at the time of diagnosis. Results: Paired staging from registry and urologist was available for 80 patients. T, N, M, and S-staging were accurate for 90%, 81%, 94%, and 54% of records, respectively. Composite staging and first-line treatment were concordant for 39% and 90% of patients, respectively. A separate review of 33 Stage IS patients per registry for composite staging revealed only 15% concordance. Conclusions: We identified significant inconsistencies with data abstracted by our institutional tumor registry for patients with testicular cancer, most notably with regards to S and composite stage. An educational intervention to improve abstraction by registry led to increased concordance. Assuming similar discrepancies may exist at other institutions and for other cancer types, caution should be used when interpreting NCDB and SEER cancer staging data. This sheds light on the need for improved clarification of staging guidelines, dynamic institutional internal auditing, and training reform within cancer registries.