tbuckley/cabot-search huggingface dataset:
Regulation of antitumor immunity by inflammation-induced epigenetic alterations
Authors: Michael Karin, Shabnam Shalapour
Journal: Cellular and Molecular Immunology (2021)

Abstract Chronic inflammation promotes tumor development, progression, and metastatic dissemination and causes treatment resistance. The accumulation of genetic alterations and loss of normal cellular regulatory processes are not only associated with cancer growth and progression but also result in the expression of tumor-specific and tumor-associated antigens that may activate antitumor immunity. This antagonism between inflammation and immunity and the ability of cancer cells to avoid immune detection affect the course of cancer development and treatment outcomes. While inflammation, particularly acute inflammation, supports T-cell priming, activation, and infiltration into infected tissues, chronic inflammation is mostly immunosuppressive. However, the main mechanisms that dictate the outcome of the inflammation-immunity interplay are not well understood. Recent data suggest that inflammation triggers epigenetic alterations in cancer cells and components of the tumor microenvironment. These alterations can affect and modulate numerous aspects of cancer development, including tumor growth, the metabolic state, metastatic spread, immune escape, and immunosuppressive or immunosupportive leukocyte generation. In this review, we discuss the role of inflammation in initiating epigenetic alterations in immune cells, cancer-associated fibroblasts, and cancer cells and suggest how and when epigenetic interventions can be combined with immunotherapies to improve therapeutic outcomes.
Identifying an immune-related gene-pair for prognosis prediction of metastatic colorectal cancer.
Authors: Qiqi Zhu, Du Cai, Wei Wang, Min-Er Zhong, Dejun Fan, Xuanhui Liu, Cheng-Hang Li, Ze-Ping Huang, Min-Yi Lv, Chuling Hu, Xin Duan, Xiaojian Wu, Feng Gao
Journal: Journal of Clinical Oncology (2021)

e15565 Background: Few robust predictive biomarkers have been applied in clinical practice due to the heterogeneity of metastatic colorectal cancer (mCRC) . Using the gene pair method, the absolute expression value of genes can be converted into the relative order of genes, which can minimize the influence of the sequencing platform difference and batch effects, and improve the robustness of the model. The main objective of this study was to establish an immune-related gene pairs signature (IRGPs) and evaluate the impact of the IRGPs in predicting the prognosis in mCRC. Methods: A total of 205 mCRC patients containing overall survival (OS) information from the training cohort ( n = 119) and validation cohort ( n = 86) were enrolled in this study. LASSO algorithm was used to select prognosis related gene pairs. Univariate and multivariate analyses were used to validate the prognostic value of the IRGPs. Gene sets enrichment analysis (GSEA) and immune infiltration analysis were used to explore the underlying biological mechanism. Results: An IRGPs signature containing 22 gene pairs was constructed, which could significantly separate patients of the training cohort ( n = 119) and validation cohort ( n = 86) into the low-risk and high-risk group with different outcomes. Multivariate analysis with clinical factors confirmed the independent prognostic value of IRGPs that higher IRGPs was associated with worse prognosis (training cohort: hazard ratio (HR) = 10.54[4.99-22.32], P &lt; 0.001; validation cohort: HR = 3.53[1.24-10.08], P = 0.012). GSEA showed that several metastasis and immune-related pathway including angiogenesis, TGF-β-signaling, epithelial-mesenchymal transition and inflammatory response were enriched in the high-risk group. Through further analysis of the immune factors, we found that the proportions of CD4+ memory T cell, regulatory T cell, and Myeloid dendritic cell were significantly higher in the low-risk group, while the infiltrations of the Macrophage (M0) and Neutrophil were significantly higher in the high-risk group. Conclusions: The IRGPs signature could predict the prognosis of mCRC patients. Further prospective validations are needed to confirm the clinical utility of IRGPs in the treatment decision.
Abstract 2610: A high performance blood test for multiple cancer early screening
Authors: Linhao Xu, Jun Wang, Weifeng Ma, Xin Liu, Ting Yang, Sihui Li, Qian Hu, Jinsheng Tao, Zhujia Ye, Zhiwei Chen, Jian-Bing Fan
Journal: Cancer Research (2021)

Abstract Introduction: Early detection is critical to improving cancer patient survival and quality of life. Cell-free DNA (cfDNA) methylation profiling is a promising diagnostic approach for early detection of cancer, even before symptoms appear. We previously reported a non-invasive and cost-effective methylation test, Aurora, which is able to detect three major cancer types with high specificity and sensitivity especially at early stages (I/II), including lung cancer (LC), breast cancer (BC), colorectal cancer (CRC). We have improved this test to include two additional major cancer types, gastric cancer (GC) and esophageal cancer (EC). Taking together, these five cancer types represent 56% of new cancer cases and 60% of cancer-related deaths in China. Methods: We developed a novel high-throughput targeted methylation profiling platform, Aurora 2.0 (an improved version of Aurora 1.0, as presented in AACR 2020), to efficiently enrich and capture cancer-specific DNA methylation markers in plasma, prior to analysis via next-generation sequencing on a MiSeqDx system. About 100 cases each for GC and EC patients (mostly at Stage I/II), together with ~200 healthy controls, have been analyzed by using Aurora 2.0 and used for model development and validation. Results and Discussion: cfDNA methylation profiles have been obtained from 409 plasma samples, comprising 206 healthy controls, 98 GC and 105 EC patients. Logistic regression model has been developed with the Area Under Curve (AUC) of 94.0% and 93.5% for GC and EC, respectively. Overall, the performance (AUC) of Aurora 2.0 for LC/BC/CRC/GC/EC are 97.3%, 96.2%, 92%, 94% and 93.5%, respectively. An independent cohort (~2,000 plasma samples, five cancer types including lung, breast, colorectal, gastric and esophageal cancers with healthy controls) study is undergoing to further validate this test prospectively. The superior performance and cost-effectiveness (~$100) of the test could make early cancer screening of multiple major cancers in symptom-free and average-risk populations more achievable. Citation Format: Linhao Xu, Jun Wang, Weifeng Ma, Xin Liu, Ting Yang, Sihui Li, Qian Hu, Jinsheng Tao, Zhujia Ye, Zhiwei Chen, Jian-Bing Fan. A high performance blood test for multiple cancer early screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2610.
Exosomes: Small vesicles with big roles in cancer, vaccine development, and therapeutics
Authors: Abhimanyu Thakur, Diana Carolina Parra, Pedram Motallebnejad, Marcelo Brocchi, Huanhuan Joyce Chen
Journal: Bioactive Materials (2021)

Cancer is a deadly disease that is globally and consistently one of the leading causes of mortality every year. Despite the availability of chemotherapy, radiotherapy, immunotherapy, and surgery, a cure for cancer has not been attained. Recently, exosomes have gained significant attention due to the therapeutic potential of their various components including proteins, lipids, nucleic acids, miRNAs, and lncRNAs. Exosomes constitute a set of tiny extracellular vesicles with an approximate diameter of 30–100 nm. They are released from different cells and are present in biofluids including blood, cerebrospinal fluid (CSF), and urine. They perform crucial multifaceted functions in the malignant progression of cancer via autocrine, paracrine, and endocrine communications. The ability of exosomes to carry different cargoes including drug and molecular information to recipient cells make them a novel tool for cancer therapeutics. In this review, we discuss the major components of exosomes and their role in cancer progression. We also review important literature about the potential role of exosomes as vaccines and delivery carriers in the context of cancer therapeutics.
To T or not to B: germline RUNX1 mutation preferences in pediatric ALL predisposition
Authors: Serine Avagyan, Anna L. Brown
Journal: Journal of Clinical Investigation (2021)

Germline RUNX1 variants have been identified in relation to myeloid malignancy predisposition, with lymphoid hematological malignancies present at a lower frequency in families. In this issue of the JCI, Li and Yang et al. examined the frequency and type of germline RUNX1 variants in pediatric patients with acute lymphoblastic leukemia (ALL). Patients with T cell ALL (T-ALL) harbored rare, damaging RUNX1 mutations that were not seen in patients with B cell ALL (B-ALL). Further, several of the T-ALL-associated RUNX1 variants had potential dominant-negative activity. RUNX1-mutated T-ALL cases were also associated with somatic JAK3 mutations and enriched for the early T cell precursor (ETP) leukemia subtype, a finding that was validated when RUNX1 and JAK3 mutations were combined in mice. This study confirms germline RUNX1 predisposition beyond myeloid malignancy, demonstrates the importance of examining both germline and somatic mutations in malignancy cohorts, and demarcates the ETP ALL subtype as a flag for germline predisposition in patients.
Airway inflammation in severe asthmatics with acid gastro-oesophageal reflux
Authors: Nicole Tanner, Sejal Saglani, Albert M Li, Andrew Bush, Louise Fleming
Journal: Thorax (2021)

The relationship between childhood asthma and gastro-oesophageal reflux (GOR) is contentious. Recent studies in adult asthmatics suggest that GOR is associated with worse control and differences in sputum proteomics related to epithelial integrity, systemic inflammation and host defence. We assessed 127 children with severe asthma undergoing bronchoscopy and pH study. There were no differences in asthma control or measures of airway inflammation or remodelling when those with acid GOR were compared with those without. These results suggest that acid GOR is not an important comorbidity in paediatric severe asthma.
High-Sensitivity C-Reactive Protein Modifies the Cardiovascular Risk of Lipoprotein(a)
Authors: Wei Zhang, Jaime Lynn Speiser, Fan Ye, Michael Y. Tsai, Miguel Cainzos-Achirica, Khurram Nasir, David M. Herrington, Michael D. Shapiro
Journal: Journal of the American College of Cardiology (2021)
Etherglycerophospholipids and ferroptosis: structure, regulation, and location
Authors: David Balgoma, Mikael Hedeland
Journal: Trends in Endocrinology and Metabolism (2021)

Two pioneering studies by Zou et al. and Cui et al. have reported that the synthesis of etherglycerophospholipids (etherPLs) sensitizes cells to ferroptosis. The location and regulation of etherPLs suggest that: (i) lipid peroxidation in the inner leaflet of the plasma membrane might be of importance in ferroptosis, and (ii) different etherPLs may differently sensitize cells to ferroptosis.
Trajectories of asthma and allergy symptoms from childhood to adulthood
Authors: Felix Forster, Markus Johannes Ege, Jessica Gerlich, Tobias Weinmann, Sylvia Kreißl, Gudrun Weinmayr, Jon Genuneit, Dennis Nowak, Erika von Mutius, Christian Vogelberg, Katja Radon
Journal: Allergy (2021)

Phenotypes of asthma and allergic diseases are mainly studied separately for children and adults. To explore the role of adolescence and young adulthood, we investigated symptom trajectories at the transition from childhood into adulthood.Latent class analysis (LCA) was conducted in a population initially recruited for the German arm of Phase II of the International Study of Asthma and Allergies in Childhood and followed-up three times until their early 30s (N=2267). Indicators included in LCA were 12-month prevalences of symptoms of wheeze, rhinoconjunctivitis, and eczema. Latent classes were further characterised regarding important traits such as skin prick tests. Logistic regression models were used to investigate associations with environmental determinants such as smoking and occupational exposures.Six latent classes were identified: an asymptomatic one as well as three with single and two with co-occurring symptoms. All trajectories essentially established between baseline assessment at around 10 years and the first follow-up at around 17 years. Probabilities for symptoms increased from childhood to adolescence, especially for wheeze-related latent classes, while they remained constant in adulthood. Wheeze-related latent classes were also positively associated with exposures during adolescence (e.g. active smoking).Distinct trajectories of asthma and allergy symptoms establish from childhood through adolescence and stabilize during early adulthood. This pattern was most notable in wheeze-related latent classes which also showed the strongest positive associations with environmental exposures in adolescence/young adulthood. Therefore, not only childhood but also adolescence is relevant for disease development and offers considerable potential for prevention and health promotion.
Soft overcomes the hard: Flexible materials adapt to cell adhesion to promote cell mechanotransduction
Authors: Qian Sun, Yong Hou, Zhiqin Chu, Qiang Wei
Journal: Bioactive Materials (2021)

Cell behaviors and functions show distinct contrast in different mechanical microenvironment. Numerous materials with varied rigidity have been developed to mimic the interactions between cells and their surroundings. However, the conventional static materials cannot fully capture the dynamic alterations at the bio-interface, especially for the molecular motion and the local mechanical changes in nanoscale. As an alternative, flexible materials have great potential to sense and adapt to mechanical changes in such complex microenvironment. The flexible materials could promote the cellular mechanosensing by dynamically adjusting their local mechanics, topography and ligand presentation to adapt to intracellular force generation. This process enables the cells to exhibit comparable or even higher level of mechanotransduction and the downstream ‘hard’ phenotypes compared to the conventional stiff or rigid ones. Here, we highlight the relevant studies regarding the development of such adaptive materials to mediate cell behaviors across the rigidity limitation on soft substrates. The concept of ‘soft overcomes the hard’ will guide the future development and application of biological materials.
Erratum. Effect of Recombinant Human Parathyroid Hormone (1-84) on Resolution of Active Charcot Neuro-osteoarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study. Diabetes Care 2021;44:1613–1621
Authors: Nina L. Petrova, Nicholas K. Donaldson, Maureen Bates, Wegin Tang, Timothy Jemmott, Victoria Morris, Tracy Dew, Lisa Meacock, David A. Elias, Cajetan F. Moniz, Michael E. Edmonds
Journal: Diabetes Care (2021)

In the article cited above, the statistical method mistakenly appeared in the abstract as “mixed effects logistic regression” and should have appeared as “on univariate mixed Cox and logistic regression,” and the subsequent phrase should have read …
Estimates of COVID-19 Cases and Deaths Among Nursing Home Residents Not Reported in Federal Data
Authors: Karen Shen, Lacey Loomer, Hannah Abrams, David C. Grabowski, Ashvin Gandhi
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Federal data underestimate the impact of COVID-19 on US nursing homes because federal reporting guidelines did not require facilities to report case and death data until the week ending May 24, 2020. <h3>Objective</h3> To assess the magnitude of unreported cases and deaths in the National Healthcare Safety Network (NHSN) and provide national estimates of cases and deaths adjusted for nonreporting. <h3>Design, Setting, and Participants</h3> This is a cross-sectional study comparing COVID-19 cases and deaths reported by US nursing homes to the NHSN with those reported to state departments of health in late May 2020. The sample includes nursing homes from 20 states, with 4598 facilities in 12 states that required facilities to report cases and 7401 facilities in 19 states that required facilities to report deaths. Estimates of nonreporting were extrapolated to infer the national (15 397 facilities) unreported cases and deaths in both May and December 2020. Data were analyzed from December 2020 to May 2021. <h3>Exposures</h3> Nursing home ownership (for-profit or not-for-profit), chain affiliation, size, Centers for Medicare &amp; Medicaid Services star rating, and state. <h3>Main Outcomes and Measures</h3> The main outcome was the difference between the COVID-19 cases and deaths reported by each facility to their state department of health vs those reported to the NHSN. <h3>Results</h3> Among 15 415 US nursing homes, including 4599 with state case data and 7405 with state death data, a mean (SE) of 43.7% (1.4%) of COVID-19 cases and 40.0% (1.1%) of COVID-19 deaths prior to May 24 were not reported in the first NHSN submission in sample states, suggesting that 68 613 cases and 16 623 deaths were omitted nationwide, representing 11.6% of COVID-19 cases and 14.0% of COVID-19 deaths among nursing home residents in 2020. <h3>Conclusions and Relevance</h3> These findings suggest that federal NHSN data understated total cases and deaths in nursing homes. Failure to account for this issue may lead to misleading conclusions about the role of different facility characteristics and state or federal policies in explaining COVID outbreaks.
Re: Ranan Dasgupta, Sarah Cameron, Lorna Aucott, et al. Shockwave Lithotripsy Versus Ureteroscopic Treatment as Therapeutic Interventions for Stones of the Ureter (TISU): A Multicentre Randomised Controlled Non-inferiority Trial. Eur Urol 2021;80:46–54
Authors: Gorrepati Rohith, Prasant Nayak
Journal: European Urology (2021)
Abstract 15516: Association Between Lipoprotein(a) and Atherosclerosis: Results From the MASALA Cohort
Authors: Mark D Huffman, Namratha R Kandula, Abigail S Baldridge, Michael Tsai, Dorairaj Prabhakaran, Alka M Kanaya
Journal: Circulation (2017)

Background: Data describing lipoprotein (a) [Lp(a)] levels and its association with atherosclerosis among South Asians are limited. Objective: To report the distribution of Lp(a) levels in the Medi...
In acute dyspnea with diagnostic uncertainty, ACP suggests POCUS may be added to the standard diagnostic pathway
Authors: Jonathan M. Kirschner, Benton R. Hunter
Journal: Annals of Internal Medicine (2021)

Source Citation Qaseem A, Etxeandia-Ikobaltzeta I, Mustafa RA, et al. Appropriate use of point-of-care ultrasonography in patients with acute dyspnea in emergency department or inpatient settings: a clinical guideline from the American College of Physicians. Ann Intern Med. 2021;174:985-93. 33900792
Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial
Authors: José Molina, Enrique Montero-Mateos, Julia Praena-Segovia, Eva León-Jiménez, Clara Natera, Luis E. López-Cortés, Lucía Valiente, Clara M. Rosso-Fernández, Marta Herrero, Ana I. Aller-García, Ángela Cano, Belén Gutiérrez-Gutiérrez, Ignacio Márquez-Gómez, Rocío Álvarez-Marín, Carmen Infante, Cristina Roca, Adoración Valiente-Méndez, Jerónimo Pachón, José María Reguera, Juan Enrique Corzo-Delgado, Julián Torre-Cisneros, Jesús Rodríguez-Baño, José Miguel Cisneros, Blanca Solano, Verónica González-Galán, Esteban Hinojosa, Francisco López-Bernal, Marta Suñer, José Ángel Noval, Álvaro Giráldez, Antonio Navarro, María Jesús Rodríguez-Hernández, Yolanda Borrego, Paloma Gil, José Antonio Lepe, Isabel Morales, Pilar Retamar, Marina de Cueto, Juan José Castón, Elisa Vidal
Journal: Clinical Microbiology and Infection (2021)
Cardiovascular Risk Associated With Ibrutinib Use in Chronic Lymphocytic Leukemia: A Population-Based Cohort Study
Authors: Husam Abdel-Qadir, Nasruddin Sabrie, Darryl Leong, Andrea Pang, Peter C. Austin, Anca Prica, Kumaraswamy Nanthakumar, Oscar Calvillo-Argüelles, Douglas S. Lee, Paaladinesh Thavendiranathan
Journal: Journal of Clinical Oncology (2021)

Ibrutinib reduces mortality in chronic lymphocytic leukemia (CLL). It increases the risk of atrial fibrillation (AF) and bleeding and there are concerns about heart failure (HF) and central nervous system ischemic events. The magnitude of these risks remains poorly quantified.Using linked administrative databases, we conducted a population-based cohort study of Ontario patients who were treated for CLL diagnosed between 2007 and 2019. We matched ibrutinib-treated patients with controls treated with chemotherapy but unexposed to ibrutinib on prior AF, age ≥ 66 years, anticoagulant exposure, and propensity for receiving ibrutinib. Study outcomes were AF-related health care contact, hospital-diagnosed bleeding, new diagnoses of HF, and hospitalizations for stroke and acute myocardial infarction (AMI). The cumulative incidence function was used to estimate absolute risks. We used cause-specific regression to study the association of ibrutinib with bleeding rates, while adjusting for anticoagulation as a time-varying covariate.We matched 778 pairs of ibrutinib-treated and unexposed patients with CLL (N = 1,556). The 3-year incidence of AF-related health care contact was 22.7% (95% CI, 19.0 to 26.6) in ibrutinib-treated patients and 11.7% (95% CI, 9.0 to 14.8) in controls. The 3-year risk of hospital-diagnosed bleeding was 8.8% (95% CI, 6.5 to 11.7) in ibrutinib-treated patients and 3.1% (95% CI, 1.9 to 4.6) in controls. Ibrutinib-treated patients were more likely to start anticoagulation after the index date. After adjusting for anticoagulation as a time-varying covariate, ibrutinib remained positively associated with bleeding (HR, 2.58; 95% CI, 1.76 to 3.78). The 3-year risk of HF was 7.7% (95% CI, 5.4 to 10.6%) in ibrutinib-treated patients and 3.6% (95% CI, 2.2 to 5.4) in controls. There was no significant difference in the risk of ischemic stroke or AMI.Ibrutinib is associated with higher risk of AF, bleeding, and HF, but not AMI or stroke.