tbuckley/cabot-search huggingface dataset:
Selective autophagy of intracellular organelles: Recent research advances
Authors: Wen Li, Pengcheng He, Yuge Huang, Yi-Fang Li, Jiahong Lu, Min Li, Hiroshi Kurihara, Zhuo Luo, Tian Meng, Mashun Onishi, Changle Ma, Lei Jiang, Yongquan Hu, Qing Gong, Dongxing Zhu, Yiming Xu, Rong Liu, Lei Liu, Cong Yi, Yushan Zhu, Ningfang Ma, Koji Okamoto, Zhiping Xie, Jinbao Liu, Rong-Rong He, Du Feng
Journal: Theranostics (2020)

Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and invading pathogens via the lysosomal system (the vacuole in plants and yeast). Autophagy is generally induced by stress, such as oxygen-, energy- or amino acid-deprivation, irradiation, drugs, etc. In addition to non-selective bulk degradation, autophagy also occurs in a selective manner, recycling specific organelles, such as mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes and lipid droplets (LDs). This capability makes selective autophagy a major process in maintaining cellular homeostasis. The dysfunction of selective autophagy is implicated in neurodegenerative diseases (NDDs), tumorigenesis, metabolic disorders, heart failure, etc. Considering the importance of selective autophagy in cell biology, we systemically review the recent advances in our understanding of this process and its regulatory mechanisms. We emphasize the 'cargo-ligand-receptor' model in selective autophagy for specific organelles or cellular components in yeast and mammals, with a focus on mitophagy and ER-phagy, which are finely described as types of selective autophagy. Additionally, we highlight unanswered questions in the field, helping readers focus on the research blind spots that need to be broken.
Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression
Authors: Adrián Blanco-Gómez, Lourdes Hontecillas-Prieto, Roberto Corchado-Cobos, Natalia García-Sancha, Nélida Salvador, Andrés Castellanos-Martín, María del Mar Sáez-Freire, Marina Mendiburu-Eliçabe, Diego Alonso-López, Javier De Las Rivas, Mar Lorente, Ana García-Casas, Sofía Del Carmen, María del Mar Abad-Hernández, Juan Jesús Cruz-Hernández, César Augusto Rodríguez-Sánchez, Juncal Claros-Ampuero, Begoña García-Cenador, Javier García-Criado, Akira Orimo, Thomas Gridley, Jesús Pérez-Losada, Sonia Castillo-Lluva
Journal: Cancer Research (2020)

Abstract SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis. Significance: Stromal SNAI2 expression enhances the tumorigenicity of luminal B HER2+ breast cancers and can identify a subset of patients with poor prognosis, making SNAI2 a potential therapeutic target for this disease.
Landscape of coordinated immune responses to H1N1 challenge in humans
Authors: Zainab Rahil, Rebecca Leylek, Christian M. Schürch, Han Chen, Zach Bjornson-Hooper, Shannon R. Christensen, Pier Federico Gherardini, Salil S. Bhate, Matthew H. Spitzer, Gabriela K. Fragiadakis, Nilanjan Mukherjee, Nelson Kim, Sizun Jiang, Jennifer Yo, Brice Gaudilliere, Melton Affrime, Bonnie Bock, Scott E. Hensley, Juliana Idoyaga, Nima Aghaeepour, Kenneth Kim, Garry P. Nolan, David R. McIlwain
Journal: Journal of Clinical Investigation (2020)

Influenza is a significant cause of morbidity and mortality worldwide. Here we show changes in the abundance and activation states of more than 50 immune cell subsets in 35 individuals over 11 time points during human A/California/2009 (H1N1) virus challenge monitored using mass cytometry along with other clinical assessments. Peak change in monocyte, B cell, and T cell subset frequencies coincided with peak virus shedding, followed by marked activation of T and NK cells. Results led to the identification of CD38 as a critical regulator of plasmacytoid dendritic cell function in response to influenza virus. Machine learning using study-derived clinical parameters and single-cell data effectively classified and predicted susceptibility to infection. The coordinated immune cell dynamics defined in this study provide a framework for identifying novel correlates of protection in the evaluation of future influenza therapeutics.
<i>TERT</i> Promoter Mutation Analysis for Blood-Based Diagnosis and Monitoring of Gliomas
Authors: Koushik Muralidharan, Anudeep Yekula, Julia L. Small, Zachary S. Rosh, Keiko M. Kang, Lan Wang, Spencer Lau, Hui Zhang, Hakho Lee, Chetan Bettegowda, Michael R. Chicoine, Steven N. Kalkanis, Ganesh M. Shankar, Brian V. Nahed, William T. Curry, Pamela S. Jones, Daniel P. Cahill, Leonora Balaj, Bob S. Carter
Journal: Clinical Cancer Research (2020)

Liquid biopsy offers a minimally invasive tool to diagnose and monitor the heterogeneous molecular landscape of tumors over time and therapy. Detection of TERT promoter mutations (C228T, C250T) in cfDNA has been successful for some systemic cancers but has yet to be demonstrated in gliomas, despite the high prevalence of these mutations in glioma tissue (>60% of all tumors).Here, we developed a novel digital droplet PCR (ddPCR) assay that incorporates features to improve sensitivity and allows for the simultaneous detection and longitudinal monitoring of two TERT promoter mutations (C228T and C250T) in cfDNA from the plasma of patients with glioma.In baseline performance in tumor tissue, the assay had perfect concordance with an independently performed clinical pathology laboratory assessment of TERT promoter mutations in the same tumor samples [95% confidence interval (CI), 94%-100%]. Extending to matched plasma samples, we detected TERT mutations in both discovery and blinded multi-institution validation cohorts with an overall sensitivity of 62.5% (95% CI, 52%-73%) and a specificity of 90% (95% CI, 80%-96%) compared with the gold-standard tumor tissue-based detection of TERT mutations. Upon longitudinal monitoring in 5 patients, we report that peripheral TERT-mutant allele frequency reflects the clinical course of the disease, with levels decreasing after surgical intervention and therapy and increasing with tumor progression.Our results demonstrate the feasibility of detecting circulating cfDNA TERT promoter mutations in patients with glioma with clinically relevant sensitivity and specificity.
Association of GNPAT p.D519G with Higher Iron Phenotypes in Women with HFE p.C282Y Homozygosity
Authors: Gordon D. McLaren, Pradyumna D. Phatak, James C. Barton, John D. Phillips, Wen-Pin Chen, V. Nathan Subraminiam, Paul C. Adams, Lyle C. Gurrin, Gregory J. Anderson, Grant A. Ramm, Lawrie W. Powell, Charles J. Parker, Mary J. Emond, Christine E. McLaren
Journal: Blood (2017)
Trends in COVID-19 Incidence After Implementation of Mitigation Measures — Arizona, January 22–August 7, 2020
Authors: M. Shayne Gallaway, Jessica Rigler, Susan Robinson, Kristen Herrick, Eugene Livar, Kenneth K. Komatsu, Shane Brady, Jennifer Cunico, Cara M. Christ
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Mitigating the spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), requires individual, community, and state public health actions to prevent person-to-person transmission. Community mitigation measures can help slow the spread of COVID-19; these measures include wearing masks, social distancing, reducing the number and size of large gatherings, pausing operation of businesses where maintaining social distancing is challenging, working from or staying at home, and implementing certain workplace and educational institution controls (1-4). The Arizona Department of Health Services' (ADHS) recommendations for mitigating exposure to SARS-CoV-2 were informed by continual monitoring of patient demographics, SARS-CoV-2 community spread, and the pandemic's impacts on hospitals. To assess the effect of mitigation strategies in Arizona, the numbers of daily COVID-19 cases and 7-day moving averages during January 22-August 7, 2020, relative to implementation of enhanced community mitigation measures, were examined. The average number of daily cases increased approximately 151%, from 808 on June 1, 2020 to 2,026 on June 15, 2020 (after stay-at-home order lifted), necessitating increased preventive measures. On June 17, local officials began implementing and enforcing mask wearing (via county and city mandates),* affecting approximately 85% of the state population. Statewide mitigation measures included limitation of public events; closures of bars, gyms, movie theaters, and water parks; reduced restaurant dine-in capacity; and voluntary resident action to stay at home and wear masks (when and where not mandated). The number of COVID-19 cases in Arizona peaked during June 29-July 2, stabilized during July 3-July 12, and further declined by approximately 75% during July 13-August 7. Widespread implementation and enforcement of sustained community mitigation measures informed by state and local officials' continual data monitoring and collaboration can help prevent transmission of SARS-CoV-2 and decrease the numbers of COVID-19 cases.
Gallbladder Perforation Into the Peritoneal Cavity
Authors: Bing F. Wang, Steven Yi, Jayanth Keshavamurthy, Hadyn Williams, Darko Pucar
Journal: Clinical Nuclear Medicine (2020)

Gallbladder perforation is an uncommon but morbid complication of acute cholecystitis with mural ischemia and necrosis. The most common site of perforation is the fundus because of limited blood supply in this region. The Niemeier classification proposed in 1934 remains the criterion standard in grading gallbladder perforation; type 1 is acute with free perforation into the peritoneal cavity, type 2 is subacute with pericholecystic abscess, and type 3 is chronic with cholecystoenteric fistula. We report a challenging case of type 1 gallbladder perforation due to acute acalculous cholecystitis.
N-Terminal Pro-B-Type Natriuretic Peptide and Clinical Outcomes
Authors: Justin A. Ezekowitz, Christopher M. O’Connor, Richard W. Troughton, Wendimagegn G. Alemayehu, Cynthia M. Westerhout, Adriaan A. Voors, Javed Butler, Carolyn S.P. Lam, Piotr Ponikowski, Michele Emdin, Mahesh J. Patel, Burkert Pieske, Lothar Roessig, Adrian F. Hernandez, Paul W. Armstrong
Journal: JACC Heart Failure (2020)

The purpose of this study was to examine the treatment effect of vericiguat in relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at randomization.Vericiguat compared with placebo reduced the primary outcome of cardiovascular death (CVD) or heart failure hospitalization (HFH) in patients with HF with reduced ejection fraction (HFrEF) in the VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial. Because an interaction existed between treatment and the primary outcome according to pre-specified quartiles of NT-proBNP at randomization, we examined this further.This study evaluated the NT-proBNP relationship with the primary outcome in 4,805 of 5,050 patients as a risk-adjusted, log-transformed continuous variable. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented.Median NT-proBNP was 2,816 pg/ml (25th to 75th percentile: 1,556 to 5,314 pg/ml). The study treatment effect varied across the spectrum of NT-proBNP at randomization (with log2 transformation, p for interaction = 0.002). A significant association between treatment effects existed in patients with levels <4,000 pg/ml and remained evident up to 8,000 pg/ml. A 23% relative risk reduction occurred in the primary endpoint with NT-proBNP ≤4,000 pg/ml (HR: 0.77; 95% CI: 0.68 to 0.88). For NT-proBNP values ≤4,000 pg/ml (n = 3,100), the HR was 0.78 (95% CI: 0.67 to 0.90) for HFH and 0.75 (95% CI: 0.60 to 0.94) for CVD. For NT-proBNP ≤8,000 pg/ml (n = 4,133), the HR was 0.85 (95% CI: 0.76 to 0.95) for the primary outcome, 0.84 (95% CI: 0.75 to 0.95) for HFH, and 0.84 (95% CI: 0.71 to 0.99) for CVD. For NT-proBNP >8,000 pg/ml (n = 672), the HR was 1.16 (95% CI: 0.94 to 1.41) for the primary outcome.A reduction in the primary composite endpoint and its CVD and HFH components was observed in patients on vericiguat compared with subjects on placebo with NT-proBNP levels up to 8,000 pg/ml. This provided new insight into the benefit observed in high-risk patients with worsening HFrEF. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).
The use of validated geriatric assessment instruments among U.S. community oncologists.
Authors: Ajeet Gajra, Yolaine Jeune-Smith, Stephanie Fortier, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2020)

129 Background: Older adults are disproportionately affected by cancer and may be under-treated due to concerns for adverse events or may suffer excessive toxicity from standard cancer treatments due to comorbidity and diminished physiologic reserve. A geriatric assessment (GA) can assist with risk stratification, inform treatment decisions and improve outcomes in older adults with cancer. This descriptive study aimed to assess knowledge, perceptions, and utilization of GA instruments among community oncologists/hematologists (cOH) with an overall goal to identify actionable disparities in the management of older adults with cancer. Methods: Questions about GA in the care of older adults with cancer were developed by two medical oncologists (AG and BAF) and presented to cOH with diverse geographic representation at live meetings and a preceding web-based survey between September 2019 and February 2020. Descriptive statistics were used to analyze the results. Results: Of the 349 participants, the response rate was 100%. The cut-off age used to define older adults by cOH was: ≥ 65 years (22%), ≥ 70 years (39%), and ≥75 (32%). The proportion of patients aged ≥ 70 years in their practices was reported as: 26-50% (48%) and &gt; 50% (22%). Most cOH (60%) performed no formal GA to inform treatment decisions. The two most common reasons for not performing GA were: “Too cumbersome to incorporate into routine practice” (44%), and “Adds no value beyond the comprehensive history and physical exam” (36%). cOH awareness of validated GA/related instruments was: Mini-Mental State Exam (MMSE; 63%), Comprehensive GA (CGA; 37%) and CARG (Cancer and Aging Research Group) GA tool (22%); 22% were not aware of any validated instruments. Outside of clinical trials, the most frequently used validated GA instruments were: MMSE (54%), CGA (23%), CARG (12%), and CRASH (9%). For older adults with cancer, ECOG performance status and comorbidities were the two GA-related surrogate factors utilized in treatment decisions (88% and 73%, respectively). Conclusions: A majority of US community oncologists do not incorporate formal GA with validated instruments in the decision-making for older patients with cancer due to lack of time, resources and awareness. Education directed towards community oncologists may change perception and practice.
The Amino-Terminal Oligomerization Domain of Angiopoietin-2 Affects Vascular Remodeling, Mammary Gland Tumor Growth, and Lung Metastasis in Mice
Authors: Emmi Kapiainen, Minna K. Kihlström, Riikka Pietilä, Mika Kaakinen, Veli-Pekka Ronkainen, Hongmin Tu, Anne Heikkinen, Raman Devarajan, Ilkka Miinalainen, Anna Laitakari, Mohammadhassan Ansarizadeh, Qin Zhang, Gong-Hong Wei, Lloyd Ruddock, Taina Pihlajaniemi, Harri Elamaa, Lauri Eklund
Journal: Cancer Research (2020)

Angiopoietin-2 (ANGPT2) is a context-dependent TIE2 agonistic or antagonistic ligand that induces diverse responses in cancer. Blocking ANGPT2 provides a promising strategy for inhibiting tumor growth and metastasis, yet variable effects of targeting ANGPT2 have complicated drug development. ANGPT2443 is a naturally occurring, lower oligomeric protein isoform whose expression is increased in cancer. Here, we use a knock-in mouse line (mice expressing Angpt2443), a genetic model for breast cancer and metastasis (MMTV-PyMT), a syngeneic melanoma lung colonization model (B16F10), and orthotopic injection of E0771 breast cancer cells to show that alternative forms increase the diversity of Angpt2 function. In a mouse retina model of angiogenesis, expression of Angpt2443 caused impaired venous development, suggesting enhanced function as a competitive antagonist for Tie2. In mammary gland tumor models, Angpt2443 differentially affected primary tumor growth and vascularization; these varying effects were associated with Angpt2 protein localization in the endothelium or in the stromal extracellular matrix as well as the frequency of Tie2-positive tumor blood vessels. In the presence of metastatic cells, Angpt2443 promoted destabilization of pulmonary vasculature and lung metastasis. In vitro, ANGPT2443 was susceptible to proteolytical cleavage, resulting in a monomeric ligand (ANGPT2DAP) that inhibited ANGPT1- or ANGPT4-induced TIE2 activation but did not bind to alternative ANGPT2 receptor α5β1 integrin. Collectively, these data reveal novel roles for the ANGPT2 N-terminal domain in blood vessel remodeling, tumor growth, metastasis, integrin binding, and proteolytic regulation. SIGNIFICANCE: This study identifies the role of the N-terminal oligomerization domain of angiopoietin-2 in vascular remodeling and lung metastasis and provides new insights into mechanisms underlying the versatile functions of angiopoietin-2 in cancer.See related commentary by Kamiyama and Augustin, p. 35.
Partha Kar: We must be honest with patients about the future of services
Authors: Partha Kar
Journal: BMJ (2020)

There’s a commonly held public assumption that the NHS can provide everything medical science has to offer, to all who need it—or, at least, that this is the stated aim. Yet prioritisation has always existed in healthcare, whether driven by policy or the embedding of the “inverse care law.” It’s just that, as a system, the NHS has rarely been able to acknowledge this publicly.

Political rhetoric around the NHS from all parties may mean that healthcare leaders have balked at the idea that prioritisation of services can be openly discussed. As a result, the NHS finds itself caught between its public perception as the country’s “jewel in the crown”—offering …
Distinct Expression of Coinhibitory Molecules on Alveolar T Cells in Patients With Rheumatoid Arthritis–Associated and Idiopathic Inflammatory Myopathy–Associated Interstitial Lung Disease
Authors: Maho Nakazawa, Katsuya Suzuki, Masaru Takeshita, Jun Inamo, Hirofumi Kamata, Makoto Ishii, Yoshitaka Oyamada, Hisaji Oshima, Tsutomu Takeuchi
Journal: Arthritis & Rheumatology (2020)

Objective To identify immunologic factors in the lungs of patients with rheumatoid arthritis–associated interstitial lung disease (RA‐ILD) and patients with idiopathic inflammatory myopathy–associated ILD (IIM‐ILD) and to examine their pathologic mechanisms. Methods Eleven patients with RA‐ILD, 16 with IIM‐ILD, 6 with drug‐induced ILD (DI‐ILD), and 8 healthy controls were enrolled. Peripheral blood (PB) and bronchoalveolar lavage (BAL) fluid were immunophenotyped by flow cytometry. Alveolar macrophages (AMs) were analyzed by coculture assay with PB naive CD4+ T cells from healthy individuals and RNA sequencing. Results Several coinhibitory molecules were coexpressed on BAL fluid T cells (CTLA‐4, programmed death 1 [PD‐1], T cell immunoglobulin and mucin domain–containing protein 3 [TIM‐3], and lymphocyte activation gene 3 protein, from most to least), whereas only PD‐1 was expressed on PB T cells. CTLA‐4+PD‐1+CD4+ T cells were characteristic of RA‐ILD, whereas CTLA‐4+PD‐1+TIM‐3+CD8+ T cells were characteristic of IIM‐ILD. BAL fluid PD‐1+CD4+ T cells rarely expressed CXCR5, but their levels correlated with levels of plasmablasts and plasma cells (ρ = 0.57, P = 0.006), indicating that most of them would be considered peripheral helper T cells. In coculture experiments, AMs from patients with RA‐ILD and IIM‐ILD induced more PD‐1 and TIM‐3 on T cells ( P &lt; 0.05), suggesting that coinhibitory molecule expression on BAL fluid T cells was partly due to AMs. RNA sequencing showed significant down‐regulation of PD ligand 1/2 genes in AMs from patients with RA‐ILD compared to those with DI‐ILD. Conclusion We have identified differences in coinhibitory molecule expression between patients with RA‐ILD and those with IIM‐ILD. PD‐1 on T cells in RA‐ILD and TIM‐3 on CD8+ T cells in IIM‐ILD might be key factors in the disease process. Evaluation of coinhibitory molecules on BAL fluid T cells could be clinically useful.
Biosimilar usage in practices within the ASCO PracticeNET learning network.
Authors: Brian Bourbeau, Elizabeth Garrett-Mayer, Mou Guharoy, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2020)

77 Background: In recent years, several antineoplastic biosimilar products have been approved and marketed for use. We analyzed data from the ASCO PracticeNET learning network to gain insights on the adoption of biosimilar products for bevacizumab, rituximab, and trastuzumab. Methods: Our analysis included the following products: bevacizumab, bevacizumab-awwb, bevacizumab-bvzr, rituximab (excluding rituximab and hyaluronidase), rituximab-abbs, trastuzumab, trastuzumab-anns, and trastuzumab-dkst, administered from July 2019 to March 2020. 19 practices submitted their billing data; practices ranged in size from 2 to 29 hematologists/oncologists. Products were identified through use of healthcare common procedure coding system codes. The proportion of biosimilar product doses administered, as a percent of total doses for all related products, was calculated per participating practice. Results: Use of biosimilar products for bevacizumab (first biosimilar approval in September 2017) was first detected in August 2019, averaging 1.4% of administered doses (confidence intervals included in Table) with a range from 0% to 27% among participating practices; by March 2020, average use increased to 31% with a range from 0% to 100%. Use of biosimilar products for rituximab (first biosimilar approval in November 2018), was first detected in January 2020, averaging 2.6% of administered doses, with range of 0% to 30%; by March 2020, average use increased to 18%, with a range of 0% to 61%. Use of biosimilar products for trastuzumab (first biosimilar approval in December 2017) was first detected in September 2019, averaging 0.9% of administered doses with a range of 0% to 17%; by March 2020, average use increased to 35%, with a range of 0% to 98%. Conclusions: The release of biosimilar products has been identified as a potential opportunity to lower the cost of drug therapy for cancer patients. Our analysis identified an approximate 2-year lag from product approval to initial utilization followed by a steady increase in the use of biosimilar products, along with a wide range of use among practices. [Table: see text]