tbuckley/cabot-search huggingface dataset:
Use of Do-Not-Resuscitate Orders for Critically Ill Patients with ESKD
Authors: John Danziger, Miguel Ángel Armengol de la Hoz, Leo Anthony Celi, Robert A. Cohen, Kenneth J. Mukamal
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Despite having high rates of comorbid illnesses and significantly shortened life expectancy, patients with ESKD may be unrealistically optimistic about their own prognoses. In their study of do-not-resuscitate (DNR) orders upon admission to intensive care in a large sample of critically ill patients from hospitals across the United States, the authors observed more frequent DNR orders among patients with diseases of other major organs compared with patients without major organ disease. However, despite overall higher rates of comorbidity and hospital mortality in patients with ESKD, they found no such difference in the use of DNR orders between patients with and without ESKD. The lower use of DNR orders in this highly comorbid group might reflect a missed opportunity to avoid overmedicalization and unnecessary patient suffering at the end of life. Background Despite having high comorbidity rates and shortened life expectancy, patients with ESKD may harbor unrealistically optimistic expectations about their prognoses. Whether this affects resuscitation orders is unknown. Methods To determine whether do-not-resuscitate (DNR) orders differ among patients with ESKD compared with other critically ill patients, including those with diseases of other major organs, we investigated DNR orders on admission to intensive care units (ICUs) among 106,873 patients in the United States. Results Major organ disease uniformly associated with increased risk of hospital mortality, particularly for cirrhosis (adjusted odds ratio [aOR], 2.67; 95% confidence interval [95% CI], 2.30 to 3.08), and ESKD (aOR, 1.47; 95% CI, 1.31 to 1.65). Compared with critically ill patients without major organ disease, patients with stroke, cancer, heart failure, dementia, chronic obstructive pulmonary disease, and cirrhosis were statistically more likely to have a DNR order on ICU admission; those with ESKD were not. Findings were similar when comparing patients with a single organ disease with those without organ disease. The disconnect between prognosis and DNR use was most notable among Black patients, for whom ESKD (compared with no major organ disease) was associated with a 62% (aOR, 1.62; 95% CI, 1.27 to 2.04) higher odds of hospital mortality, but no appreciable difference in DNR utilization (aOR, 1.06; 95% CI, 0.66 to 1.62). Conclusions Unlike patients with diseases of other major organs, critically ill patients with ESKD were not more likely to have a DNR order than patients without ESKD. Whether this reflects a greater lack of advance care planning in the nephrology community, as well as a missed opportunity to minimize potentially needless patient suffering, requires further study.
NR4A nuclear receptors restrain B cell responses to antigen when second signals are absent or limiting
Authors: Corey Tan, Ryosuke Hiwa, James L. Mueller, Vivasvan Vykunta, Kenta Hibiya, Mark Noviski, John Huizar, Jeremy F. Brooks, Jose Garcia, Cheryl Heyn, Zhongmei Li, Alexander Marson, Julie Zikherman
Journal: Nature Immunology (2020)
Effects of Low-Fat, Mediterranean, or Low-Carbohydrate Weight Loss Diets on Serum Urate and Cardiometabolic Risk Factors: A Secondary Analysis of the Dietary Intervention Randomized Controlled Trial (DIRECT)
Authors: Chio Yokose, Natalie McCormick, Sharan K. Rai, Na Lu, Gary Curhan, Dan Schwarzfuchs, Iris Shai, Hyon K. Choi
Journal: Diabetes Care (2020)

OBJECTIVE Weight loss diets may reduce serum urate (SU) by lowering insulin resistance while providing cardiometabolic benefits, something urate-lowering drugs have not shown in trials. We aimed to examine the effects of weight loss diets on SU and cardiometabolic risk factors. RESEARCH DESIGN AND METHODS This secondary study of the Dietary Intervention Randomized Controlled Trial (DIRECT) used stored samples from 235 participants with moderate obesity randomly assigned to low-fat, restricted-calorie (n = 85); Mediterranean, restricted-calorie (n = 76); or low-carbohydrate, non–restricted-calorie (n = 74) diets. We examined SU changes at 6 and 24 months overall and among those with hyperuricemia (SU ≥416 μmol/L), a relevant subgroup at risk for gout. RESULTS Among all participants, average SU decreases were 48 μmol/L at 6 months and 18 μmol/L at 24 months, with no differences between diets (P &amp;gt; 0.05). Body weight, HDL cholesterol (HDL-C), total cholesterol:HDL-C ratio, triglycerides, and insulin concentrations also improved in all three groups (P &amp;lt; 0.05 at 6 months). Adjusting for covariates, changes in weight and fasting plasma insulin concentrations remained associated with SU changes (P &amp;lt; 0.05). SU reductions among those with hyperuricemia were 113, 119, and 143 μmol/L at 6 months for low-fat, Mediterranean, and low-carbohydrate diets (all P for within-group comparison &amp;lt; 0.001; P &amp;gt; 0.05 for between-group comparisons) and 65, 77, and 83 μmol/L, respectively, at 24 months (all P for within-group comparison &amp;lt; 0.01; P &amp;gt; 0.05 for between-group comparisons). CONCLUSIONS Nonpurine-focused weight loss diets may simultaneously improve SU and cardiovascular risk factors likely mediated by reducing adiposity and insulin resistance. These dietary options could provide personalized pathways to suit patient comorbidity and preferences for adherence.
Complete Tumor Regression by Liposomal Bortezomib in a Humanized Mouse Model of Multiple Myeloma
Authors: Anil K. Deshantri, Marcel H.A.M. Fens, Ruud W.J. Ruiter, Josbert M. Metselaar, Gert Storm, Sanjay N. Mandhane, Gerard H.M. Graat, Eef G.W. Lentjes, Huipin Yuan, Joost D. de Bruijn, Tuna Mutis, Anton C.M. Martens, Richard W.J. Groen, Raymond M. Schiffelers
Journal: HemaSphere (2020)

Supplemental Digital Content is available in the text
Predicting the progression of mild cognitive impairment using machine learning: A systematic, quantitative and critical review
Authors: Manon Ansart, Stéphane Epelbaum, Giulia Bassignana, Alexandre Bône, Simona Bottani, Tiziana Cattai, Raphaël Couronné, Johann Faouzi, Igor Koval, Maxime Louis, Elina Thibeau-Sutre, Junhao Wen, Adam Wild, Ninon Burgos, Didier Dormont, Olivier Colliot, Stanley Durrleman
Journal: Medical Image Analysis (2020)
Abstract 3258: Reconstituted functional Tim-3/Gal-9 immune checkpoint cell line to screen for novel Tim-3 ICBs
Authors: Fang Zhang, Pei Wu, Jun Liu, Baiqiu Wang
Journal: Cancer Research (2020)

Abstract Background: Tim-3 (T-cell immunoglobin and mucin-domain containing-3) has emerged as a promising novel immune checkpoint target playing non-redundant and synergistic roles with PD-1 in triggering T cell exhaustion, however, the complexity of Tim-3-interacting ligands (Gal-9, Ceacam1 and others) has posed a challenge to reconstitute functional Tim-3-targeting immune checkpoint blockers (ICBs) cellular screening system. Materials and methods: To address this challenge, we have engineered Tim-3 Advanced Genomic Manipulated human Jurkat T IL-2-Luc2P reporter cells (Tim-3 AGM T cells) via multiple steps of electroporation-mediated genomic manipulation, and validated the functionality of this reconstituted Tim-3 immune checkpoint cellular system using IL-2-Luc2P reporter assay and IL-2 ELISA following TCR and CD28 engagement. Results: We found that anti-CD3/CD28-induced T cell activation in the Tim-3 AGM T cells as assessed by IL-2-Luc2P reporter was significantly suppressed (~80%) after over-expression of Gal-9 but not the empty vector control, validating functionality of the reconstituted Tim-3/Gal-9 immune checkpoint complex. Conclusions: Such an innovative reconstituted functional Tim-3/Gal-9 immune checkpoint reporter cell line can enable high through-put screening for novel Tim-3 ICBs including small or large molecule therapeutics and following in-depth mechanistic studies. Citation Format: Fang Zhang, Pei Wu, Jun Liu, Baiqiu Wang. Reconstituted functional Tim-3/Gal-9 immune checkpoint cell line to screen for novel Tim-3 ICBs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3258.
Methylation-mediated LINC00261 suppresses pancreatic cancer progression by epigenetically inhibiting c-Myc transcription
Authors: Songsong Liu, Yao Zheng, Yujun Zhang, Junfeng Zhang, Fuming Xie, Shixiang Guo, Jianyou Gu, Jiali Yang, Ping Zheng, Jiejuan Lai, Liangyu Yin, Huaizhi Wang
Journal: Theranostics (2020)

Due to the limitations of strategies for its early diagnosis and treatment, pancreatic cancer (PC) remains a substantial human health threat. We previously discovered a methylation-mediated lncRNA, LINC00261, which is downregulated in PC tissues. However, the underlying role of LINC00261 in PC remains largely unknown.
Toward Historical Accountability and Remembrance: The German Society for Internal Medicine and Its Legacies From the Nazi Past
Authors: Hans-Georg Hofer, Ralf Forsbach, Ulrich R. Fölsch
Journal: Annals of Internal Medicine (2020)

After decades of silence, the German Society for Internal Medicine (DGIM) has made considerable efforts to come to terms with its role and actions during the Nazi era (1933 to 1945). This is particularly important because, with more than 27 000 members, the DGIM is the largest medical society in present-day Germany. Since 1882, the society's annual congress in Wiesbaden has provided a forum and focus for the key medical topics of the day. Based on ongoing historical research, this article is organized in 2 parts. The first describes how the DGIM willingly adapted to the ideology and politics of the Nazi regime, showing no solidarity with its persecuted Jewish members. To illustrate their fates, the cases of Leopold Lichtwitz, who was forced to resign as elected chairman in 1933, and committee member Julius Bauer are investigated. Both men emigrated to the United States. Light is also shed on the decisions of those who led the society during the Nazi era and on the involvement of high-ranking members in medical crimes. The second part of the article analyzes developments in the postwar period and considers why it took so long to hold up a mirror to the past. Although critical voices could be heard from both outside and within the society, they remained isolated and without consequence. Only the past 2 decades have brought about both general and specific developments toward historical accountability and an active culture of remembrance. With a declaration first published in 2015, a new website bringing history and memory together, and a strong commitment to the norms and values of liberal democracy, the DGIM has found its way to a clear position—and has lessons to teach.
Abstract 6585: Systems biology for investigating drug resistance mechanism of melanoma
Authors: Yapeng Su, Guideng Li, Melissa Ko, Hanjun Cheng, Ronghui Zhu, Min Xue, Lidia Robert, Raphael Levine, Antoni Ribas, Garry Nolan, Wei Wei, Sylvia Plevritis, David Baltimore, James R. Heath
Journal: Cancer Research (2020)

Abstract Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line Cancers commonly develop resistance against chemotherapeutics or targeted therapies through various types of genetic or non-genetic mechanisms. Non-genetic mechanisms have been shown to occur early on and can provide a latent reservoir of cells for the emergence of various different type of mechanisms, yet very limited understanding of process were resolve main from bulk analysis. Considering the heterogeneous nature of the tumor cells, a single-cell level characterization of the process worth detailed further investigation. Using MAPK inhibition of BRAF-mutant melanomas as a model system, we resolved that cells take different paths to go from drug-sensitive to drug-resistant state. Using a microfludic-based single-cell integrated proteomic and metabolic assay, we assayed for a panel of signaling, phenotypic, and metabolic regulators at four time points during the first five days of drug treatment. Dimensional reduction of the resultant data set, coupled with information theoretic analysis, uncovered a complex cell state landscape and identified two distinct paths connecting drug-naïve and drug-tolerant states. Cells are shown to exclusively traverse one of the two pathways depending on the level of the lineage restricted transcription factor MITF in the drug-naïve cells. The two trajectories are associated with distinct signaling and metabolic susceptibilities, and are independently druggable. Our results update the paradigm of adaptive resistance development in an isogenic cell population and offer insight into the design of more effective combination therapies. Citation Format: Yapeng Su, Guideng Li, Melissa Ko, Hanjun Cheng, Ronghui Zhu, Min Xue, Lidia Robert, Raphael Levine, Antoni Ribas, Garry Nolan, Wei Wei, Sylvia Plevritis, David Baltimore, James R. Heath. Systems biology for investigating drug resistance mechanism of melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6585.
Abstract 3254: MOTO-CARs™: A novel macrophage-based chimeric antigen receptor technology
Authors: Michelle Hannah Townsend, Zachary D. Ewell, Kelsey A. Bennion, Guoying Wang, Jonathan Skidmore, David Lum, Michael Boyer, Kim L. O'Neill
Journal: Cancer Research (2020)

Abstract We report the development of a novel macrophage-mediated immunotherapy targeting mesothelin-expressing solid tumors. Although the advent of immunotherapy heralded a new era in cancer treatment, it has been accompanied by severe limitations, including antigen escape, cytokine release syndrome (CRS), and the inability to penetrate solid tumors. We sought to ameliorate these issues by developing a macrophage toll-like chimeric antigen receptor (MOTO-CAR™) designed to target and activate upon cancer antigen recognition. Here we show evidence supporting this proof-of-concept MOTO-CAR™ technology in a murine macrophage cell line (RAW 264.7) targeting a mesothelin-expressing, triple-negative, mammary gland squamous carcinoma cell line (HCC-1806). The MOTO-CAR™ construct was transfected into macrophage cells with an average efficiency above 50%. The presence of the chimeric construct was confirmed via mesothelin scFv amplification of isolated mRNA, and the engineered macrophages stably expressed the chimeric receptor for over 7 days, with the highest level of expression approximately 24 hours post transfection. We found that upon exposure to HCC-1806 cells, MOTO-CARs™ are not only effective at eliminating the cancer cells, but also secrete significant levels of TNF-α when compared to mock controls (p= 0.009), indicating activation and polarization to an M1 phenotype upon target recognition. In vitro cytotoxicity assays confirmed that macrophages containing the MOTO-CAR™ construct increasingly targeted and killed HCC-1806 cells when compared to the mock control (p &amp;lt; 0.0001) in three different effector to target ratios. Furthermore, in NSG mice containing HCC-1806-derived xenografts, tumor burdens were significantly lower in mice treated with MOTO-CARs™ when compared to the mock control (p = 0.006). In these models, the MOTO-CARs were administered through the tail vein, which indicates the MOTO-CARs™ can traffic effectively to the tumor site in vivo. Both TLR4 and TLR2 based toll-like receptor signaling domains were evaluated with TLR4 vectors showing higher killing and better efficacy against target cancer cells. Following initial testing in RAW 264.7 macrophages, similar results were observed when MOTO-CARs™ derived from primary human monocytes were co-incubated with the same target cells. These data illustrate the potential for MOTO-CARs™ to be a powerful alternative to current immunotherapies targeting solid tumors. Citation Format: Michelle Hannah Townsend, Zachary D. Ewell, Kelsey A. Bennion, Guoying Wang, Jonathan Skidmore, David Lum, Michael Boyer, Kim L. O'Neill. MOTO-CARs™: A novel macrophage-based chimeric antigen receptor technology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3254.
Layered dissolving microneedles as a need-based delivery system to simultaneously alleviate skin and joint lesions in psoriatic arthritis
Authors: Kaiyue Yu, Xiuming Yu, Sisi Cao, Yixuan Wang, Yuanhao Zhai, Fengdie Yang, Xiaoyuan Yang, Yi Lu, Chuanbin Wu, Yuehong Xu
Journal: Acta Pharmaceutica Sinica B (2020)

Psoriatic arthritis (PsA) is a complicated psoriasis comorbidity with manifestations of psoriatic skin and arthritic joints, and tailoring specific treatment strategies for simultaneously delivering different drugs to different action sites in PsA remains challenging. We developed a need-based layered dissolving microneedle (MN) system loading immunosuppressant tacrolimus (TAC) and anti-inflammatory diclofenac (DIC) in different layers of MNs, i.e., TD-MN, which aims to specifically deliver TAC and DIC to skin and articular cavity, achieving simultaneous alleviation of psoriatic skin and arthritic joint lesions in PsA. In vitro and in vivo skin permeation demonstrated that the inter-layer retained TAC within the skin of ∼100 μm, while the tip-layer delivered DIC up to ∼300 μm into the articular cavity. TD-MN not only efficiently decreased the psoriasis area and severity index scores and recovered the thickened epidermis of imiquimod-induced psoriasis but also alleviated carrageenan/kaolin-induced arthritis even better than DIC injection through reducing joint swelling, muscle atrophy, and cartilage destruction. Importantly, TD-MN significantly inhibited the serum TNF-α and IL-17A in psoriatic and arthritic rats. The results support that this approach represents a promising alternative to multi-administration of different drugs for comorbidity, providing a convenient and effective strategy for meeting the requirements of PsA treatment.
Current smoking status is associated with reduced sputum immunoglobulin M and G expression in COPD
Authors: Steven P. Cass, Yuqiong Yang, Jing Xiao, Joshua J.C. McGrath, Matthew F. Fantauzzi, Danya Thayaparan, Fengyan Wang, Zhenyu Liang, Fei Long, Christopher S. Stevenson, Rongchang Chen, Martin R. Stampfli
Journal: European Respiratory Journal (2020)

<b>Current smoking status in subjects with mild to moderate COPD was associated with reduced total induced sputum IgM and IgG. This reduction in immunoglobulins was independent of inhaled corticosteroid use.</b>https://bit.ly/2FtBg1t
SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control
Authors: Magdalene K. Montgomery, Jacqueline Bayliss, Camille Devereux, Ayenachew Bezawork-Geleta, David Roberts, Cheng Huang, Ralf B. Schittenhelm, Andrew Ryan, Scott L. Townley, Luke A. Selth, Trevor J. Biden, Gregory R. Steinberg, Dorit Samocha-Bonet, Ruth C. R. Meex, Matthew J. Watt
Journal: Science Translational Medicine (2020)

Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3',5'-cyclic monophosphate (cAMP)-cAMP-dependent protein kinase (PKA)-cAMP response element-binding protein (CREB) signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Overexpression of SMOC1 in the liver or once-weekly intraperitoneal injections of a stabilized SMOC1-FC fusion protein induced durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without adverse effects on adiposity, liver histopathology, or inflammation. Furthermore, circulating SMOC1 correlated with hepatic and systemic insulin sensitivity and was decreased in obese, insulin-resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.
Abstract 4709: Loss of GPSM2 promotes the metastasis of non-small cell lung cancer by inducing the expression of Snail
Authors: Bofang Liu, Mingming Deng, Jingdong Zhang, Feifei Li, Weidong Han, Hongming Pan
Journal: Cancer Research (2020)

Abstract Background/Aims: Non-small cell lung cancer (NSCLC) is the leading global cause of cancer-related death. Due to the lack of reliable diagnostic or prognostic biomarkers, the prognosis of NSCLC remains poor. Consequently, there is an urgent need to explore the mechanisms underlying this condition in order to identify effective biomarkers. G protein signaling modulator 2 (GPSM2) is widely recognized as a determinant of mitotic spindle orientation. However, its role in cancer, especially NSCLC, remains uncertain. Methods: Tissue microarray (TMA) were used to compare differences in GPSM2 expression, and its relationship with clinical characteristics and prognosis. Wound healing assay, transwell assay and lung metastatic mice model were used to explore the biological function of GPSM2 on NSCLC cells in vitro and in vivo. Western blot and immunohistochemistry were conducted to investigate the potential pathways of GPSM2. Results: In this study, we found that GPSM2 was downregulated in NSCLC tissues and was correlated with a poor prognosis,and the expression status of GPSM2 was a favorable independent prognostic factor(HR = 0.222; 95% CI = 0.052 - 0.959; P = 0.044). Furthermore, the knockdown of GPSM2 promoted NSCLC cell metastasis in vitro and in vivo and accelerated the process of epithelial-to-mesenchymal transition (EMT). Mechanistically, we demonstrated that silencing GPSM2 induced cell metastasis and EMT via the ERK/GSK-3β/Snail pathway. Conclusion: These results confirm that GPSM2 plays an important role in NSCLC. Moreover, GPSM2, as an independent prognostic factor, may be a potential prognostic biomarker and drug target for NSCLC. Citation Format: Bofang Liu, Mingming Deng, Jingdong Zhang, Feifei Li, Weidong Han, Hongming Pan. Loss of GPSM2 promotes the metastasis of non-small cell lung cancer by inducing the expression of Snail [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4709.