tbuckley/cabot-search huggingface dataset:
Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses
Authors: Jennifer A. Lo, Masayoshi Kawakubo, Vikram R. Juneja, Mack Y. Su, Tal H. Erlich, Martin W. LaFleur, Lajos V. Kemeny, Mamunur Rashid, Mohsen Malehmir, S. Alireza Rabi, Rumya Raghavan, Jennifer Allouche, Gyulnara Kasumova, Dennie T. Frederick, Kristen E. Pauken, Qing Yu Weng, Marcelo Pereira da Silva, Yu Xu, Anita A. J. van der Sande, Whitney Silkworth, Elisabeth Roider, Edward P. Browne, David J. Lieb, Belinda Wang, Levi A. Garraway, Catherine J. Wu, Keith T. Flaherty, Constance E. Brinckerhoff, David W. Mullins, David J. Adams, Nir Hacohen, Mai P. Hoang, Genevieve M. Boland, Gordon J. Freeman, Arlene H. Sharpe, Dieter Manstein, David E. Fisher
Journal: Science Translational Medicine (2021)

Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8+ T cell populations specific for melanocyte antigens was observed only in patients who responded to anti-PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti-PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti-PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod.
Abstract PS17-24: Inhibition of short-form ron eliminates breast cancer metastases through an immune-mediated mechanism
Authors: Shu-Chin Alicia Lai, Harika Gundlapalli, Huseyin A Ekiz, Alana L Welm
Journal: Cancer Research (2021)

Abstract Metastatic breast cancer is the overwhelming cause of breast cancer mortality and is still incurable. The rapid development of immunotherapy is an exciting new area of research in metastatic breast cancer. However, the extreme immunosuppressive tumor environment poses a major challenge. A better understanding of how the immune system can be harnessed against metastatic cancer is required to improve patient outcomes. We previously showed that expression of the receptor tyrosine kinase Ron in the host, rather than Ron's tumor expression, contributed to tumor-associated immunosuppression and duo inhibition of Ron and CTLA-4 significantly reduced metastatic outgrowth. However, the actual mechanism remains unclear. The present study provides evidence that the N-terminal truncated isoform, short-form Ron (SF-Ron), is the major contributor in suppressing the anti-tumor immune responses and promoting metastatic outgrowth. Genetic deletion of host SF-Ron nearly eliminated breast cancer metastasis in mice, lead to systemic immune-activation, increased recruitment of lymphocytes to the site of metastasis, and augmented tumor-specific T-cell responses. Lack of SF-Ron also leads to the accumulation of CD4+ T-cells in the metastatic lungs and endowed with anti-tumor potential. Importantly, mice treated with small molecule Ron kinase inhibitor that targets both Ron and SF-Ron, produced significantly higher, active, tumor-specific CD8+ T-cells. Our study indicates that blocking Ron, especially the SF-Ron, remodels the metastatic lung microenvironment to enhance anti-tumor immunity. This study sheds light on the potential non-redundant roles of full-length and SF-Ron isoforms in mediating breast cancer metastasis and anti-tumor immune responses; and highlights the relevance of combining Ron inhibitors with immunotherapeutic agents to potentially improve treatment efficacy for metastatic breast cancer patients. Citation Format: Shu-Chin Alicia Lai, Harika Gundlapalli, Huseyin A Ekiz, Alana L Welm. Inhibition of short-form ron eliminates breast cancer metastases through an immune-mediated mechanism [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-24.
IL-6R blockade by chikusetsusaponin IVa butyl ester inhibits Th17 cell differentiation and ameliorates collagen-induced arthritis
Authors: Jie Yang, Yuanyuan Ling, Di Hua, Chenglei Zhao, Xiaoyan Sun, Xueting Cai, Jiao Chen, Chunping Hu, Peng Cao
Journal: Cellular and Molecular Immunology (2021)
Analysis of Active and Passive Tobacco Exposures and Blood Pressure in US Children and Adolescents
Authors: Rebecca V. Levy, Kaye E. Brathwaite, Harini Sarathy, Kimberly Reidy, Frederick J. Kaskel, Michal L. Melamed
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Hypertension is a leading cause of cardiovascular disease in adults; preclinical associations between hypertension and cardiovascular disease are seen in childhood. Nicotine is a known toxin, but its association with pediatric hypertension is unclear. <h3>Objective</h3> To test the hypothesis that tobacco exposure is associated with the presence of elevated blood pressure in US children and adolescents and that this association is dose dependent. <h3>Design, Setting, and Participants</h3> This cross-sectional study used data from the 2007 to 2016 National Health and Nutrition Examination Survey (NHANES), a population-based nationally representative sample of US children and adolescents. Children were eligible if they were aged 8 to 19 years at the time of participation in the main NHANES study. Exclusion criteria included those of the main NHANES study, inability to complete testing, or missing questionnaires. Of the 10 143 participants in NHANES aged 8 to 19 during the study years, 8520 were included in the analysis. Analysis was conducted from October 12, 2019, to July 9, 2020. <h3>Exposures</h3> Tobacco exposure, defined as serum cotinine levels greater than 0.05 µg/L, or reporting living with a smoker or smoking themselves. <h3>Main Outcomes and Measures</h3> Elevated blood pressure, classified as greater than 90% for a child's age, sex, and height according to the 2017 American Academy of Pediatrics Clinical Practice Guidelines. The a priori hypothesis that there is a positive association between tobacco exposure and elevated blood pressure in the study population was tested. Analysis included logistic regression with adjustment for possible confounders. Subgroup and sensitivity analyses were conducted. <h3>Results</h3> A total of 8520 children were included in the analysis, representing 41 million US children. The mean (SD) age of the participants was 13.1 (0.05) years, 51% (95% CI, 49%-52%) were male, and 58% (95% CI, 54%-62%) were non-Hispanic White individuals. Participants with any tobacco smoke exposure were more likely than those without exposure to be older (mean [SD] age, 13.3 [0.07] years vs 12.8 [0.06] years), male (53% [95% CI, 51%-55%] vs 49% [95% CI, 47%-50%]), and non-Hispanic Black individuals (19% [95% CI, 16%-22%] vs 10% [95% CI, 8%-12%]). The odds of having elevated blood pressure was 1.31 (95% CI, 1.06-1.61) for any tobacco exposure after adjustment; odds were similar across subgroups and remained significant in multiple sensitivity analyses. <h3>Conclusions and Relevance</h3> This study suggests that tobacco exposure is associated with elevated blood pressure in US children and adolescents. This modifiable risk factor represents a target for further research into reducing hypertension in children and adolescents.
Covid-19: Difficult decisions require reciprocal understanding among decision makers
Authors: Woody Caan
Journal: BMJ (2021)

In selected cases of rheumatoid disease, intra-synovial installation of radionuclides may be used as a means of controlling recurring synovial effusions. In addition to an effective beta emission, the isotope chosen must be complexed into a stable particle that will be rapidly incorporated into the synovial tissue and remain there. <sup>32</sup>P-chromic phosphate was evaluated in nine patients following installation into the knee joint. In eight of these, no leakage of radio-activity could be detected. In one case, beginning 4 days postinstillation, some migration of radioactivity to the ipsilateral inguinal nodes and, to a lesser extent, the sacrum and liver was found. This suggests that <sup>32</sup>P-chromic phosphate has greater stability than materials previously used.
Abstract PS15-11: Intraoperative radiation therapy (IORT) for1200 early breast tumors
Authors: Melinda Epstein, Melvin Silverstein, Peter Chen, Kevin Lin, Brian Kim, Sadia Khan, Lincoln Snyder, Lisa E. Guerra, Colleen Coleman
Journal: Cancer Research (2021)

Abstract Introduction: Two prospective randomized trials, TARGIT-A and ELIOT, have shown intraoperative radiation therapy (IORT) to be a safe alternative with a low-risk of local recurrence compared to whole breast radiation therapy following breast conserving surgery for selected low-risk patients. We report the first 1200 tumors treated with this modality at our facility.Methods: 1200 distinct breast cancers in 1169 patients (31 bilateral) were treated with breast conserving surgery and X-ray IORT, using the Xoft Accent System from June 2010 to November 2018. Patients were enrolled in an IORT registry trial and data were collected at 1 week, 1 month, 6 months, 1 year, and yearly thereafter. The primary endpoint was local recurrence.Results: To date, there have been 61 events in 54 patients: 50 ipsilateral local recurrences (14 DCIS and 36 invasive), 7 regional nodal recurrences and 4 distant recurrences. Of local recurrences, 9 were within the IORT field, 21 outside of the IORT field but within the same quadrant as the index cancer, and 20 were new cancers in different quadrants. There has been no breast cancer related deaths and 27 non-breast cancer deaths. Currently, with a median follow-up of 52 months, Kaplan Meier analysis projects 5.2 % local recurrence rate at 5 years. In the table below, the five-year probability of local recurrence is analyzed by quadrant and/or type of recurrence (all recurrences or just invasive). Using the 2017, ASTRO Categories, 520 patients (43%) were suitable for IORT, 415 (35%) were cautionary, and 265 (22%) were unsuitable for IORT after final histopathology was evaluated.Conclusion: IORT is profoundly convenient. When used as the only adjuvant breast irradiation, it eliminates approximately 15-35 outpatient visits. This has become increasingly important during the current COVID-19 pandemic. In the group of patients described here, more that 100,000 patient-hours were saved. The local, regional, and distant recurrence rates observed in this trial were slightly higher than those of the prospective randomized TARGIT-A and ELIOT Trials. This may be explained by 22% of our patients being considered unsuitable for IORT by ASTRO Criteria. The low complication rates previously reported by our group as well as the low recurrence rates reported in this study support the cautious use and continued study of X-ray IORT in women with low-risk breast cancer. Citation Format: Melinda Epstein, Melvin Silverstein, Peter Chen, Kevin Lin, Brian Kim, Sadia Khan, Lincoln Snyder, Lisa E. Guerra, Colleen Coleman. Intraoperative radiation therapy (IORT) for1200 early breast tumors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-11.
Haloperidol, clonidine and resolution of delirium in critically ill patients: a prospective cohort study
Authors: Lisa Smit, Sandra M. A. Dijkstra-Kersten, Irene J. Zaal, Mathieu van der Jagt, Arjen J. C. Slooter
Journal: Intensive Care Medicine (2021)

Haloperidol and clonidine are commonly used to treat agitation in delirious intensive care unit (ICU) patients, but it is unclear whether these agents may shorten the duration of delirium. The objective of this study was to determine whether haloperidol, clonidine, or their combined administration to delirious ICU patients results in delirium resolution.This was a cohort study on a mixed ICU, excluding patients with a primary neurological disorder. The main outcome was the probability of delirium resolution, using propensity score matching and Markov multinomial logistic regression models for daily transitions. Secondary outcomes were delirium duration, number of delirium days, ventilation days, length of stay in the ICU and hospital, and ICU mortality.A total of 3614 patients were included (1165 delirious [32%]; 2449 non-delirious [68%]). Delirium occurred on 4708 (18.9%) of 24,906 days. The probability of delirium resolution was lower in delirious patients who received haloperidol (OR 0.47, 95% CI 0.39-0.57), clonidine (OR 0.78, 95% CI 0.63-0.97), or both (OR 0.45, 95% CI 0.36-0.56) compared to untreated delirious patients. Delirious patients who received haloperidol, clonidine, or both had generally longer delirium duration, more delirium and ventilation days, and spent more time in the ICU and in hospital than untreated delirious patients. These agents had no effect on ICU mortality.Haloperidol and clonidine use in delirious ICU patients may be associated with reduced probability of delirium resolution. This finding, however, merits further investigation given inherent limitations of this observational analysis.
Immune function in childhood cancer survivors: a Children's Oncology Group review
Authors: Gregory M T Guilcher, Linda Rivard, Jennifer T Huang, Nicola A M Wright, Lynette Anderson, Hesham Eissa, Wendy Pelletier, Shanti Ramachandran, Tal Schechter, Ami J Shah, Ken Wong, Eric J Chow
Journal: The Lancet Child & Adolescent Health (2021)
ATG5 promotes eosinopoiesis but inhibits eosinophil effector functions
Authors: Nina Germic, Aref Hosseini, Darko Stojkov, Kevin Oberson, Meike Claus, Charaf Benarafa, Sara Calzavarini, Anne Angelillo-Scherrer, Isabelle C. Arnold, Anne Müller, Carsten Riether, Shida Yousefi, Hans-Uwe Simon
Journal: Blood (2021)
MEDALT: single-cell copy number lineage tracing enabling gene discovery
Authors: Fang Wang, Qihan Wang, Vakul Mohanty, Shaoheng Liang, Jinzhuang Dou, Jincheng Han, Darlan Conterno Minussi, Ruli Gao, Li Ding, Nicholas Navin, Ken Chen
Journal: Genome biology (2021)

Abstract We present a Minimal Event Distance Aneuploidy Lineage Tree (MEDALT) algorithm that infers the evolution history of a cell population based on single-cell copy number (SCCN) profiles, and a statistical routine named lineage speciation analysis (LSA), whichty facilitates discovery of fitness-associated alterations and genes from SCCN lineage trees. MEDALT appears more accurate than phylogenetics approaches in reconstructing copy number lineage. From data from 20 triple-negative breast cancer patients, our approaches effectively prioritize genes that are essential for breast cancer cell fitness and predict patient survival, including those implicating convergent evolution. The source code of our study is available at https://github.com/KChen-lab/MEDALT .
1α,25-Dihydroxyvitamin D3 Encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas
Authors: Avishek K. Singh, Chuanqi Cai, Sreenivasulu Kilari, Chenglei Zhao, Michael L. Simeon, Edwin Takahashi, Elazer R. Edelman, Hyunjoon (Joon) Kong, Thanila Macedo, Ravinder J. Singh, Matthew W. Urban, Rajiv Kumar, Sanjay Misra
Journal: Journal of the American Society of Nephrology (2021)

Few therapies prevent venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation in arteriovenous fistulas (AVF). Expression of the immediate early response gene X-1 (Iex-1), also known as Ier3, is associated with VNH and stenosis in murine AVFs. The study aimed to determine if local release of Ier3 long-acting inhibitor 1α,25(OH)2D3 from poly(lactic-co-glycolic acid) (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (1,25 NP) could affect VNH/VS formation in a large animal model.Immediately after AVF creation in a porcine model of renal failure, 1,25 NP or vehicle control was injected into the adventitia space of AVF outflow veins. Scanning electron microscopy and dynamic light scattering characterized drug and control nanoparticles. Animals were sacrificed 3 and 28 days later for gene expression, immunohistologic, magnetic resonance imaging and angiography, and ultrasound analyses. Whole transcriptome RNA sequencing with differential gene expression analysis was performed on outflow veins of AVF.Encapsulation of 1α,25(OH)2D3 in PLGA nanoparticles formed nanoparticles of uniform size that were similar to nanoparticles without 1α,25(OH)2D3. The 1,25 NP-treated AVFs exhibited lower VNH/VS, Ier3 gene expression, and IER-3, MCP-1, CD68, HIF-1α, and VEGF-A immunostaining, fibrosis, and proliferation. Blood flow and lumen area increased significantly, whereas peak systolic velocity and wall shear stress decreased. Treatment increased Young's modulus and correlated with histologic assessment of fibrosis and with no evidence of vascular calcification. RNA sequencing analysis showed changes in the expression of genes associated with inflammatory, TGFβ1, and apoptotic pathways.Local release of 1,25 NP improves AVF flow and hemodynamics, and reduces stenosis in association with reduction in inflammation, apoptosis, and fibrosis in a porcine model of arteriovenous fistula.
Dual stimuli-responsive polyurethane-based hydrogels as smart drug delivery carriers for the advanced treatment of chronic skin wounds
Authors: Rossella Laurano, Monica Boffito, Michela Abrami, Mario Grassi, Alice Zoso, Valeria Chiono, Gianluca Ciardelli
Journal: Bioactive Materials (2021)

The design of multi-stimuli-responsive vehicles for the controlled and localized release of drugs is a challenging issue increasingly catching the attention of many research groups working on the advanced treatment of hard-to-close wounds. In this work, a thermo- and pH-responsive hydrogel (P-CHP407) was prepared from an ad hoc synthesized amphiphilic poly(ether urethane) (CHP407) exposing a significant amount of –COOH groups (8.8 ± 0.9 nmol/gpolymer). The exposure of acid moieties in P-CHP407 hydrogel led to slightly lower initial gelation temperature (12.1 °C vs. 14.6 °C, respectively) and gelation rate than CHP407 hydrogel, as rheologically assessed. Nanoscale hydrogel characterization by Low Field NMR (LF-NMR) spectroscopy suggested that the presence of carboxylic groups in P-CHP407 caused the formation of bigger micelles with a thicker hydrated shell than CHP407 hydrogels, as further proved by Dynamic Light Scattering analyses. In addition, P-CHP407 hydrogel showed improved capability to change its internal pH compared to CHP407 one when incubated with an alkaline buffer (pH 8) (e.g., pHchange_5min = 3.76 and 1.32, respectively). Moreover, LF-NMR characterization suggested a stronger alkaline-pH-induced interaction of water molecules with micelles exposing –COOH groups. Lastly, the hydrogels were found biocompatible according to ISO 10993 and able to load and release Ibuprofen: delivery kinetics of Ibuprofen was enhanced by P-CHP407 hydrogels at alkaline pH, suggesting their potential use as smart delivery systems in the treatment of chronic infected wounds.
Structural Racism in the COVID-19 Pandemic: Don’t Forget about the Children!
Authors: Jonathan M. Marron
Journal: The American Journal of Bioethics (2021)

Click to increase image sizeClick to decrease image sizeThis article refers to:Structural Racism in the COVID-19 Pandemic: Moving ForwardThis article is referred to by:An Open Dialogue on Health Disparities and Structural Racism: Response to Open Peer Commentaries DISCLOSURE STATEMENTDr. Marron serves as a paid member of the Ethics Advisory Board for Partner Therapeutics and has received an honorarium for giving a lecture to employees of Sanofi-Genzyme Global Oncology. Neither entity had a role in this work. No potential conflict of interest was reported by the author(s).Additional informationFundingDr. Marron’s work is supported by funding from Conquer Cancer, the Harvard Medical School Center for Bioethics, and the Dana-Farber Cancer Institute Division of Population Sciences.
Diagnostic Performance of 18F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase III, Multicenter Study
Authors: Michael J. Morris, Steven P. Rowe, Michael A. Gorin, Lawrence Saperstein, Frédéric Pouliot, David Josephson, Jeffrey Y.C. Wong, Austin R. Pantel, Steve Y. Cho, Kenneth L. Gage, Morand Piert, Andrei Iagaru, Janet H. Pollard, Vivien Wong, Jessica Jensen, Tess Lin, Nancy Stambler, Peter R. Carroll, Barry A. Siegel
Journal: Clinical Cancer Research (2021)

Current FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR).
Impact of Angiotensin Converting Enzyme Inhibitors/angiotensin Receptor Blockers on Mortality and Severity of Covid-19 Pneumonia
Authors: A. Aggarwal, A. Jain, M. Goel, J. Tusha, V. Khanam, S. Bidhan, A. Khan, M. Dhawan, V. Tegeltija, S. Kumar
Journal: Circulation (2020)
ミトラマイシンAとトルフェナム酸併用の膵癌療法はSp 1 分解と相乗的抗腫瘍活性を促進する
Authors: Jia Zhiliang, Gao Yong, Wang Liwei, Li Qiang, Zhang Jun, LE Xiangdong, Wei Daoyan, C Yao James, Z Chang David, Huang Suyun, Xie Keping
Journal: Cancer Research (2010)
Persistent antigen exposure via the eryptotic pathway drives terminal T cell dysfunction
Authors: Elyse A. Watkins, Jennifer T. Antane, Jaeda L. Roberts, Kristen M. Lorentz, Sarah Zuerndorfer, Anya C. Dunaif, Lucas J. Bailey, Andrew C. Tremain, Mindy Nguyen, Roberto C. De Loera, Rachel P. Wallace, Rachel K. Weathered, Stephan Kontos, Jeffrey A. Hubbell
Journal: Science Immunology (2021)

Although most current treatments for autoimmunity involve broad immunosuppression, recent efforts have aimed to suppress T cells in an antigen-specific manner to minimize risk of infection. One such effort is through targeting antigen to the apoptotic pathway to increase presentation of the antigen of interest in a tolerogenic context. Erythrocytes present a rational candidate to target because of their high rate of eryptosis, which facilitates continual uptake by antigen-presenting cells in the spleen. Here, we develop an approach that binds antigens to erythrocytes to induce sustained T cell dysfunction. Transcriptomic and phenotypic analyses revealed signatures of self-tolerance and exhaustion, including up-regulation of PD-1, CTLA4, Lag3, and TOX. Antigen-specific T cells were incapable of responding to an adjuvanted antigenic challenge even months after antigen clearance. With this strategy, we prevented pathology in a mouse experimental autoimmune encephalomyelitis model. CD8+ T cell education occurred in the spleen and was dependent on cross-presenting Batf3+ dendritic cells. These results demonstrate that antigens associated with eryptotic erythrocytes induce lasting T cell dysfunction that could be protective in deactivating pathogenic T cells.