tbuckley/cabot-search huggingface dataset:
Abstract 1559: TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation leading to enhanced effector function and anti-tumor immunity in pre-clinical models
Authors: Shelley E. Ackerman, Joseph C. Gonzalez, Josh D. Gregorio, Jason C. Paik, Felix J. Hartmann, Justin A. Kenkel, Arthur Lee, Angela Luo, Cecelia I. Pearson, Murray L. Nguyen, Benjamin Ackerman, Lauren Y. Sheu, Richard P. Laura, Steven J. Chapin, Brian S. Safina, Sean C. Bendall, David Dornan, Edgar G. Engleman, Michael N. Alonso
Journal: Cancer Research (2019)

Abstract Deficient anti-tumor immunity often results from an immunosuppressive tumor microenvironment (TME) that renders antigen presenting cells (APCs) unable to effectively stimulate T cells. Recent studies indicate that local delivery of immunostimulatory adjuvants can activate tumor resident APCs, driving uptake, processing and presentation of tumor neoantigens to T cells that mediate anti-tumor immunity. To overcome challenges associated with intratumoral delivery of such adjuvants, we developed a novel class of TLR immune-stimulating antibody conjugates (TAC) that comprise a TLR7/8 agonist conjugated to tumor-targeting monoclonal antibodies. In vitro co-cultures with human cancer cell lines and leukocytes revealed that TACs potently activate primary APCs, leading to increased co-stimulatory molecule expression (e.g. CD40, CD86) and secretion of pro-inflammatory cytokines (e.g. TNFα). The TACs also enhanced antibody-mediated effector functions such as ADCC and ADCP. Surprisingly, these constructs also induced dendritic cell (DC) differentiation from monocytes, as measured by changes in cellular morphology and DC surface markers (e.g. CD14 downregulation). CyTOF-based analysis of intracellular signaling in human leukocytes revealed a unique signaling signature of the conjugate compared to a mixture of its components, suggesting a novel biological mechanism by which the conjugate stimulates APCs. Finally, we demonstrated in vivo efficacy in syngeneic tumor models in which TAC treatment led to tumor clearance and development of immunologic memory. These results provide a strong rationale for this technology as a platform for cancer immunotherapy. Citation Format: Shelley E. Ackerman, Joseph C. Gonzalez, Josh D. Gregorio, Jason C. Paik, Felix J. Hartmann, Justin A. Kenkel, Arthur Lee, Angela Luo, Cecelia I. Pearson, Murray L. Nguyen, Benjamin Ackerman, Lauren Y. Sheu, Richard P. Laura, Steven J. Chapin, Brian S. Safina, Sean C. Bendall, David Dornan, Edgar G. Engleman, Michael N. Alonso. TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation leading to enhanced effector function and anti-tumor immunity in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1559.
The nature of human IL-6
Authors: Anne Puel, Jean-Laurent Casanova
Journal: The Journal of Experimental Medicine (2019)

Countless functions have been attributed experimentally to IL-6. In this issue of JEM, Spencer et al. (https://doi.org/10.1084/jem.20190344) reveal essential, nonredundant functions of human IL-6. Patients with genetic deficiencies of the IL-6 receptor suffer from “hyper IgE syndrome.”
Abstract 3759: Host and neoplastic cell secretions of proteolytic enzymes potentiate metastasis
Authors: Samantha S. Dykes, Henrietta O. Fasanya, Dietmar W. Siemann
Journal: Cancer Research (2019)

Abstract The presence of macrophages within breast tumors is associated with metastatic potential. Tumor-associated macrophages are often stimulated by Interleukin-4, resulting in a pro-tumorigenic (M2-like) phenotype and the secretion of growth factors and proteases, including the lysosomal protease cathepsin L (CTSL). CTSL is often secreted by breast cancer cells and stromal cells and contributes to tumor invasion, metastasis, and angiogenesis. We hypothesized that secretion of the proteolytic enzyme cathepsin L by both tumor-associated macrophages and neoplastic cells facilitate tumor invasion and dissemination. Initial studies found that inhibiting CTSL using the novel cathepsin L/K inhibitors KGP94 and KGP207 prevented in vitro M2 macrophage invasion and reduced macrophage-stimulated invasion of 4T1 murine breast cancer cells. Interestingly, KGP94 and KGP207 also reduced the expression of several M2-associated markers, suggesting that CTSL activity may be important for Interleukin-4-driven M0 to M2 differentiation. Furthermore, CTSL shRNA knockdowns revealed that CTSL supplied from both the tumor cell and the macrophage population is important for tumor cell invasion. These data suggest that tumor cells and macrophages may both contribute to the CTSL-driven metastatic phenotype of breast cancer. Taken together, these studies highlight the importance of CTSL in macrophage functions and suggest that cathepsin inhibition strategies may be therapeutically beneficial by impairing the progression of tumors with high infiltration of M2 macrophages. Citation Format: Samantha S. Dykes, Henrietta O. Fasanya, Dietmar W. Siemann. Host and neoplastic cell secretions of proteolytic enzymes potentiate metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3759.
Abstract 16542: Predictors of Mortality in Patients With Light Chain (AL) Amyloidosis Heart Failure: A Multi-variate Analysis
Authors: Usman Tahir, Georghe Doros, John S Kim, Lawreen H Connors, Flora Sam
Journal: Circulation (2015)

Background: AL deposition in the heart occurs in about half of all patients affected by systemic AL amyloidosis, conferring an extremely poor prognosis. Cardiac involvement in AL amyloid (AL-CMP) may result in clinical heart failure (HF). Once HF occurs, the median survival is ~6 months if untreated. We thus sought to determine clinical characteristics and predictors of mortality in AL-CMP with HF. Methods: Between 2004-2014, patients with biopsy-proven AL-CMP, Stage C HF and without prior immunosuppressive therapy were enrolled at first visit to the Amyloid Clinic at Boston University Medical Center. Routine laboratory tests, physical examination and echocardiography were performed. Results: The AL-CMP cohort comprised of 165 patients. Mean age was 61.6±9.8 yrs., predominantly white (76.4%) and 60.6% were men. Median time to survival was 10.9 months (95% CI 6.2, 14.7) Figure 1. Age, atrial fibrillation, NYHA class, CRP, BNP, LV ejection fraction, relative wall thickness and intraventricular septum size were independent predictors of all cause mortality in univariate analysis. Only age [HR 1.04 (1.01-1.06)], log BNP [HR 1.45 (1.15-1.8)], CRP [HR 1.02 (1.00-1.04)], NYHA class [HR 1.50 (1.02-2.2)] and relative wall thickness [HR 6.70 (2.45-18.30)] were predictors of all cause mortality in multivariate analysis (P&lt;0.05). Conclusions: In addition to using cardiac biomarkers such as BNP and troponin, which are predictors of prognosis and are used to guide staging and treatment in AL amyloidosis, we identified additional prognostic markers once patients with AL cardiac amyloid develop HF. Relative wall thickness is the strongest predictor of mortality. These markers can be used to help identify AL cardiac amyloid patients with HF at greatest risk for poor outcomes.
Trends in Health Equity in the United States by Race/Ethnicity, Sex, and Income, 1993-2017
Authors: Frederick J. Zimmerman, Nathaniel W. Anderson
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Health equity is an often-cited goal of public health, included among the 4 overarching goals of the Department of Health and Human Services' Healthy People 2020. Yet it is difficult to find summary assessments of national progress toward this goal. <h3>Objectives</h3> To identify variation in several measures of health equity from 1993 to 2017 in the United States and to test whether there are significant time trends. <h3>Design, Setting, and Participants</h3> Survey study using 25 years of data, from January 1, 1993, to December 31, 2017, from the Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System to assess trends in health equity and health justice by race/ethnicity, sex, and income in 3 categories by year. <h3>Main Outcomes and Measures</h3> Health equity was assessed separately for each of 2 health constructs: healthy days—the average of physical and mental healthy days over the previous 30 days—and general health in 5 categories, rescaled to approximate a continuous variable. For each health construct, average health was calculated along with 4 measures of health equity: disparities across 3 income groups; black-white disparities; health justice—a measure of the correlation of health outcomes with income, race/ethnicity and sex; and a summary health equity metric. <h3>Results</h3> Among the 5 456 006 respondents, the mean (SD) age was 44.5 (12.7) years; 3 178 688 (58.3%) were female; 4 163 945 (76.3%) were non-Latinx white; 474 855 (8.7%) were non-Latinx black; 419 542 (7.7%) were Latinx; and 397 664 (7.3%) were of other race/ethnicity. The final sample included 5 456 006 respondents for self-reported health and 5 349 527 respondents for healthy days. During the 25-year period, the black-white gap showed significant improvement (year coefficient: healthy days, 0.021; 97.5% CI, 0.012 to 0.029;<i>P</i> &lt; .001; self-reported health, 0.030; 97.5% CI, 0.025 to 0.035;<i>P</i> &lt; .001). The health equity metric for self-reported health showed no significant trend. For healthy days, the Health Equity Metric declined over time (year coefficient: healthy days, −0.025; 97.5% CI, −0.033 to −0.017;<i>P</i> &lt; .001). Health justice declined over time (year coefficient: healthy days, −0.045; 97.5% CI, −0.053 to −0.038;<i>P</i> &lt; .001; self-reported health, −0.035; 97.5% CI, −0.046 to−0.023;<i>P</i> &lt; .001), and income disparities worsened (year coefficient: healthy days, −0.060; 97.5% CI, −0.076 to −0.044;<i>P</i> &lt; .001; self-reported health, −0.029; 97.5% CI, −0.046 to −0.012;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Results of this analysis suggest that there has been a clear lack of progress on health equity during the past 25 years in the United States. Achieving widely shared goals of improving health equity will require greater effort from public health policy makers, along with their partners in medicine and the sectors that contribute to the social determinants of health.
CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma
Authors: Craig S. Sauter, Brigitte Senechal, Isabelle Rivière, Ai Ni, Yvette Bernal, Xiuyan Wang, Terence Purdon, Malloury Hall, Ashvin N. Singh, Victoria Z. Szenes, Sarah Yoo, Ahmet Dogan, Yongzeng Wang, Craig H. Moskowitz, Sergio Giralt, Matthew J. Matasar, Miguel-Angel Perales, Kevin J. Curran, Jae Park, Michel Sadelain, Renier J. Brentjens
Journal: Blood (2019)
Abstract 614: Cytomegalovirus (CMV) reactivation and patient survival in head and neck cancer
Authors: Heather H. Nelson, Jeffrey S. Miller, DeVon Hunter-Schlichting, Rondi A. Butler, Karl T. Kelsey
Journal: Cancer Research (2019)

Abstract There is building evidence that cytomegalovirus (CMV) may contribute to the development of solid tumors, however to date this has not been investigated in head and neck cancer (HNC). CMV is a highly prevalent, latent herpesvirus infecting over 50% of the population. CMV maintains latency in CD34+ cells, and recent work has demonstrated these latently infected cells preferentially differentiate into immunosuppressive monocytes. However, CMV is not solely immune suppressive as highly cytotoxic adaptive natural killer (NK) cells arise specifically in response to CMV reactivation. Here, we have investigated whether biomarkers of CMV reactivation are associated with patient survival in non-smoking HNC (n=184). CMV DNAemia was assessed using digital PCR, and a threshold of 1000 copies/mL serum was defined as reactivation; 22% of patients met this definition of CMV reactivation, however they did not have significantly worse survival than those without CMV reactivation (HR 1.5 (95% CI 0.7 - 3.0)). Monocytes that mobilize to the cancer site contribute to tumor-associated inflammation. Therefore, we explored whether a biomarker of inflammation, CRP, modified the association of CMV reactivation and HNC patient survival. In the absence of inflammation, there was no association between CMV reactivation and patient survival (HR 0.90 (95% CI 0.30 - 2.71)). However, those with both CMV reactivation and high inflammation had dramatically worse survival (HR 8.86 (95% CI 3.63 - 21.64)). These data are consistent with the recent report that CMV infected monocytes are immunosuppressive and suggest that stimulation of these monocytes to the tumor site may negatively impact patient survival. Future work should address the generalizability of this finding to other cancer types and determine whether CMV infected myeloid cells are present in the tumor microenvironment. Citation Format: Heather H. Nelson, Jeffrey S. Miller, DeVon Hunter-Schlichting, Rondi A. Butler, Karl T. Kelsey. Cytomegalovirus (CMV) reactivation and patient survival in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 614.
Abstract 4662: YYFZBJS ameliorates the progression of colon carcinogenesis in ApcMin/+ mice by inhibiting regulatory T-cell generation
Authors: Hua Sui, Kaijuan Gu, Junze Ren, Haotian Wen, Ting Wang, Jing Hu, Liu Yang, Qing Ji, Qi Li
Journal: Cancer Research (2019)

Abstract Colorectal cancer (CRC) is the third most common solid tumor in the world and shows resistance to several immunotherapies, particularly immune checkpoint blockade which has therapeutic effects on many other types of cancer. T cell (Treg) represents one of the main populations of effector immune cells in antitumor immunity, has been considered as a double-edged sword during the progression of colon carcinogenesis. Our previous studies showed that traditional Chinese herbs had potential anticancer effects in improving the quality of life and therapeutic effect. However, little is known whether the mechanism of TCM formula is depended on the Treg-mediate innate immunity. Here, we used C57BL/6 ApcMin/+ mice, an animal model of human intestinal tumorigenesis, to investigate tumor-associated lymphocyte subsets and the mechanisms of their accumulation into gastrointestinal adenomas, and to evaluate the effects of YYFZBJS on the progression of colon carcinogenesis in vivo and in vitro. Compared to unaffected spleen, intestinal lymphatic, and mesenteric lymph nodes (MLN), accumulated CD4+CD25+ FoxP3 positive Treg cells were reduced after YYFZBJS treatment in ApcMin/+ mice. Treatment with YYFZBJS blocked tumor initiation and progression in the transgenic mouse models (ApcMin/+) with less change of body weight and survival rates. Moreover, YYFZBJS significantly reduced the expression of IL-6, IL-10, TGF-β, and other oncogenes markers such as MMP-2, MMP-9, cyclinD1 and c-Myc in Peripheral Blood and adenomatous tissue. In conclusion, we show that the Treg is involved in CRC development and progression and we identify YYFZBJS as a new potential drug target for the treatment of CRC. Note: This abstract was not presented at the meeting. Citation Format: Hua Sui, Kaijuan Gu, Junze Ren, Haotian Wen, Ting Wang, Jing Hu, Liu Yang, Qing Ji, Qi Li. YYFZBJS ameliorates the progression of colon carcinogenesis in ApcMin/+ mice by inhibiting regulatory T-cell generation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4662.
Abstract 5031: Regulatory T cell ablation accelerates early stage breast cancer progression
Authors: Wei Du, Leandro Martinez, Valentina Robila, Nicholas Clark, Michael Idowu, Paula Bos, Paula Bos
Journal: Cancer Research (2019)

Abstract Breast cancer is the most common malignancy in women worldwide. Early detection of pre-invasive breast tumor has dramatically improved due to the routine screening for women. Ductal carcinoma in situ is a non-obligate precursor of breast cancer, and it only progresses to invasive breast cancer in about 40% of patients. We have previously shown that transient ablation of regulatory T (Treg) cells in established breast tumors results in significant reduction of primary and lung metastatic tumor growth. In this study, we aim to investigate the specific role of Treg cells at the pre-malignant stages. Using a spontaneous, stage-wise MMTV-driven polyoma middle T (PyMT) model of murine mammary carcinogenesis, crossed to Foxp3DTR knock-in mice where injection of diphtheria toxin leads to a complete ablation of Treg cells for around 7 days, we found that ablation of Treg cells at the pre-invasive tumor stage resulted in a significant increase in the number of mammary glands developing tumors, as well as tumor growth compared to control mice. Histological examination of tissues revealed that the area of the incipient tumors was larger in Treg cell-ablated mice, and presented a more advanced tumor stage. In addition, Treg cell ablation resulted in a pronounced mammary inflammatory infiltrate, including an increase in tumor-associated macrophages and a soluble cytokine network conducive to tumor progression. Interestingly, Treg cell ablation increased the percentage of cancer stem/progenitor cells in the mammary compartment. Overall, our study demonstrates that unlike their role in established cancers, Treg cells ablation promotes breast cancer progression at early stages. Citation Format: Wei Du, Leandro Martinez, Valentina Robila, Nicholas Clark, Michael Idowu, Paula Bos, Paula Bos. Regulatory T cell ablation accelerates early stage breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5031.
The Gamma Globulins and Their Clinical Significance
Authors: David Gitlin, Paul A. M. Gross, Charles A. Janeway
Journal: New England Journal of Medicine (1959)

(Continued)*Clinical Disturbances of Gamma-Globulin MetabolismAlterations in gamma-globulin metabolism associated with clinical disease may occur in a variety of ways, and the disease may or may not be a direct consequence of the alteration. Thus, plasma gamma globulins may be decreased, with a consequent deficiency of specific antibodies, because of decreased synthesis, as in agammaglobulinemia, or because of renal loss and increased catabolism, as in the nephrotic syndrome in children. On the other hand, gamma globulins may be increased in chronic infection, and although the increase may be attributable to continued or repeated antigenic stimulation, the infection may be . . .
Abstract 550: Tumor-conditional anti-CTLA-4 uncouples anti-tumor efficacy from immunotherapy-related toxicity
Authors: Steven C. Pai, Donald M. Simons, Xiaoqing Lu, Wendy Ritacco, Michael Evans, Gillian Kingsbury, Lawrence Fong
Journal: Cancer Research (2019)

While immune checkpoint blockade leads to potent anti-tumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in multi-organ inflammation including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA-4 antibody (anti-CTLA-4 DVD) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA-4 binding domain. Upon reaching the tumor, the outer domain is cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA-4 blockade. Anti-CTLA-4 DVD significantly reduced multi-organ immune toxicity by preserving tissue-resident regulatory T cells (Tregs) in Rag 1-/- mice that received naive donor CD4+ T cells from wild-type C57BL/6j mice. Moreover, anti-CTLA-4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2 bearing C57BL/6j mice. Tregs depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA-4 without the FcγR binding portion (anti-CTLA-4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrated a new approach to anti-CTLA-4 blockade that depletes tumor-infiltrating, but not tissue-resident Tregs, preserving anti-tumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA-4 DVD provides an avenue to uncouple anti-tumor efficacy from immunotherapy-induced toxicities.   Citation Format:  Steven C. Pai, Donald M. Simons, Xiaoqing Lu, Wendy Ritacco, Michael Evans, Gillian Kingsbury, Lawrence Fong. Tumor-conditional anti-CTLA-4 uncouples anti-tumor efficacy from immunotherapy-related toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 550.
Diagnostic Likelihood Thresholds That Define a Working Diagnosis of Idiopathic Pulmonary Fibrosis
Authors: Simon L. F. Walsh, David J. Lederer, Christopher J. Ryerson, Martin Kolb, Toby M. Maher, Richard Nusser, Venerino Poletti, Luca Richeldi, Carlo Vancheri, Margaret L. Wilsher, Katerina M. Antoniou, Juergen Behr, Elisabeth Bendstrup, Kevin K. Brown, Tamera J. Corte, Vincent Cottin, Bruno Crestani, Kevin R. Flaherty, Ian N. Glaspole, Jan Grutters, Yoshikazu Inoue, Yasuhiro Kondoh, Michael Kreuter, Kerri A. Johannson, Brett Ley, Fernando J. Martinez, Maria Molina-Molina, Antonio Morais, Hilario Nunes, Ganesh Raghu, Moises Selman, Paolo Spagnolo, Hiroyuki Taniguchi, Sara Tomassetti, Dominique Valeyre, Marlies Wijsenbeek, Wim A. Wuyts, Athol U. Wells
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: The level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting surgical lung biopsy (SLB) in patients suspected of idiopathic pulmonary fibrosis (IPF) is unknown.Objectives: To determine how often physicians advocate SLB in patient subgroups defined by IPF likelihood and risk associated with SLB, and to identify the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy with requesting SLB.Methods: An international cohort of respiratory physicians evaluated 60 cases of interstitial lung disease, giving: 1) differential diagnoses with diagnostic likelihood; 2) a decision on the need for SLB; and 3) initial management. Diagnoses were stratified according to diagnostic likelihood bands described by Ryerson and colleagues.Measurements and Main Results: A total of 404 physicians evaluated the 60 cases (24,240 physician–patient evaluations). IPF was part of the differential diagnosis in 9,958/24,240 (41.1%) of all physician–patient evaluations. SLB was requested in 8.1%, 29.6%, and 48.4% of definite, provisional high-confidence and provisional low-confidence diagnoses of IPF, respectively. In 63.0% of provisional high-confidence IPF diagnoses, antifibrotic therapy was prescribed without requesting SLB. No significant mortality difference was observed between cases given a definite diagnosis of IPF (90–100% diagnostic likelihood) and cases given a provisional high-confidence IPF diagnosis (hazard ratio, 0.97; P = 0.65; 95% confidence interval, 0.90–1.04).Conclusions: Most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a provisional high-confidence diagnosis or "working diagnosis" of IPF can be made (likelihood ≥ 70%). SLB is recommended in only a minority of patients with suspected, but not definite, IPF.