tbuckley/cabot-search huggingface dataset:
Additive anti-tumor effect of Avastin and Immunotoxin combination therapy on tumor-bearing mouse models
Authors: Sookhee Bang, Raffit Hassan, Ira Pastan
Journal: Cancer Research (2005)

4989  Avastin (Bevacizumab; Genentech, South San Francisco, CA) is a human mAb against VEGF-A. Avastin slows or prevents blood vessel growth and thereby inhibits tumor growth. Avastin has been approved for the treatment of colon cancer and is being tested in other cancers. Additionally, the combination of the Avastin and chemotherapy in nude mice with human cancer xenografts shows an increased activity compared with chemotherapy alone or antibody alone. Because tumor penetration is an essential step in immunotoxin action and Avastin affects capillary density and function, we investigated the effect of combining Avastin with immunotoxins. Mice bearing human tumor xenografts (A431/K5 expressing mesothelin or CA46 Burkitt’s lymphoma expressing CD22) were treated with 1. Avastin (5 mg/ kg i.p. 2 times/week for 1 week), 2. immunotoxin (SS1P, 0.2 mg/ kg QOD x 3 for A431/K5 or HA22, 0.2 mg/ kg QOD x 3 for CA46, or 3. a combination of immunotoxin plus Avastin. Mice were implated with tumors subcutaneously and treated began on day 7. In the A431/K5 model, mice treated with the Avastin plus SS1P exhibited significantly reduced mean tumor volumes compared with mice treated with the control (88.8 mm3 vs. 1,715 mm3 at day 17, P
Active PI3K abrogates central tolerance in high-avidity autoreactive B cells
Authors: Sarah A. Greaves, Jacob N. Peterson, Pamela Strauch, Raul M. Torres, Roberta Pelanda
Journal: The Journal of Experimental Medicine (2019)

Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell–mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell–intrinsic expression of a constitutively active form of PI3K-P110α by high-avidity autoreactive B cells of mice completely abrogates central B cell tolerance and further promotes these cells to escape from the bone marrow, differentiate in peripheral tissue, and undergo activation in response to self-antigen. Upon stimulation with T cell help factors, these B cells secrete antibodies in vitro but remain unable to secrete autoantibodies in vivo. Overall, our data demonstrate that activation of the PI3K pathway leads high-avidity autoreactive B cells to breach central, but not late, stages of peripheral tolerance.
CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses
Authors: Lalit K. Beura, Nancy J. Fares-Frederickson, Elizabeth M. Steinert, Milcah C. Scott, Emily A. Thompson, Kathryn A. Fraser, Jason M. Schenkel, Vaiva Vezys, David Masopust
Journal: The Journal of Experimental Medicine (2019)

This study examines the extent to which memory CD4+ T cells share immunosurveillance strategies with CD8+ resident memory T cells (TRM). After acute viral infection, memory CD4+ T cells predominantly used residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8+ T cells. In contrast, memory CD4+ T cells were more likely to be resident within lymphoid organs than CD8+ T cells. Migration properties of memory-phenotype CD4+ T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4+ and CD8+ TRM shared overlapping transcriptional signatures and location-specific features, such as granzyme B expression in the small intestine, revealing tissue-specific and migration property–specific, in addition to lineage-specific, differentiation programs. Functionally, mucosal CD4+ TRM reactivation locally triggered both chemokine expression and broad immune cell activation. Thus, residence provides a dominant mechanism for regionalizing CD4+ T cell immunity, and location enforces shared transcriptional, phenotypic, and functional properties with CD8+ T cells.
Haplo-Identical Transplants Using Post Transplant Cyclophosphamide (PTCy) Are Associated with Good Outcomes If Transplanted with Early Disease - a Single Centre Analysis from India
Authors: Biju George, Aby Abraham, Anu Korula, Anup Joseph Devasia, Kavitha M Lakshmi, Fouzia N., Uday Prakash Kulkarni, Alok Srivastava, Vikram Mathews
Journal: Blood (2018)
Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
Authors: Sara M. Tolaney, Hao Guo, Sonia Pernas, William T. Barry, Deborah A. Dillon, Lauren Ritterhouse, Bryan P. Schneider, Fei Shen, Kit Fuhrman, Michele Baltay, Chau T. Dang, Denise A. Yardley, Beverly Moy, P. Kelly Marcom, Kathy S. Albain, Hope S. Rugo, Mathew J. Ellis, Iuliana Shapira, Antonio C. Wolff, Lisa A. Carey, Beth Overmoyer, Ann H. Partridge, Clifford A. Hudis, Ian E. Krop, Harold J. Burstein, Eric P. Winer
Journal: Journal of Clinical Oncology (2019)

The Adjuvant Paclitaxel and Trastuzumab trial was designed to address treatment of patients with small human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The primary analysis of the Adjuvant Paclitaxel and Trastuzumab trial demonstrated a 3-year disease-free survival (DFS) of 98.7%. In this planned secondary analysis, we report longer-term outcomes and exploratory results to characterize the biology of small HER2-positive tumors and genetic factors that may predispose to paclitaxel-induced peripheral neuropathy (TIPN).In this phase II study, patients with HER2-positive breast cancer with tumors 3 cm or smaller and negative nodes received paclitaxel (80 mg/m2) with trastuzumab for 12 weeks, followed by trastuzumab for 9 months. The primary end point was DFS. Recurrence-free interval (RFI), breast cancer-specific survival, and overall survival (OS) were also analyzed. In an exploratory analysis, intrinsic subtyping by PAM50 (Prosigna) and calculation of the risk of recurrence score were performed on the nCounter analysis system on archival tissue. Genotyping was performed to investigate TIPN.A total of 410 patients were enrolled from October 2007 to September 2010. After a median follow-up of 6.5 years, there were 23 DFS events. The 7-year DFS was 93% (95% CI, 90.4 to 96.2) with four (1.0%) distant recurrences, 7-year OS was 95% (95% CI, 92.4 to 97.7), and 7-year RFI was 97.5% (95% CI, 95.9 to 99.1). PAM50 analyses (n = 278) showed that most tumors were HER2-enriched (66%), followed by luminal B (14%), luminal A (13%), and basal-like (8%). Genotyping (n = 230) identified one single-nucleotide polymorphism, rs3012437, associated with an increased risk of TIPN in patients with grade 2 or greater TIPN (10.4%).With longer follow-up, adjuvant paclitaxel and trastuzumab is associated with excellent long-term outcomes. Distribution of PAM50 intrinsic subtypes in small HER2-positive tumors is similar to that previously reported for larger tumors.
Georgia limits abortion to six weeks and eyes Supreme Court
Authors: Owen Dyer
Journal: BMJ (2019)

The US state of Georgia’s majority Republican legislature has passed a bill outlawing abortions once a fetal heartbeat can be detected, effectively changing the latest point at which a woman can terminate a pregnancy from 20 weeks gestation to about six.

The state’s Republican governor Brian Kemp has praised the bill, called the Living Infants Fairness and Equality (LIFE) Act, and is expected to sign it into law this week.

But …
Epithelial cell–derived cytokines: more than just signaling the alarm
Authors: Florence Roan, Kazushige Obata-Ninomiya, Steven F. Ziegler
Journal: Journal of Clinical Investigation (2019)

The epithelial cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 are central regulators of type 2 immunity, which drives a broad array of allergic responses. Often characterized as "alarmins" that are released by the barrier epithelium in response to external insults, these epithelial cell-derived cytokines were initially thought to act only early in allergic inflammation. Indeed, TSLP can condition dendritic cells to initiate type 2 responses, and IL-33 may influence susceptibility to asthma through its role in establishing the immune environment in the perinatal lungs. However, TSLP, IL-33, and IL-25 all regulate a broad spectrum of innate immune cell populations and are particularly potent in eliciting and activating type 2 innate lymphoid cells (ILC2s) that may act throughout allergic inflammation. Recent data suggest that a TSLP/ILC axis may mediate steroid resistance in asthma. Recent identification of memory Th2 cell subsets that are characterized by high receptor expression for TSLP, IL-33, and IL-25 further supports a role for these cytokines in allergic exacerbations. There is therefore growing interest in developing biologics that target TSLP, IL-33, and IL-25. This Review provides an overview of TSLP, IL-33, and IL-25 and the development of blocking antibodies that target these epithelial cell-derived cytokines.
Location, location, location: Tissue resident memory T cells in mice and humans
Authors: Peter A. Szabo, Michelle Miron, Donna L. Farber
Journal: Science Immunology (2019)

The discovery of T cells resident in diverse tissues has altered our understanding of adaptive immunity to encompass site-specific responses mediated by tissue-adapted memory T cells throughout the body. Here, we discuss the key phenotypic, transcriptional, and functional features of these tissue-resident memory T cells (TRM) as established in mouse models of infection and translated to humans by novel tissue sampling approaches. Integration of findings from mouse and human studies may hold the key to unlocking the potential of TRM for promoting tissue immunity and preventing infection.
Eosinophils capture viruses, a capacity that is defective in asthma
Authors: Yanaika S. Sabogal Piñeros, Suzanne M. Bal, Annemiek Dijkhuis, Christof J. Majoor, Barbara S. Dierdorp, Tamara Dekker, Esmée P. Hoefsmit, Peter I. Bonta, Daisy Picavet, Nicole N. van der Wel, Leo Koenderman, Peter J. Sterk, Lara Ravanetti, René Lutter
Journal: Allergy (2019)

Abstract Background Activated eosinophils cause major pathology in stable and exacerbating asthma; however, they can also display protective properties like an extracellular antiviral activity. Initial murine studies led us to further explore a potential intracellular antiviral activity by eosinophils. Methods To follow eosinophil‐virus interaction, respiratory syncytial virus (RSV) and influenza virus were labeled with a fluorescent lipophilic dye (DiD). Interactions with eosinophils were visualized by confocal microscopy, electron microscopy, and flow cytometry. Eosinophil activation was assessed by both flow cytometry and ELISA. In a separate study, eosinophils were depleted in asthma patients using anti‐IL‐5 (mepolizumab), followed by a challenge with rhinovirus‐16 (RV16). Results DiD‐RSV and DiD‐influenza rapidly adhered to human eosinophils and were internalized and inactivated (95% in ≤ 2 hours) as reflected by a reduced replication in epithelial cells. The capacity of eosinophils to capture virus was reduced up to 75% with increasing severity of asthma. Eosinophils were activated by virus in vitro and in vivo. In vivo this correlated with virus‐induced loss of asthma control. Conclusions This previously unrecognized and in asthma attenuated antiviral property provides a new perspective to eosinophils in asthma. This is indicative of an imbalance between protective and cytotoxic properties by eosinophils that may underlie asthma exacerbations.
RETRACTED ARTICLE: miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization
Authors: Xiaobin Lin, Shuyi Wang, Min Sun, Chunxiao Zhang, Chen Wei, Chaogang Yang, Rongzhang Dou, Qing Liu, Bin Xiong
Journal: Journal of Hematology & Oncology (2019)

Abstract Background Tumor microenvironment (TME) is a complex environment containing tumor cells, tumor-associated macrophages (TAMs), interstitial cells, and non-cellular components. Epithelial–mesenchymal transition (EMT), as a major actor in cancer tumorigenicity and metastasis, was involved in the interaction between TAMs and tumor cells. However, the potential mechanisms of EMT and how EMT-programmed tumor cells affect M2-like TAMs still need further exploration. Methods An integrated analysis of nine CRC miRNA expression datasets was performed. Functional assays, including the EdU, clone formation, wound healing, and transwell assays, were used to determine the anticancer role of miR-195-5p in human CRC progression. Furthermore, RNA immunoprecipitation, RNA decay, and dual-luciferase reporter assays were used to determine the mechanism of miR-195-p CRC progression. Then co-culture, migration, and ELISA assays were applied to determine the role of miR-195-5p in macrophage recruitment and alternative polarization. Xenograft mouse models were used to determine the role of miR-195-5p in CRC tumorigenicity and TAM polarization in vivo. Results An integrated analysis confirmed that miR-195-5p was significantly downregulated in CRC tissues, and patients with a low level of miR-195-5p had significantly shortened overall survival as revealed by the TCGA-COAD dataset. Altered miR-195-5p in colon cancer cells led to distinct changes of proliferation, migration, invasion, and EMT. Mechanistically, miR-195-5p regulated NOTCH2 expression in a post-transcriptional manner by directly binding to 3′-UTR of the Notch2 mRNA. Subsequently, miR-195-5p/NOTCH2 suppressed GATA3-mediated IL-4 secretion in CRC cells and ultimately inhibited M2-like TAM polarization. Conclusions miR-195-5p may play a vital role in regulating NOTCH2-mediated tumor cell EMT, thereby affecting IL-4-related M2-like TAM polarization in CRC.
Abstract 19496: A New Exercise Testing Model Performs Better than the Duke Treadmill Score to Identify Patients at Increased Risk for All-cause Mortality
Authors: Paul C Cremer, Yuping Wu, Lee Pierson, Danielle Brennan, Leslie Cho
Journal: Circulation (2015)

Background: Cardiovascular mortality has declined with advances in primary and secondary prevention, yet risk assessment for patients undergoing exercise treadmill testing is generally still based upon the Duke Treadmill Score (DTS). We hypothesized that a new risk score would perform better than the DTS. Methods: We studied 59,877 consecutive patients who had exercise testing between Januray 1, 2000 and October 27, 2011 with the sample divided equally into derivation and validation cohorts. The primary outcome was all-cause mortality. Risk scores for men and women were developed from Cox proportional hazards models. The DTS was compared to new risk scores in the validation cohort with C-statistics, category-free net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results: Over a median follow-up of 8 years, there were 2,521 deaths. In the multivariable model, age, exercise capacity, heart rate recovery, weight, and renal disease were associated with mortality in men and women. Diabetes mellitus and history of smoking were associated with mortality in women whereas heart failure, current smoking, and hypertension were associated with mortality in men. C-statistics, NRI, and IDI were all improved with the new risk scores (Table). In particular, the new risk scores correctly reclassified patients with events, especially in women. Patients in the highest tertile of risk score also had substantial mortality during follow-up (Figure). Conclusions: We have developed new risk scores for men and women that perform better than the DTS, particularly in patients at the highest risk for all-cause mortality.
CCL2 in Schnitzler syndrome
Authors: K. Krause, R. Sabat, E. Witte‐Händel, A. Schulze, V. Puhl, M. Maurer, K. Wolk
Journal: British Journal of Dermatology (2019)

Schnitzler syndrome is a very rare chronic disease, which usually develops in the second half of life. It appears as skin rashes, muscle/skeletal pain and fever episodes. The trigger and molecular processes in the disease are not understood. However, drugs that inhibit the inflammatory molecule called interleukin‐1ß were found to relieve the disease. The authors of this German study wondered which further molecules are involved in Schnitzler syndrome. For this purpose, a range of molecules with inflammatory properties was quantified in the blood of the patients and, as a comparison, in healthy people and patients with other inflammatory diseases. Patients with Schnitzler syndrome were found to have strongly elevated levels of CCL2, a molecule known to attract inflammatory cells to affected tissues and to have a special role in bone alterations. CCL2 levels were particularly high in severely affected patients, especially those with intense bone pain. In the bone, CCL2 is known to be produced by certain bone‐modifying cells. Laboratory experiments revealed that CCL2 was also highly produced by immune cells and connective tissue cells (fibroblasts). Interleukin‐1ß as well as the inflammatory molecule TNF‐α triggered the production of CCL2 by these cells. When patients were treated with an interleukin‐1ß‐blocking drug, health improvement was paralleled by a drop of CCL2 levels. The authors concluded that in Schnitzler syndrome CCL2 is an important player in the inflammation process in bones and other body sites and may be used in the clinic as an indicator of disease severity.
Heart Rate, Autonomic Function, and Future Changes in Glucose Metabolism in Individuals Without Diabetes: The Whitehall II Cohort Study
Authors: Christian Stevns Hansen, Kristine Færch, Marit Eika Jørgensen, Marek Malik, Daniel R. Witte, Eric J. Brunner, Adam G. Tabák, Mika Kivimäki, Dorte Vistisen
Journal: Diabetes Care (2019)

OBJECTIVE Autonomic nervous system dysfunction is associated with impaired glucose metabolism, but the temporality of this association remains unclear in individuals without diabetes. We investigated the association of autonomic function with 5-year changes in glucose metabolism in individuals without diabetes. RESEARCH DESIGN AND METHODS Analyses were based on 9,000 person-examinations for 3,631 participants without diabetes in the Whitehall II cohort. Measures of autonomic function included 5-min resting heart rate and six heart rate variability (HRV) indices. Associations between baseline autonomic function measures and 5-year changes in fasting and 2-h plasma glucose, serum insulin concentrations, insulin sensitivity (insulin sensitivity index [ISI0–120] and HOMA of insulin sensitivity), and β-cell function (HOMA of β-cell function) were estimated in models adjusting for age, sex, ethnicity, metabolic factors, and medication. RESULTS A 10-bpm higher resting heart rate was associated with 5-year changes in fasting and 2-h insulin and ISI0–120 of 3.3% change (95% CI 1.8; 4.8), P &amp;lt; 0.001; 3.3% change (1.3; 5.3), P = 0.001; and −1.4% change (−2.4; −0.3), P = 0.009, respectively. In models adjusted for age, sex, and ethnicity, higher baseline values of several HRV indices were associated with a 5-year decrease in fasting and 2-h insulin and ISI0–120. However, significance was lost by full adjustment. A majority of HRV indices exhibited a trend toward higher values being associated with lower insulin levels and higher insulin sensitivity. CONCLUSIONS Higher resting heart rate in individuals without diabetes is associated with future unfavorable changes in insulin levels and insulin sensitivity. Associations may be mediated via autonomic function; however, results are inconclusive. Resting heart rate may be a risk marker for future pathophysiological changes in glucose metabolism.
Exploring Campylobacter seasonality across Europe using The European Surveillance System (TESSy), 2008 to 2016
Authors: IR Lake, FJ Colón-González, J Takkinen, M Rossi, B Sudre, J Gomes Dias, L Tavoschi, A Joshi, JC Semenza, G Nichols
Journal: Eurosurveillance (2019)

Background Campylobacteriosis is the most commonly reported food-borne infection in the European Union, with an annual number of cases estimated at around 9 million. In many countries, campylobacteriosis has a striking seasonal peak during early/mid-summer. In the early 2000s, several publications reported on campylobacteriosis seasonality across Europe and associations with temperature and precipitation. Subsequently, many European countries have introduced new measures against this food-borne disease. Aim To examine how the seasonality of campylobacteriosis varied across Europe from 2008–16, to explore associations with temperature and precipitation, and to compare these results with previous studies. We also sought to assess the utility of the European Surveillance System TESSy for cross-European seasonal analysis of campylobacteriosis. Methods Ward’s Minimum Variance Clustering was used to group countries with similar seasonal patterns of campylobacteriosis. A two-stage multivariate meta-analysis methodology was used to explore associations with temperature and precipitation. Results Nordic countries had a pronounced seasonal campylobacteriosis peak in mid- to late summer (weeks 29–32), while most other European countries had a less pronounced peak earlier in the year. The United Kingdom, Ireland, Hungary and Slovakia had a slightly earlier peak (week 24). Campylobacteriosis cases were positively associated with temperature and, to a lesser degree, precipitation. Conclusion Across Europe, the strength and timing of campylobacteriosis peaks have remained similar to those observed previously. In addition, TESSy is a useful resource for cross-European seasonal analysis of infectious diseases such as campylobacteriosis, but its utility depends upon each country’s reporting infrastructure.
Abstract 13814: Cognitive Impairment is Independent of Depression and Anxiety in Predicting Death and Readmissions Within 30 Days of Discharge for Heart Failure
Authors: Quan L Huynh, Kazuaki Negishi, Leigh Blizzard, Makoto Saito, Carmine De Pasquale, James Hare, Dominic Leung, Tony Stanton, Kristy Sanderson, Alison Venn, Thomas Marwick
Journal: Circulation (2015)

Background: Cognitive impairment, depression and anxiety are common in heart failure (HF). This study investigated the relationship of these factors with short-term outcomes in HF. Methods: This study included 343 HF patients from an Australia-wide longitudinal study of HF. Baseline clinical and administrative data, mental health (PHQ-9 and GAD-7 scores), cognitive function (MOCA score) and 2D echocardiograms were collected before hospital discharge. The study outcomes were death and readmission within 30 days of discharge. Logistic regression, Harrell’s C-statistic and integrated discrimination improvement were used for analysis. Results: Of 343 HF patients, 60 (17%) had severe depression (PHQ-9&gt;15), 43 (12%) had severe generalized anxiety (GAD-7&gt;15), and 233 (68%) were cognitively impaired (MOCA&lt;26). PHQ-9 and GAD-7 scores were closely correlated (r=0.76 p&lt;0.001), but were not associated with the MOCA score (r=0.00 and r=0.01 respectively). Within 30 days of discharge, 21 (6%) patients died and 77 (22%) and were readmitted. Death and readmission within 30 days of discharge were more likely to occur among patients with severe depression (odds ratio OR=2.52, p=0.007), severe anxiety (OR=2.46, p=0.01) and cognitive impairment (OR=2.80, p=0.001). After adjusting for standard clinical predictors included in the Yale prediction model, MOCA score (OR 0.87 p&lt;0.001), PHQ-9 score (OR=1.06 p=0.003) and GAD-7 score (OR=1.06 p=0.002) remained predictive of HF 30-day readmission or death. Compared with a basic clinical predictive model, MOCA, GAD-7 and PHQ-9 scores provided incremental value (integrated discrimination improvement estimate 0.129, p&lt;0.001) in predicting 30-day death and readmission among HF patients (see Figure). Conclusions: Depression/anxiety and cognitive impairment are independent and incremental to standard predictors of short-term outcomes in HF.