tbuckley/cabot-search huggingface dataset:
Responsiveness and interpretability of the Hand Eczema Severity Index
Authors: J.A.F. Oosterhaven, M.L.A. Schuttelaar
Journal: British Journal of Dermatology (2019)

The Hand Eczema Severity Index (HECSI) is used to measure the severity of hand eczema. It is unclear what HECSI scores mean and what is the minimally important change (MIC). Furthermore, its responsiveness has not been studied.To study the responsiveness and interpretability of the HECSI.This was a prospective study covering two time points: baseline and after 4-12 weeks. Responsiveness was assessed using a criterion approach, with at least one-step improvement on the 'Photographic guide for severity of hand eczema' as the anchor for important improvement. Interpretability of single scores was determined by defining severity bands based on agreement with the anchor. For change scores, the smallest detectable change (SDC) was calculated in patients indicating no change and the MIC was obtained in patients indicating that they had changed using three methods: mean cutoff, receiver operating characteristic (ROC) curve and 95% limit.In total, 294 patients participated (160 male, mean age 44·9 years). HECSI scores improved or deteriorated in parallel with the anchor. The area under the ROC curve was 0·86 (95% confidence interval 0·81-0·91). The final severity band for single scores had a κ-coefficient of agreement of 0·694: clear, 0; almost clear, 1-16; moderate, 17-37; severe, 38-116; very severe, ≥ 117. The SDC in 93 unchanged patients was 40·3 points. The obtained MIC values were all smaller than the SDC.The HECSI has good responsiveness. This study gives meaning to HECSI scores, which can be applied to clinical decision making and the design of clinical trials. We recommend that an improvement of 41 points on the HECSI is regarded as the minimally measurable true change. What's already known about this topic? The Hand Eczema Severity Index (HECSI) is one of the most widely used measurement instruments to measure the severity of hand eczema. The HECSI has good reliability, but its responsiveness and interpretability have not been studied. What does this study add? This study shows good responsiveness of the HECSI. A severity grading for single scores is proposed. The smallest detectable change and minimally important change for improvement are determined. What are the clinical implications of this work? The obtained values help to interpret HECSI scores in daily practice and clinical studies, and may facilitate researchers in the calculation of sample sizes for clinical trials.
Abstract 3197: BI-907828, a novel and potent MDM2-p53 antagonist, acts synergistically in a triple combination with anti-PD-1 and anti-LAG-3 antibodies in syngeneic mouse models of cancer
Authors: Dorothea Rudolph, Ulrike Weyer-Czernilofsky, Markus Reschke, Martina Sykora, Jörg Rinnenthal, Sophia Blake, Gabriela Gremel, Andreas Wernitznig, Andreas Gollner, Norbert Kraut, Jürgen Moll
Journal: Cancer Research (2019)

Abstract MDM2-p53 antagonists block the interaction between the Tumor Protein p53 and MDM2, its key negative regulator, and represent a new therapeutic concept for cancer therapy. MDM2-p53 antagonists are designed to restore p53 activity in TP53 wild-type tumors. Several MDM2-p53 antagonists are currently being evaluated in early clinical development. BI-907828 is a novel and potent MDM2-p53 antagonist with optimized drug-like properties that has shown efficacy in human tumor xenograft models at daily low oral dose as well as intermittent high dose schedules. Recent preclinical studies in syngeneic mouse models of cancer have demonstrated that BI-907828, apart from its direct tumor-targeting activity, also has immunomodulatory activity shown to contribute to efficacy. Single-agent BI-907828 induced anti-tumor immunological memory that controlled tumor growth in a re-challenge study. Moreover, a dual combination with an anti-mouse PD-1 checkpoint inhibitor resulted in synergistic efficacy in a syngeneic mouse model of cancer (AACR 2018, abstract 4866). Here we present data for the triple combination of BI-907828 with two checkpoint inhibitors. In syngeneic mouse tumor models (Colon-26 and B16-F10), the combination of BI-907828 with tool antibodies against mouse PD-1 and mouse LAG-3 shows high response rates of 50-90% with tumor regressions observed for even very large tumors. Moreover, efficacy of the triple combination is superior to each single agent and all dual combinations. An antibody-mediated depletion study suggests a contribution of CD8+ T cells but not of CD4+ T cells to full efficacy of the triple combination. FACS analysis of tumors isolated from Colon-26 tumor-bearing mice indicates that treatment with the triple combination leads to expansion of tumor-infiltrating CD8+ T cells. In summary, BI-907828 is a novel, potent, orally bioavailable MDM2-p53 antagonist that shows synergistic efficacy in a triple combination with antibodies targeting the immune checkpoints PD-1 and LAG-3 in syngeneic mouse models of cancer. BI-907828 is currently under evaluation in a Phase I clinical study (NCT03449381). Citation Format: Dorothea Rudolph, Ulrike Weyer-Czernilofsky, Markus Reschke, Martina Sykora, Jörg Rinnenthal, Sophia Blake, Gabriela Gremel, Andreas Wernitznig, Andreas Gollner, Norbert Kraut, Jürgen Moll. BI-907828, a novel and potent MDM2-p53 antagonist, acts synergistically in a triple combination with anti-PD-1 and anti-LAG-3 antibodies in syngeneic mouse models of 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 3197.
Abstract 124: Evaluating heterogeneity of tumor microenvironment using single cell RNA sequencing
Authors: Untack Cho, Yong Sang Song, Woong-Yang Park, Hae-Ock Lee, Youngjin Han
Journal: Cancer Research (2019)

Abstract Tumor microenvironment interacts with cancer cells, causing tumor progression. Tumor microenvironment consists of cellular and acelluar components. We investigated cellular components of tumor microenvironment and heterogeneity of ovarian cancer. We performed single cell RNA sequencing analysis of cellular components of malignant ascites from a patient with advanced ovarian cancer. Among the various cell types including cancer cells, B cells, macrophages and fibroblasts, macrophage was the most dominant in malignant ascites. To determine the heterogeneity of ovarian cancer, we obtained primary ovarian cancer tissue from ovarian cancer patient. We performed single cell RNA sequencing analysis of cellular components derived from ovarian cancer tissue. We determined intra-heterogeneity of ovarian cancer and cellular components of ovarian cancer tissue. Taken together, we determined cellular components of ovarian cancer tissue and ascites and intra-heterogeneity of ovarian cancer. This study can provide insight of tumor microvironment and help understanding of ovarian cancer heterogeneity. Citation Format: Untack Cho, Yong Sang Song, Woong-Yang Park, Hae-Ock Lee, Youngjin Han. Evaluating heterogeneity of tumor microenvironment using single cell RNA sequencing [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 124.
A prospective single center study from a developing country to evaluate the prevalence of vitamin-D deficiency in patients with de novo hematologic malignancies.
Authors: Nishitha Shetty, Manju Sengar, Hari Menon, Uma Bhaskar Dangi, Meera Ghadge, Nitin Inamdar, Bhoopal Shinde, Santhosh Kumar, Joydeep Ghosh, Deepan Rajamanickam K., Vipul Sheth, Deepa susan Philip, Chandrakant MV
Journal: Journal of Clinical Oncology (2013)

e18004 Background: Vitamin-D deficiency is a global problem due to lack of sunlight exposure or dietary deficiency. Few studies have correlated vitamin-D deficiency with poor outcome in patients with diffuse large B-cell lymphomas and chronic lymphocytic leukemia. Expression of vitamin-D receptors on both normal and malignant hematopoietic cells suggests its possible role in pathogenesis, response to therapy and as a potential therapeutic target in haematological cancers. Given the high prevalence of malnutrition in our country and the potential impact of vitamin-D deficiency in haematological malignancies we conducted this prospective study to identify its prevalence in this subset of patients. Methods: Consecutive patients (15-50 years) with de novo haematological cancers who were registered at our centre over a three months period were evaluated. Patients who had received bisphosphonates or calcium and vitamin-D supplementation were excluded. Demographic variables, performance status, lifestyle (sedentary or non-sedentary), diet (vegetarian or mixed), consumption of milk products, serum 25 (OH) D, albumin and calcium levels were recorded. Levels &lt;30ng/ml and &lt;20ng/ml were considered as insufficient and deficient respectively. Results: A total of 126 patients (70% males) were enrolled. Median age was 35 years. Distribution as per histology was acute leukemia-59, lymphomas-53, chronic myeloid leukemia-14. 78% patients had non-sedentary life style and were consuming mixed diet and milk. 90% patients had performance status ≤2. Serum albumin&gt;3.5 gm/dL and normal calcium levels were seen in 90%. Vitamin-D deficiency was seen in 12% patients whereas 73% patients were vitamin D insufficient. Keeping the cut-off &lt;25 ng/mL, 82% patients were deficient. Deficiency did not correlate with age, underlying diagnosis, lifestyle or dietary habits. Conclusions: Our study identified a very high prevalence of vitamin-D deficiency in patients with haematological malignancies. This could be one of the factors responsible for the aggressive nature of disease and poor outcome in our patients.
Abstract 10: Transcriptional Profiling of the Neuroprotective Mechanisms of Inhaled Nitric Oxide in a Swine Model of Pediatric Cardiac Arrest
Authors: Marco Hefti, Kumaran Senthil, Constantine D Mavroudis, Michael Karlsson, Johannes Ehinger, Vinay M Nadkarni, Robert M Sutton, Robert A Berg, Ryan W Morgan, Todd J Kilbaugh
Journal: Circulation (2018)

Introduction: Neurologic morbidity is common after pediatric cardiac arrest and inhaled nitric oxide (iNO) may be protective. RNA sequencing may have a role in identifying differences in gene expression related to neurologic injury following cardiac arrest and the neuroprotective mechanism of iNO. Hypothesis: We hypothesized that genes related to energetically intensive functions such as synaptic vesicle trafficking would be downregulated after cardiac arrest and that this finding would be less prominent with iNO therapy. Methods: One-month old piglets underwent sham anesthesia or 7 minutes of asphyxia, induction of VF, and randomized and blinded therapy with AHA guideline-based CPR with iNO (iNO + ) or without iNO (iNO - ). Four hours post-ROSC, animals were euthanized and RNA was extracted from cerebral cortical tissue and sequenced on an Illumina HiSeq instrument. STAR was used to align reads to the SusScrofa11.1 reference followed by quantification with sub-reads. Normalization and differential expression analyses were performed using DESeq2 with RIN, RNA concentration, shocks delivered, epinephrine doses, post-ROSC epinephrine use, cerebral blood flow, ETCO 2 , and blood gas values as covariates. Benjamini-Hochberg-adjusted p values &lt;0.05 were considered statistically significant. Results: Sham animals (n=5) and cardiac arrest animals with ROSC (iNO+ n=9; iNO- n=6) were included in analyses. 817 genes were differentially expressed between cardiac arrest and sham. 798 genes were differentially expressed between iNO + and iNO - . 24 genes were differentially expressed in opposite directions in the two comparisons, making them candidates for protective mechanisms of iNO. These included genes related to synaptic vesicle function (RAB27B, PACSIN1, DOC2A) and maintenance of synaptic structure (SH2D5, CA10). Cardiac arrest induced downregulation of synaptic vesicle genes including SNAP25 and synaptophysin, while iNO induced upregulation of others in the same ontology, including synapsins and synaptogamins. Conclusions: Piglets subjected to asphyxial cardiac arrest exhibited downregulation of genes related to synaptic vesicle trafficking. This was partially prevented by treatment with iNO.
Outcomes of prognostic disclosure: Effects on advanced cancer patients’ prognostic understanding, mental health, and relationship with their oncologist.
Authors: Andrea Catherine Enzinger, Baohui Zhang, Tracy A. Balboni, Deborah Schrag, Holly Gwen Prigerson
Journal: Journal of Clinical Oncology (2013)

9519 Background: Many oncologists are reluctant to discuss life expectancy with advanced cancer patients. We examined the frequency of prognostic disclosure and its impact on patients’ prognostic understanding, the patient-doctor relationship, and psychological distress. Methods: Coping with Cancer was an NCI-funded, multi-site prospective cohort of 726 patients with advanced incurable cancer, enrolled 2002-2008. At baseline, patients were asked if their oncologist had ever discussed prognosis, and if so what estimate was communicated. Patients also estimated their prognosis. The therapeutic alliance scale measured patient-doctor relationship, and the McGill QOL instrument assessed symptoms of depression and anxiety. Multivariable analyses (MVA) assessed relationships between prognostic disclosure and psychological symptoms, controlling for confounds. Results: Among this cohort of terminally ill patients (median survival 4mos), most (72%) wanted to be told their life expectancy. Only 19.8% (104/525) of patients had received a prognostic estimate from their oncologist (median estimate 6mos; IQR 6-15mos). When queried about factors informing their prognostic understanding, 85.9% of patients cited personal or religious beliefs; only 11.7% cited a physician’s estimate. Of the 299 patients willing to estimate their life expectancy, patients who had been previously informed of their prognosis were substantially more realistic in their own estimate (median 12mos v 48mos, Wilcoxon test p&lt;0.001). Moreover, patients’ and oncologists’ prognostic estimates were significantly correlated (ρ=0.49, p&lt;0.001). Prognostic disclosure was not associated with poor patient-doctor relationship rating (Fisher’s Exact, p=0.625), nor was it associated with depressive symptoms (β 0.06, p=0.242) or anxiety (β 0.06, p=0.234) in MVA. Conclusions: Few advanced cancer patients are informed of their life expectancy, although most want this information. Prognostic disclosure is associated with substantial improvement in patients’ prognostic understanding, without compromising the patient-doctor relationship or increasing psychological distress.
Abstract 1619: Cervical cancer screening knowledge and behavior among female undergraduates
Authors: Joseph Agboeze, Matthew Igwe Nwali, Nkiru Ezeani
Journal: Cancer Research (2019)

Abstract Background; Cervical cancer is a highly preventable disease that disproportionally affects women in developing countries with an estimated incidence rate of 33 cases per 100,000 women in Nigeria.. Over the year’s awareness and uptake of cervical cancer screening services have remained poor in developing countries. Lack of knowledge and poor attitude towards the disease and risk factors can affect screening practice and development of preventive behavior for cervical cancer Objective; This study assessed the level of knowledge and barriers towards cervical cancer screening among female university students. Method; We conducted a cross-sectional study of 234 female students at Ebonyi State University Abakaliki Nigeria from March to July 2017 using multistage sampling technique. Apretested questionnaire was used to collect data on socio-demographic characteristics, knowledge, and screening history. Data were analysed with Epi info version 7.1.4. Results; Participants’ mean age was 22 years (sd=3).Of the respondents 79.5% were not aware of cervical cancer screening while 58.9% and 78.5% had poor knowledge on cervical cancer and Human papilomavirus vaccination respectively. Major sources of information were health workers 70% and 35% Radio while only 4.0% have had Pap smear test. Common barriers include lack of centres where such services are obtainable 88% and fear of cancer being discovered 9%. Reported risk factors were multiple sexual partners 24.2% and early onset of sexual intercourse 19.8%. A significant association was found between institutional and personal barriers and having a Pap smear test. Conclusion Comprehensive education on cervical cancer screening in universities is critical in reducing the morbidity and mortality associated with cervical cancer. Few screening centres contributed to poor cervical screening uptake. Note: This abstract was not presented at the meeting. Citation Format: Joseph Agboeze, Matthew Igwe Nwali, Nkiru Ezeani. Cervical cancer screening knowledge and behavior among female undergraduates [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 1619.
Abstract 938: Disruption of TOX overcomes CAR T-cell dysfunction function in solid tumor
Authors: Hyungseok Seo, Joyce Chen, Arundhoti Das, Avinash Bhandoola, Anjana Rao
Journal: Cancer Research (2019)

Abstract Adoptive cell therapy with chimeric antigen receptor expressing T (CAR T) cells has shown promising therapeutic efficacy against leukemia and lymphoma. However, CAR T cells in solid tumors fail to be as effective as in liquid tumors since they enter into a hyporesponsive (exhausted or dysfunctional) state that is induced by chronic antigen stimulation in cancer. Here, we show that CAR T cells in solid tumors exhibit low effector function and high expression of inhibitory receptors such as PD-1, Tim-3 and Lag 3. We also show that the nuclear factor, Thymocyte selection-associated HMG box protein, TOX - a target of the transcription factor NFAT - is highly expressed in CAR T cells in solid tumors with PD-1 expression. To determine how TOX transcription factors contribute to exhaustion/ dysfunction in CAR T cells, we developed CAR T cells targeting huCD19 and lacking TOX and TOX 2. Surprisingly, treatment of huCD19 expressing melanoma or colorectal tumor-bearing mice with CAR T cells doubly deficient in TOX and TOX2 resulted in the eradication of solid tumors and prolonged survival of the tumor-bearing mice, compared to mice treated with WT CAR T cells or CAR T cells lacking TOX or TOX2 alone. Tumor-infiltrating CAR T cells (CAR TILs) doubly deficient in TOX and TOX2 did not increase their expression of inhibitory receptors such as PD-1, Lag3 and CD160 and showed higher expression of TCF1 compared to WT CAR TILs. Our data identify TOX and TOX2 -high mobility group transcription factors belonging to the TOX family - as critical transcriptional factors for inducing hyporesponsiveness in CAR T cells in solid tumors. Our data suggest that disruption of TOX expression or activity could be a promising strategy for cancer immunotherapy. Citation Format: Hyungseok Seo, Joyce Chen, Arundhoti Das, Avinash Bhandoola, Anjana Rao. Disruption of TOX overcomes CAR T-cell dysfunction function in solid tumor [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 938.
Abstract 2812: Triple-negative breast cancer cell-intrinsic glucocorticoid receptor activity and modulation of the immune microenvironment
Authors: Deniz N. Dolcen, Diana West Szymanski, Ananth Panchamukhi, Xiaomeng Wang, Randy F. Sweis, Rita Nanda, Suzanne Conzen
Journal: Cancer Research (2019)

Abstract Background: Variation in the infiltration of TNBC immune microenvironment is not well understood. Our lab previously demonstrated that high glucocorticoid receptor (GR; nuclear hormone receptor) activity in TNBC models is associated with tumor cell-intrinsic anti-inflammatory gene expression pathways. In addition, high GR expression in early-stage TNBC is associated with a significantly lower rate of recurrence-free survival suggesting a role for GR-associated mechanisms in TNBC progression. GR activation in lymphocytes is well known to result in their apoptosis; however, a current gap in knowledge regarding GR biology is whether tumor-cell intrinsic GR activity modulates immune cells in the microenvironment. We hypothesized that TNBC cell-intrinsic GR activity may inhibit antitumor T cell activity in the tumor microenvironment. Methods and Results: We divided TCGA primary TNBC RNAseq expression data based on GR expression and determined enrichment for immune cells using two transcriptome parsing algorithms. We found that TNBCs with high GR expression are significantly enriched for the T cell-inflamed gene expression signature, suggesting the presence of T cells in the microenvironment. The xCell algorithm found that TNBCs with high GR expression are significantly enriched for the CD4+ naïve T cell transcriptome, which is absent in TNBCs with low GR-expression. To begin to determine whether GR activation in TNBC cells induces the secretion of cytokines and/or growth factors that result in the chemotaxis of CD4+ naïve T cells, we collected conditioned cell culture media from control versus GR-active TNBC cells and performed multiplex cytokine ELISA. We found that G-CSF secretion by TNBC cells was significantly increased following GR activation; G-CSF has been shown to promote immunosupressive Treg cell differentiation. Conclusions: Prior data suggest that breast tumor-infiltrating immunosuppressive Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Thus targeting GR in TNBC may be an important therapeutic approach to potentiate antitumor T cell responses and suppress the Treg population in the tumor microenvironment. Ongoing work is aimed at further delineating a mechanism by which GR can modulate the immune tumor microenvironment. Citation Format: Deniz N. Dolcen, Diana West Szymanski, Ananth Panchamukhi, Xiaomeng Wang, Randy F. Sweis, Rita Nanda, Suzanne Conzen. Triple-negative breast cancer cell-intrinsic glucocorticoid receptor activity and modulation of the immune microenvironment [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 2812.
Residual β cell function and monogenic variants in long-duration type 1 diabetes patients
Authors: Marc Gregory Yu, Hillary A. Keenan, Hetal S. Shah, Scott G. Frodsham, David Pober, Zhiheng He, Emily A. Wolfson, Stephanie D’Eon, Liane J. Tinsley, Susan Bonner-Weir, Marcus G. Pezzolesi, George Liang King
Journal: Journal of Clinical Investigation (2019)

BACKGROUND. In the Joslin Medalist Study (Medalists), we determined whether significant associations exist between β cell function and pathology and clinical characteristics.
Abstract 18768: Increased Stress-related Neural Tissue Activity Potentiates Inflammation and Impedes the Anti-inflammatory Impact of Statins
Authors: Basma Hammad, Micheal T Osborne, Amorina Ishai, Ying Wang, Brian Tung, Amos Baruch, Micheal Klimas, Lisa M Shin, Zahi Fayad, Jon T Glies, Roger Pitman, Ahmed Tawakol
Journal: Circulation (2017)

Introduction: Chronic psychosocial stress increases resting amygdalar activity (AA: a validated measure of neural tissue response to stress). Higher AA results in activation of an amygdalar-hematop...