tbuckley/cabot-search huggingface dataset:
Decreasing inpatient chemotherapy initiation delays at Memorial Regional Hospital.
Authors: Michel Vulfovich, Matthew Philip Salzberg, Marie Louis-Jeune, Khang Pham, Kelly King, Jessica Jacques, Ulonda Lanier, Amy Morris
Journal: Journal of Clinical Oncology (2021)

225 Background: Between June and December 2019, hematology-oncology patients admitted for elective chemotherapy at Memorial Regional Hospital had a median delay of 10 hours to initiate chemotherapy infusion from time of admission. This contributes to increased cost to the healthcare system and patient dissatisfaction. By September 2020, elective inpatient median time from admission to chemotherapy initiation at Memorial Regional Hospital will be reduced by 20%. Methods: Multidisciplinary team formed to evaluate the time from admission to initiation of chemotherapy for patients who are electively admitted for chemotherapy in 8 Central based on time stamps available in the electronic health records. Patients electively admitted by a non MCI oncologist were excluded. Data collections included time stamp between each process from admission to administration of 1st chemotherapy. Longest time lapse between each process was counted as an occurrence/contributor to delay. Top 80% contributors identified from Pareto chart allowed team to identify countermeasures. Priority Matrix of implementation in PDSA cycle based on highest impact and ease of implementation. Statistical process control chart was developed. Results: (see table). Conclusions: PDSA Cycle 1, obtaining labs 24-48 hours prior to admission, resulted in a 10% reduction in chemotherapy initiation time. PDSA Cycle 2, enhancing “ok to treat” communication, resulted in a further reduction of time to treatment. The combination of PDSA Cycle 1 &amp; 2 resulted in a 40% reduction in time to chemotherapy initiation, exceeding the planned aim of 20%. Balance measures reflected no reduction in the mean number of overnight stays between baseline and PDSA Cycle 2 (4 nights) that could contribute to a decreased cost. Results and recommendations to adopt at all inpatient oncology departments within the healthcare system will be presented to leadership for support. Data automation through collaborative efforts with information technology is in process to assist with continuous monitoring. Future state, the quality improvement tools gained from ASCO QTP will be utilized to evaluate and improve workflow issues in the outpatient oncology setting. Nationally recognized organizations are encouraged to propose a benchmark for admission time to first chemotherapy administration based on the evaluation of current available data. Additional studies are needed to evaluate chemotherapy treatment delays in other settings.[Table: see text]
Epigenome-Wide DNA Methylation and Pesticide Use in the Agricultural Lung Health Study
Authors: Thanh T. Hoang, Cancan Qi, Kimberly C. Paul, Mikyeong Lee, Julie D. White, Marie Richards, Scott S. Auerbach, Stuart Long, Srishti Shrestha, Tianyuan Wang, Laura E. Beane Freeman, Jonathan N. Hofmann, Christine Parks, Cheng-Jian Xu, Beate Ritz, Gerard H. Koppelman, Stephanie J. London
Journal: Environmental Health Perspectives (2021)

BACKGROUND: Pesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations.Epigenetic modifications, such as DNA methylation, may contribute.Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides.OBJECTIVES: We conducted an EWAS of DNA methylation in relation to several pesticide active ingredients.METHODS: The Agricultural Lung Health Study is a case-control study of asthma, nested within the Agricultural Health Study.We analyzed blood DNA methylation measured using Illumina's EPIC array in 1,170 male farmers of European ancestry.For pesticides still on the market at blood collection (2009-2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use.We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users.RESULTS: Using family-wise error rate (p < 9 × 10 -8 ) or false-discovery rate (FDR <0:05), we identified 162 differentially methylated CpGs across 8 of 9 currently marketed active ingredients (acetochlor, atrazine, dicamba, glyphosate, malathion, metolachlor, mesotrione, and picloram) and one banned organochlorine (heptachlor).Differentially methylated CpGs were unique to each active ingredient, and a dose-response relationship with lifetime days of use was observed for most.Significant CpGs were enriched for transcription motifs and 28% of CpGs were associated with whole blood cis-gene expression, supporting functional effects of findings.We corroborated a previously reported association between dichlorodiphenyltrichloroethane (banned in the United States in 1972) and epigenetic age acceleration.DISCUSSION: We identified differential methylation for several active ingredients in male farmers of European ancestry.These may serve as biomarkers of chronic exposure and could inform mechanisms of long-term health outcomes from pesticide exposure.
Homogeneously high expression of CD32b makes it a potential target for CAR-T therapy for chronic lymphocytic leukemia
Authors: Guoling Wang, Xiaolei Sun, Shiyu Zuo, Chuo Li, Qing Niu, Yonghui Xia, Yuan Meng, Min Liu, Zihao Fang, Xi Yang, Yanyu Jiang, Sheng Wang, Haidong Cui, Huifang Huang, Erlie Jiang, Dongming Zhou, Qi Deng, Jing Pan, Xiaoming Feng
Journal: Journal of Hematology & Oncology (2021)

CD19 chimeric antigen receptor (CAR)-T cells have been used to treat patients with refractory chronic lymphocytic leukemia (CLL). However, approximately 50% of patients do not respond to this therapy. To improve the clinical outcome of these patients, it is necessary to develop strategies with other optimal targets to enable secondary or combinational CAR-T cell therapy. By screening a panel of surface antigens, we found that CD32b (FcγRIIb) was homogeneously expressed at high site density on tumor cells from CLL patients. We then developed a second-generation CAR construct targeting CD32b, and T cells transduced with the CD32 CAR efficiently eliminated the CD32b+ Raji leukemic cell line in vitro and in a mouse xenograft model. Furthermore, CD32b CAR-T cells showed cytotoxicity against primary human CLL cells that were cultured in vitro or transplanted into immunodeficient mice. The efficacy of CD32b CAR T cells correlated with the CD32b density on CLL cells. CD32b is not significantly expressed by non-B hematopoietic cells. Our study thus identifies CD32b as a potential target of CAR-T cell therapy for CLL, although further modification of the CAR construct with a safety mechanism may be required to minimize off-target toxicity.
From community to validated measure: Development and validation of the patient-informed cancer communication scale (PICCS).
Authors: Lauren M. Hamel, Roger Soulliere, Fatmeh Baidoun, Tanina Foster, Elisabeth I. Heath, Susan Eggly
Journal: Journal of Clinical Oncology (2021)

159 Background: Assessing patient-centered communication (PCC) is critical to improving quality patient-centered cancer care. While shown to be reliable and valid, most PCC measures were created by researchers, likely neglecting concerns of patients, families, and community members. PCC measures should be driven, in part, by the patient population of interest, especially given disparities in clinical communication. Our objective was to develop and validate a patient-informed PCC scale to assess cancer treatment discussions. Methods: As part of a larger study on communication and minority accrual to trials, we convened a panel of black and white cancer survivors, caregivers, and advocates. Panel members (n = 11) included 5 black and 3 white men and 1 black and 2 white women. Among them were 6 survivors and 5 caregivers. Panel members met regularly over six months to observe and discuss video-recorded treatment discussions between black and white men with prostate cancer and their physicians. Through an iterative process of generating and refining a list of physician communication behaviors they considered to be critical to PCC in a diverse patient population, they produced a list of 22 items, titled Patient-Informed Cancer Communication Scale (PICCS). We then applied the list as an observational scale to a set of video-recorded treatment discussions (n = 61) from the larger study. Trained raters applied the list and had acceptable inter-rater reliability. We used findings to determine constructs using scale development and factor analysis, then validated the scale through correlation with established scales. Results: We evaluated each item for content validity and feasibility. We divided some items that were assessing multiple attributes. The result was a 28-item scale. Using Classical Test Theory, we reduced the scale to 22 items. Using factor analysis, we identified five factors, including: 1. Treatment options (10 items a =.92); 2. Clinical relationship (6-items a =.92); 3. Prognosis and goals of treatment (2-items a =.79); 4. Explanations (2-items a =.43); and 5. Context (1-item). To validate, we correlated factors with two validated scales, one measuring physician PCC and the other patient active participation. Factor 1 was positively correlated with patient active participation ( r=.46; p=.003); Factor 2 with PCC ( r=.54, p. &lt;.001); Factor 3 with patient active participation ( r=.48; p=.002); and Factor 5 with PCC ( r=.47, p=.002). The full PICCS scale was positively correlated with patient active participation ( r=.37, p=.02). PICCS Factor 4 was not correlated to the scales. Conclusions: This community-engaged research produced a reliable and valid patient-informed scale to assess PCC during cancer clinical interactions. Next steps include translating the findings by using PICCS to train physicians to communicate effectively in a diverse patient population.
P13.11 Transcriptional CDK inhibitors, CYC065 and THZ1 promote apoptosis in preclinical models of primary and recurrent GBM tumour cells and glioma stem cells
Authors: V Juric, H Duessmann, H Jahns, M Verreault, A Idbaih, M L Lamfers, A M Hopkins, J H Prehn, M Rehm, B M Murphy
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Activation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation of CDKs are a feature of many tumours including glioblastoma (GBM), the most common and aggressive primary brain tumour. Patient resistance to the current standard of care, temozolomide and radiotherapy, is common and highlights the need to discover more effective treatment strategies. Additionally, glioma stem cells (GSCs), tumour initiating cells contribute to treatment resistance in GBM. Targeting GBM tumour cells and GSCs using transcriptional CDK inhibitors, CYC065 and THZ1 is a potential novel treatment to prevent relapse of the tumour. MATERIAL AND METHODS The therapeutic efficacy of two CDK inhibitors (CKIs) was tested in a panel of ten low-passage GBM patient-derived gliomasphere cultures and semi-in vivo chick embryo xenograft models. Specifically, transcriptional inhibitors targeting CDK9/2 (CYC065) and CDK7 (THZ1) were used. Mechanism of cell death was examined following CKI treatment. Additionally, dependence on anti-apoptotic proteins was studied using genetic depletion and BH3 profiling. Fluorescence activated cell sorting (FACS) and light-sheet fluorescence microscopy (LSFM) were employed to study stem cell populations in recurrent GBM and evaluation of CKI efficacy against GSCs. RESULTS We here demonstrate that CYC065 and THZ1 treatments cause loss of cell viability and induce caspase-dependent apoptosis in primary and recurrent patient-derived gliomaspheres while sparing primary cortical neurons. Importantly, apoptosis responses manifested across a range of time points that significantly correlated with the cell doubling time. Mechanistically, CYC065 and THZ1 downregulate the anti-apoptotic protein Mcl-1, which suffices to sensitise gliomasphere cultures to treatment-induced apoptosis in a Bim-dependent manner. Additionally, high expression levels of chemo- and radio-resistant GSCs were found in recurrent gliomaspheres. CKIs induced apoptosis in isolated CD133 and CD44 biomarker-positive cells while TMZ was ineffective, highlighting the potential of these drugs to overcome resistance to conventional chemotherapy. Additionally, using LSFM we shown that CD133, CD44 GSC biomarker-negative cells convert into GSC biomarker-positive cells and contribute to the enrichment in GSCs in recurrent GBM which could potentially explain the TMZ ineffectiveness. Finally, CKIs reduced proliferation and promoted apoptosis in chick embryo xenograft models of primary and recurrent GBM. CONCLUSION Collectively, these data demonstrate that CYC065 and THZ1 display high anti-cancer activity in primary and recurrent GBM and provide scientific rationale for the further development of CDK inhibitors to potentiate their clinical utilization in the future.
Nintedanib in Patients With Systemic Sclerosis–Associated Interstitial Lung Disease: Subgroup Analyses by Autoantibody Status and Modified Rodnan Skin Thickness Score
Authors: Masataka Kuwana, Yannick Allanore, Christopher P. Denton, Jörg H. W. Distler, Virginia Steen, Dinesh Khanna, Marco Matucci‐Cerinic, Maureen D. Mayes, Elizabeth R. Volkmann, Corinna Miede, Martina Gahlemann, Manuel Quaresma, Margarida Alves, Oliver Distler
Journal: Arthritis & Rheumatology (2021)

Using data from the SENSCIS trial, these analyses were undertaken to assess the effects of nintedanib versus placebo in subgroups of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), based on characteristics previously identified as being associated with the progression of SSc-ILD.Patients with SSc-ILD were randomized to receive either nintedanib or placebo, stratified by anti-topoisomerase I antibody (ATA) status. We assessed the rate of decline in forced vital capacity (FVC) (expressed in ml/year) over 52 weeks in subgroups based on baseline ATA status, modified Rodnan skin thickness score (MRSS) (<18 versus ≥18), and SSc subtype (limited cutaneous SSc [lcSSc] versus diffuse cutaneous SSc [dcSSc]).At baseline, 60.8% of 576 patients who received treatment with either nintedanib or placebo were positive for ATA, 51.9% had dcSSc, and 77.5% of 574 patients with MRSS data available had an MRSS of <18. The effect of nintedanib versus placebo on reducing the rate of decline in FVC (ml/year) was numerically more pronounced in ATA-negative patients compared to ATA-positive patients (adjusted difference in the rate of FVC decline, 57.2 ml/year [95% confidence interval (95% CI) -3.5, 118.0] versus 29.9 ml/year [95% CI -19.1, 78.8]), in patients with a baseline MRSS ≥18 compared to those with a baseline MRSS of <18 (adjusted difference in the rate of FVC decline, 88.7 ml/year [95% CI 7.7, 169.8] versus 26.4 ml/year [95% CI -16.8, 69.6]), and in patients with dcSSc compared to those with lcSSc (adjusted difference in the rate of FVC decline, 56.6 ml/year [95% CI 3.2, 110.0] versus 25.3 ml/year [95% CI -28.9, 79.6]). However, all exploratory interaction P values were nonsignificant (all P > 0.05), indicating that there was no heterogeneity in the effect of nintedanib versus placebo between these subgroups of patients.In patients with SSc-ILD, reduction in the annual rate of decline in FVC among patients receiving nintedanib compared to those receiving placebo was not found to be heterogenous across subgroups based on ATA status, MRSS, or SSc subtype.
Paul Mapleston Smith
Authors: J. S. M. W. R. Williams
Journal: BMJ (2015)

Paul Mapleston Smith was born in Harrow in 1936 and was educated at the Merchant Taylor’s School in Northwood. He studied medicine at St Thomas’ Hospital, London, where he later became registrar in the department of metabolic diseases. Part of his rotation took him to Southampton in 1965, where he met Roger Williams, whose influence undoubtedly initiated and stimulated Paul’s love of hepatology and gastroenterology. During this year Paul established several studies on iron clearance, using the whole body counter at the Royal Navy Physiology Laboratory at Alverstoke, Hampshire. In 1966 he drove his VW Beetle from Southampton to the new liver unit at King’s College Hospital, with all the laboratory equipment on the backseat. There, as the institution’s first research fellow, he completed his MD on aspects of haemochromatosis. In 1968 he …
A Review of the Diagnosis and Management of Headache
Authors: James T. Langland
Journal: JAMA (2021)

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Community-wide hackathons to identify central themes in single-cell multi-omics (vol 22, 220, 2021)
Authors: Kim-Anh Le Cao, Al J Abadi, Emily F Davis-Marcisak, Lauren Hsu, Arshi Arora, Alexis Coullomb, Atul Deshpande, Yuzhou Feng, Pratheepa Jeganathan, Melanie Loth, Chen Meng, Wancen Mu, Vera Pancaldi, Kris Sankaran, Dario Righelli, Amrit Singh, Joshua S Sodicoff, Genevieve L Stein-O'Brien, Ayshwarya Subramanian, Joshua D Welch, Yue You, Ricard Argelaguet, Vincent J Carey, Ruben Dries, Casey S Greene, Susan Holmes, Michael I Love, Matthew E Ritchie, Guo-Cheng Yuan, Aedin C Culhane, Elana Fertig
Journal: Genome biology (2021)
OS12.7.A Characterization of intra-tumoral heterogeneity and differential immune activation during malignant progression of meningiomas on single cell level
Authors: C Blume, H Dogan, L Schweizer, W Wick, M Weller, M Mann, M Kalamarides, A von Deimling, M Schlesner, F Sahm
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND As the most common intracranial tumor, meningiomas have caused increasing interest in the field of medical research. Based on their mutational profile, meningiomas can be separated into two main groups: NF2 altered meningiomas, which can occur at WHO grades 1 to 3, and non-NF2 mutant meningiomas with mutations in other genes, such as TRAF7, AKT1, KLF4, and SMO, which are usually of WHO grade 1. While this means that non-NF2 mutant meningiomas usually follow a benign course, risk stratification for NF2 mutant meningiomas remains difficult. As of now, the underlying mechanisms contributing to the malignant phenotype of some NF2 mutant meningiomas remained unknown, even though some molecular markers have been associated with an increased risk of recurrence. Here, we sought to characterize robust molecular subgroups for meningiomas and identify the critical steps in malignant progression of these tumors. MATERIAL AND METHODS We applied bulk RNA sequencing and proteomic analyses for 44 meningioma samples as well as single nuclei RNA sequencing analyses for an additional set of 26 meningiomas with a total of 46,002 nuclei. Both datasets comprised samples across the molecular landscape of meningiomas and WHO grades 1, 2, and 3. RESULTS The meningioma subgroups previously identified on epigenomic level were found consistently also on transcriptomic, proteomic, and phospho-proteomic levels. In addition, strong differences in numbers and types of infiltrating immune cells between subgroups became apparent. A decreased number of infiltrating macrophages and an activation to a more proinflammatory phenotype was observed for WHO grade 3 tumors. This observation correlated with lower expression levels of CSF1 in tumor cells of WHO grade 3 meningiomas, which was predicted to stimulate macrophages in WHO grade 1 and 2 tumors. Moreover, we identified several tumor cell subpopulations, each defined by a distinct phenotype, shared across samples. Their proportions in the tumor strongly depended on tumor grade. Especially a subpopulation characterized by an elevated stress response and TGFβ signaling activity was found specifically in WHO grade 3 cases. CONCLUSION Our findings establish molecular subgroups for meningiomas that are robust across multiple levels with characteristic differences in pathway activities and demonstrate a subtype-specific immune activation, both of which may be basis for novel treatment strategies.
TGF-β-induced CD4+ FoxP3+ regulatory T cell-derived extracellular vesicles modulate Notch1 signaling through miR-449a and prevent collagen-induced arthritis in a murine model
Authors: Jingrong Chen, Feng Huang, Yuluan Hou, Xiaorong Lin, Rongzhen Liang, Xiaojiang Hu, Jun Zhao, Julie Wang, Nancy Olsen, Song Guo Zheng
Journal: Cellular and Molecular Immunology (2021)