tbuckley/cabot-search huggingface dataset:
Knockdown of NEAT1 induces tolerogenic phenotype in dendritic cells by inhibiting activation of NLRP3 inflammasome
Authors: Maomao Zhang, Yang Zheng, Yong Sun, Shuang Li, Liangqi Chen, Xiangyuan Jin, Xinyu Hou, Xianglan Liu, Qi Chen, Jing Li, Mingyang Liu, Xianghui Zheng, Yongxiang Zhang, Jian Wu, Bo Yu
Journal: Theranostics (2019)

Rationale: Tolerogenic dendritic cells (tol-DCs) play essential roles in immune-related diseases and induce immune tolerance by shaping T-cell responses.Accumulating evidence suggests that long noncoding RNAs (lncRNAs) play important regulatory roles in the immune system.However, the potential roles and underlying mechanisms of lncRNAs in tol-DCs remain unclear.Methods: RNA in-situ hybridization, histochemistry, and qRT-PCR were performed to determine the distribution and expression of NEAT1 in DCs.Flow cytometry was used to analyze the tolerogenic function of DCs.Small sequencing, followed by bioinformatic analysis, was performed to determine the target genes of NEAT1.The mechanism of NEAT1 was explored using a luciferase reporter, chromatin immunoprecipitation assays, and Immunofluorescence.In-vivo experiments were used to investigate the induction of immune tolerance via NEAT1-knockdown DCs.Results: Our results show that lncRNA NEAT1 can induce tolerogenic phenotype in DCs.Mechanistically, small RNA-seq analysis revealed that NEAT1 knockdown preferentially affected the expression of miR-3076-3p.Furthermore, NEAT1 used the NLRP3 inflammasome as a molecular decoy for miR-3076-3p, thus facilitating the expression of tolerogenic phenotype in DCs.Moreover, the transcription factor E2F1 acted as a repressor of NEAT1 transcription via activity of H3K27ac.Our results also indicate that NEAT1 knockdown in DCs can induce immune tolerance in models of experimental autoimmune myocarditis and heart transplantation.Conclusions: Taken together, our study shows the mechanism used by NEAT1 in inducing tol-DCs and highlights the therapeutic potential of targeting NEAT1 for the treatment of immune-related diseases.
Which social measures relate to cancer screening &amp; healthy behaviors?
Authors: Kezhen Fei, Daliz Cruz, Jenny J. Lin, Radhi Yagnik, Emily Gallagher, Nina A. Bickell
Journal: Journal of Clinical Oncology (2019)

e18142 Background: Much of cancer health services research relies on administrative data, yet, there have been calls for more granular racial &amp; social disparities data. Subjective SES (sSES) is associated with health status &amp; behaviors, independent of objective SES (oSES) measures like income, education and race. We assessed the relationship between breast cancer patients’ oSES and sSES with their cancer screening and health behaviors. Methods: Data are part of a large prospective study evaluating the role of insulin resistance in women with newly diagnosed breast cancer. Patients were asked to place where they stand in their communities on the MacArthur Scale of Subjective Social Status ladder (sSES). oSES measures include race, income &amp; education. We assessed diet, activity, breast &amp; pap screening. Group comparisons used chi-square and t-tests as appropriate. We ran logistic multivariate models with age, race, insurance, comorbidity &amp; income. Results: Of 1035 breast cancer patients with an average age of 58±12 yrs, 81% were White and 19% Black, 63% graduated college, 47%W &amp; 16%B women reported an income of &gt; $100,000/yr. The median sSES = 8; 20% had high sSES ( &gt; 8). There were no racial differences observed in sSES (high sSES: 22% B vs 20% W; p = 0.7). More patients with high sSES graduated college (76% vs 61%, p = 0.0002) &amp; had income &gt; $100K/yr (62% vs 36%, p &lt; .0001) than patients with lower sSES. Of the oSES, women with higher income were more likely to undergo both cancer screenings as compared to patients with lower income. College education did not impact cancer screenings. Black women were less likely to get pap smears. Patients with high as compared to low sSES had higher cancer screening rates and healthy behaviors. Conclusions: Income and sSES are positively associated with cancer screening and health behaviors; education &amp; race are associated with activity &amp; diet. Race is associated with pap screening.[Table: see text]
Hurricane-Associated Mold Exposures Among Patients at Risk for Invasive Mold Infections After Hurricane Harvey — Houston, Texas, 2017
Authors: Nancy A. Chow, Mitsuru Toda, Audrey F. Pennington, Enock Anassi, Robert L. Atmar, Jean M. Cox-Ganser, Juliana Da Silva, Bobbiejean Garcia, Dimitrios P. Kontoyiannis, Luis Ostrosky-Zeichner, Lauren M. Leining, Jennifer McCarty, Mayar Al Mohajer, Bhavini Patel Murthy, Ju-Hyeong Park, Joann Schulte, Jennifer A. Shuford, Kimberly A. Skrobarcek, Samantha Solomon, Jonathan Strysko, Tom M. Chiller, Brendan R. Jackson, Ginger L. Chew, Karlyn D. Beer
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

In August 2017, Hurricane Harvey caused unprecedented flooding and devastation to the Houston metropolitan area (1). Mold exposure was a serious concern because investigations after Hurricanes Katrina and Rita (2005) had documented extensive mold growth in flood-damaged homes (2,3). Because mold exposure can cause serious illnesses known as invasive mold infections (4,5), and immunosuppressed persons are at high risk for these infections (6,7), several federal agencies recommend that immunosuppressed persons avoid mold-contaminated sites (8,9). To assess the extent of exposure to mold and flood-damaged areas among persons at high risk for invasive mold infections after Hurricane Harvey, CDC and Texas health officials conducted a survey among 103 immunosuppressed residents in Houston. Approximately half of the participants (50) engaged in cleanup of mold and water-damaged areas; these activities included heavy cleanup (23), such as removing furniture or removing drywall, or light cleanup (27), such as wiping down walls or retrieving personal items. Among immunosuppressed persons who performed heavy cleanup, 43% reported wearing a respirator, as did 8% who performed light cleanup. One participant reported wearing all personal protective equipment (PPE) recommended for otherwise healthy persons (i.e., respirator, boots, goggles, and gloves). Immunosuppressed residents who are at high risk for invasive mold infections were exposed to mold and flood-damaged areas after Hurricane Harvey; recommendations from health care providers to avoid exposure to mold and flood-damaged areas could mitigate the risk to immunosuppressed persons.
KEYNOTE-756: Randomized, double-blind, phase 3 study of pembrolizumab vs placebo combined with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk, early-stage estrogen receptor–positive, human epidermal growth factor receptor 2–negative (ER+/HER2−) breast cancer.
Authors: Fatima Cardoso, Aditya Bardia, Fabrice Andre, David W. Cescon, Heather L. McArthur, Melinda L. Telli, Sherene Loi, Javier Cortes, Peter Schmid, Nadia Harbeck, Carsten Denkert, Christian Jackisch, Liyi Jia, Kim M. Hirshfield, Vassiliki Karantza
Journal: Journal of Clinical Oncology (2019)

TPS601 Background: Although ER+/HER2− breast cancer (BC) has better overall prognosis than other subtypes, a high-risk subpopulation is characterized by high-grade tumors, decreased sensitivity to endocrine therapy (ET), higher responsiveness to chemotherapy (CT), and worse prognosis. Based on prior studies, increased pathological complete response (pCR) rates after neoadjuvant CT may have a substantial impact for patients with high-risk, early-stage HR+/HER2− BC. KEYNOTE-756 (ClinicalTrials.gov, NCT03725059) is a global, randomized, double-blind, phase 3 study of pembrolizumab (vs placebo) + CT as neoadjuvant treatment followed by pembrolizumab (vs placebo) + ET as adjuvant treatment for patients with high-risk, early-stage ER+/HER2− BC. Methods: Patients with T1c-2 cN1-2 (tumor size ≥2 cm) or T3-4 cN0-2 grade 3, invasive, ductal ER+/HER2− BC will be stratified by lymph node involvement (positive vs negative), tumor PD-L1 status (positive [CPS≥1] vs negative [CPS &lt; 1]), ER positivity (ER+ ≥10% vs ER+ &lt; 10%), and anthracycline dosing schedule (every 3 weeks [Q3W] vs Q2W), then randomized 1:1 to neoadjuvant treatment with pembrolizumab 200 mg Q3W or placebo combined with paclitaxel (80 mg/m 2 Q1W) for 4 cycles followed by doxorubicin (60 mg/m 2 ) or epirubicin (100 mg/m 2 ), each with cyclophosphamide (600 mg/m 2 ) Q2/3W for 4 cycles. After definitive surgery (± radiation therapy, as indicated), patients will receive adjuvant treatment of pembrolizumab (200 mg Q3W) or placebo for 9 more administrations combined with ET, which can be given for up to 10 years. There will be no crossover between treatment arms when moving from neoadjuvant to adjuvant treatment. Dual primary endpoints are pCR rate (ypT0/Tis ypN0) and event-free survival (EFS). Secondary endpoints include ypT0/Tis and ypT0 ypN0 pCR rates in all patients and all 3 pCR definitions in those with PD-L1+ tumors, EFS in patients with PD-L1+ tumors, overall survival, safety, and health-related quality of life. Interim analyses are planned. Enrollment is currently ongoing. Clinical trial information: NCT03725059.
Survey to evaluate quality of cancer patient care: A questionnaire based analysis in a tertiary hospital.
Authors: Haritha Ackula, Ying Ning, Vishal Jindal, Shekhar Patil, Ahmad Daniyal Siddiqui
Journal: Journal of Clinical Oncology (2019)

e18320 Background: As the burden of cancer is on the rise, there is a need to understand the logistics in caring for cancer patients. Internists and nurses are integral part of cancer care team, alongside oncologists. Our aim was to assess their knowledge, attitude and practice in order to identify areas of strength and limitation to help devise opportunities to enhance care. Methods: A close ended cross-sectional survey was conducted among internal medicine physicians, residents and nurses. We developed 36 questions broadly based on cancer-care and distributed them randomly. Additionally, subjects were asked to list factors limiting their ability to provide effective care. We semi quantitatively graded the depth of awareness amongst participants. A total of 95 health care providers were included in the final analysis. Results: Only 62% of participants were accurate in knowledge based questions. About 57% believed all cancer patients benefit from less aggressive treatment and considered chemotherapy side-effects to be the most common cause of hospitalization. Total of 94% reported effective care coordination by visiting nurses, primary care providers in outpatient settings decrease readmissions. Seventy percent thought a dedicated inpatient service run by Oncologists would be better for cancer patient care, with 96% preferring co-management. Around 80% felt they were better able to manage decompensated heart failure and fulminant liver disease than oncological emergencies like neutropenic fever. All the attendings (100%) were comfortable discussing new cancer diagnosis compared to 65% residents and 60% nurses. However 58% of them would like the health care proxy to be involved in all goals of care decisions, irrespective of patient’s capacity. Conclusions: Surprisingly, the baseline knowledge about cancer-care is suboptimal and there is a significant gap in expected versus real cancer-care delivery. Most commonly encountered factors hindering patient-care were lack of awareness of cancer illness trajectories and unclear goals of care with inter-provider disparities/gaps in understanding them. Initiatives such as targeted education, shared care plan and engaging patients at every step is crucial.
Pathological response and survival with neoadjuvant therapy in melanoma: A pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).
Authors: Alexander M. Menzies, Elisa A. Rozeman, Rodabe Navroze Amaria, Alexander Chan Chi Huang, Richard A. Scolyer, Michael T. Tetzlaff, Bart A. Van De Wiel, Serigne Lo, Ahmad A. Tarhini, Hussein Abdul-Hassan Tawbi, Elizabeth M. Burton, Giorgos Karakousis, Paolo Antonio Ascierto, Andrew Spillane, Michael A. Davies, Alexander Christopher Jonathan Van Akkooi, Tara C. Mitchell, Georgina V. Long, Jennifer Ann Wargo, Christian U. Blank
Journal: Journal of Clinical Oncology (2019)

9503 Background: Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) correlates with survival, and is recognized as a path to regulatory approval in several cancers. Recent trials have reported that neoadjuvant immunotherapy (IT) and targeted therapy (TT) regimens achieve high pCR rates and impressive recurrence-free survival in stage III melanoma, however, the relationship between pCR, relapse-free (RFS) and overall survival (OS) in larger datasets of melanoma patients (pts) remains unknown. Methods: We pooled data from 6 modern NST clinical trials of anti-PD-1 based immunotherapy or BRAF/MEK targeted therapy conducted across institutions participating in the INMC. Pts with RECIST measurable, surgically resectable clinical stage III melanoma who underwent surgery were included. NST regimens included nivolumab (as monotherapy or in combination with ipilimumab), pembrolizumab or dabrafenib+trametinib. Baseline disease characteristics, treatment regimen, pCR and RFS were examined. Results: 184 pts with clinical stage III melanoma (AJCCv7: 100 IIIB, 84 IIIC) completed NST (133 IT, 51 TT) and underwent surgery. Median age was 57y (range 18-87). A pCR was observed in 41% of patients; 51 (38%) with IT and 24 (47%) with TT. Median follow-up post-surgery is 13 mo (95% CI 12-16); 10 mo with IT and 22 mo with TT. 44 (24%) pts have recurred (17 loco-regional, 21 distant, 6 both sites at first recurrence), 18 (14%) after IT and 26 (51%) after TT. 12-month RFS was improved with IT vs TT (83% vs 65%, p &lt; 0.001). For those with pCR, 7% have recurred, 0/51 (0%) after IT, 7/17 (41%) after TT. For those without pCR, 34% have recurred, 18/82 (22%) after IT and 19/27 (70%) after TT. 12-month RFS was improved in those with pCR vs without pCR (95% vs 62%, p &lt; 0.001), including in those with IT (100% vs 72%, p &lt; 0.001) and TT (88% vs 43%, p &lt; 0.001). 16 (9%) patients have died including two who had a pCR, both from TT. Conclusions: Neoadjuvant IT and TT are active regimens in resectable clinical stage III melanoma patients and are associated with high pCR rate. The ability to achieve pCR correlates with improved RFS and remarkably no patient with pCR from immunotherapy has recurred to date.
Impact on U251 glioma cell radiosensitivity and CFL1 level via inhibiting cell motility regulator ROCKII of RhoA-RockII-CFL1 pathway.
Authors: Mengjie Zhao, Ling Chen, Yong Xiao, Hong Xiao, Hongyi Liu
Journal: Journal of Clinical Oncology (2019)

e14630 Background: In response to ionizing radiation, cofilin1 (CFL1) is essential for actin dynamics and tumor metastasis. In our previous study, CFL1 was revealed up-regulated in radioresistant astrocytomas of surgical samples and positively correlated with glioma cell radioresistance. Methods: The present study aims to clarify the potential mechanism of CFL1-mediated radioresistance and to find new molecular targets to improve the radiosensitivity of U251 glioma cell. Radioresistant U251 (RR-U251) was established by serially irradiation with 5Gy until 60 Gy of irradiation was accumulated on human U251 glioma cell. Y-27632, PAK1-shRNA and PAK1-shRNA were respectively utilized to inhibit CFL1 upstream regulators in normal U251 and RR-U251 cells. CFL1 expression level and the alteration of radiosensitivity were evaluated; the cell radiosensitivity was assessed through cell vitality, invasion and migration experiments after irradiation. Results: 20 ¦Ìmol/L Y-27632 was screened and administrated to inhibit ROCKII in glioma cells followed by 5Gy radiation treatment. The CFL1 level was reduced in both normal U251 and RR-U251 cells. Meanwhile, cell viability, migration and invasion abilities significantly decreased in RR-U251 cells. After being transfected with PAK1-shRNA, cell radiosensitivity were significantly improved in both normal U251 and RR-U251 cells; while CFL1 level showed no significant difference after PAK1 silence . After inhibiting MRCK¦Á expression, cell viability, migration and invasion capabilities significantly reduced in both normal and radioresistant cells; while CFL1 levels showed no significant decrease. Conclusions: The results of the present study indicate that inhibiting ROCKII of RhoA-RockII-CFL1 pathway could improve radiosensitivity of radioresistant glioma cells and simultaneously down-regulate CFL1 expression; while the inhibiton of PAK1 or MRCK¦Á ameliorated the radiosensitivity with no significant regulation effect on CFL1. In conclusion, the present study emphasize the involvement of ROCKII in CFL1-mediated radioresistant phenotype and provide potential biomarkers for improvement of further clinical radiotherapy.
Abstract 16658: Krüpple-like Factor 11 Inhibits Arterial Thrombosis via Suppression of Tissue Factor in Vascular Wall
Authors: Wenying Liang, Yanbo Fan, Haocheng Lu, Wenting Hu, Ziyi Chang, Jifeng Zhang, Yuqing E Chen
Journal: Circulation (2017)

Introduction: Emerging studies have indicated the important link between vessel wall and thrombosis, while the precise mechanisms mediating the injured vessel wall-induced arterial thrombosis remai...
Toxicities of single agent and combination immune checkpoint inhibitors in patients with autoimmune diseases.
Authors: Samuel Cytryn, Elizaveta Efuni, Sabina Sandigursky
Journal: Journal of Clinical Oncology (2019)

e14176 Background: Autoimmunity is associated with increased risk of malignancy. However, patients with pre-existing autoimmune diseases (AIDs) have been excluded from trials of immune checkpoint inhibitors (ICIs) known to cause immune activation and lead to immune related adverse events (irAEs). Data is limited on the safety and efficacy of these agents when used in AID patients and physicians are therefore wary to use them in this at-risk population. Methods: We conducted a single institution retrospective study to evaluate the safety and efficacy of ICI therapy in patients with pre-existing AIDs from 2011 to 2018. Primary endpoints were irAEs and AID flares. The secondary endpoint was overall survival (OS). Results: Of 84 total patients, 70 (83%) received ICI monotherapy and 14 (17%) received combination therapy. AIDs included: rheumatic 40 (48%), dermatologic 25 (30%), endocrine 16 (19%) and gastrointestinal 14 (17%) diseases of which 18 (21%) were on immune suppression. Combination therapy was associated with higher rates of severe grade 3-4 irAEs in 5/14 (36%) patients versus 8/70 (11%) with monotherapy (p = 0.022). ICIs were discontinued due to irAEs in 10/84 (12%) of all patients; 4/14 (29%) in the combination group and 6/70 (9%) in the monotherapy group (p = 0.057). While 32 patients (38%) had at least one AID flare, ICI was only permanently discontinued in 2 patients. Flare rates were higher for combination use: 8/14 (57%) compared to 23/70 (33%) for monotherapy (p = 0.086). Combination therapy was associated with higher median OS 27.8 months [95% CI 11.4-44.3] compared to monotherapy 12.3 months [95% CI 9.7-14.8] (p = 0.0007). OS had a positive correlation with flare (p = 0.007) and severe irAEs (p = 0.037). Conclusions: Our data suggest that rates of irAEs in patients with pre-existing AIDs are similar to those reported in the literature with single agent ICIs. While risk of severe irAEs and flares is increased with combination therapy, they are associated with overall survival. In our cohort, irAEs and flares were manageable and in most patients did not require permanent discontinuation for monotherapy or combination therapy suggesting that ICIs should be offered to this population, albeit with caution.
Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040.
Authors: Thomas Yau, Yoon-Koo Kang, Tae-You Kim, Anthony B. El-Khoueiry, Armando Santoro, Bruno Sangro, Ignacio Melero, Masatoshi Kudo, Ming-Mo Hou, Ana Matilla, Francesco Tovoli, Jennifer J. Knox, Aiwu Ruth He, Bassel F. El-Rayes, Mirelis Acosta-Rivera, Jaclyn Neely, Yun Shen, Carlos Baccan, Christine Marie Dela Cruz, Chiun Hsu
Journal: Journal of Clinical Oncology (2019)

4012 Background: NIVO monotherapy (mono) is approved for sorafenib (SOR)-treated pts with HCC based on data from CheckMate 040 (NCT01658878), which reported an objective response rate (ORR) of 14% and median overall survival (mOS) of 16 months (mo). This is the first report of efficacy and safety of the NIVO + IPI combination in SOR-treated pts with aHCC. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included safety and tolerability. Secondary endpoints included ORR (BICR per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS. Cutoff was 25 Sep 2018. Results: 148 SOR-treated pts were randomized. Minimum follow-up for OS from last pt randomization date to data cutoff was 24 mo. At baseline: 88% had vascular invasion or extrahepatic spread, 91% had BCLC stage C, 84% discontinued SOR due to disease progression and 14% due to toxicity. Overall, ORR was 31% (7 had a complete response [CR]) with a median DOR of 17 mo; DCR was 49% and 24-mo OS rate was 40%. Pts in arm A had a mOS of 23 mo and 4 pts had a CR. The table shows additional efficacy results by arm. Overall, NIVO + IPI was well tolerated; 37% of pts had a grade 3–4 treatment-related adverse event (TRAE; most common: pruritus and rash); 5% had grade 3–4 TRAEs leading to discontinuation. Conclusions: NIVO + IPI led to clinically meaningful responses and had an acceptable safety profile in SOR-treated pts, with an ORR twice that of NIVO mono (31% and 14%, respectively). Pts in arm A had the most promising mOS of 23 mo. Clinical trial information: NCT01658878. [Table: see text]