tbuckley/cabot-search huggingface dataset:
Anti-CD105 Antibody Eliminates Tumor Microenvironment Cells and Enhances Anti-GD2 Antibody Immunotherapy of Neuroblastoma with Activated Natural Killer Cells
Authors: Hong-Wei Wu, Michael A. Sheard, Jemily Malvar, G. Esteban Fernandez, Yves A. DeClerck, Laurence Blavier, Hiroyuki Shimada, Charles P. Theuer, Richard Sposto, Robert C. Seeger
Journal: Clinical Cancer Research (2019)

We determined whether elimination of CD105+ cells in the tumor microenvironment (TME) with anti-CD105 antibodies enhanced anti-disialoganglioside (GD2) antibody dinutuximab therapy of neuroblastoma when combined with activated natural killer (aNK) cells.The effect of MSCs and monocytes on antibody-dependent cellular cytotoxicity (ADCC) mediated by dinutuximab with aNK cells against neuroblastoma cells was determined in vitro. ADCC with anti-CD105 mAb TRC105 and aNK cells against MSCs, monocytes, and endothelial cells, which express CD105, was evaluated. Anti-neuroblastoma activity in immunodeficient NSG mice of dinutuximab with aNK cells without or with anti-CD105 mAbs was determined using neuroblastoma cell lines and a patient-derived xenograft.ADCC mediated by dinutuximab with aNK cells against neuroblastoma cells in vitro was suppressed by addition of MSCs and monocytes, and dinutuximab with aNK cells was less effective against neuroblastomas formed with coinjected MSCs and monocytes in NSG mice than against those formed by tumor cells alone. Anti-CD105 antibody TRC105 with aNK cells mediated ADCC against MSCs, monocytes, and endothelial cells. Neuroblastomas formed in NSG mice by two neuroblastoma cell lines or a patient-derived xenograft coinjected with MSCs and monocytes were most effectively treated with dinutuximab and aNK cells when anti-human (TRC105) and anti-mouse (M1043) CD105 antibodies were added, which depleted human MSCs and murine endothelial cells and macrophages from the TME.Immunotherapy of neuroblastoma with anti-GD2 antibody dinutuximab and aNK cells is suppressed by CD105+ cells in the TME, but suppression is overcome by adding anti-CD105 antibodies to eliminate CD105+ cells.
Help for homeless people
Authors: Prizzi Zarsadias
Journal: BMJ (2010)

“I want to help people.” Do you remember saying or writing that phrase when you applied to medical school? I do. When we’re on the path to becoming a doctor “helping people” becomes synonymous with treating patients. It can be easy to forget that the people who probably need our help the most don’t present as patients in hospital or at the general practice. Dr Max Pemberton reminds us of this in his book Where Does It Hurt? (the sequel to Trust Me I’m A Junior Doctor ) when he patrols the streets looking for people …
Nonsocial and social cognition in schizophrenia: current evidence and future directions
Authors: Michael F. Green, William P. Horan, Junghee Lee
Journal: World Psychiatry (2019)

Cognitive impairment in schizophrenia involves a broad array of nonsocial and social cognitive domains. It is a core feature of the illness, and one with substantial implications for treatment and prognosis. Our understanding of the causes, consequences and interventions for cognitive impairment in schizophrenia has grown substantially in recent years. Here we review a range of topics, including: a) the types of nonsocial cognitive, social cognitive, and perceptual deficits in schizophrenia; b) how deficits in schizophrenia are similar or different from those in other disorders; c) cognitive impairments in the prodromal period and over the lifespan in schizophrenia; d) neuroimaging of the neural substrates of nonsocial and social cognition, and e) relationships of nonsocial and social cognition to functional outcome. The paper also reviews the considerable efforts that have been directed to improve cognitive impairments in schizophrenia through novel psychopharmacology, cognitive remediation, social cognitive training, and alternative approaches. In the final section, we consider areas that are emerging and have the potential to provide future insights, including the interface of motivation and cognition, the influence of childhood adversity, metacognition, the role of neuroinflammation, computational modelling, the application of remote digital technology, and novel methods to evaluate brain network organization. The study of cognitive impairment has provided a way to approach, examine and comprehend a wide range of features of schizophrenia, and it may ultimately affect how we define and diagnose this complex disorder.
Abstract LB-331: Bidirectional crosstalk between leptin and IGF-1 signaling transactivates epidermal growth factor receptor and promotes invasion and migration of triple-negative breast cancer cells
Authors: Neeraj K Saxena, LaTonia Taliaferro Smith, Brandi Brandon, Frank A Anania, Dipali Sharma
Journal: Cancer Research (2008)

Abstract Introduction: Obesity is an independent risk factor for breast cancer and obese breast cancer patients exhibit a higher risk for larger tumor burden, increased metastasis, and poor response to endocrine therapy. Obesity affects breast carcinogenesis by autocrine and paracrine effects of adipocytokine leptin and IGF-1. We have previously shown that leptin induces growth stimulation of breast cancer cells by recruiting histone acetyltransferases and mediator complex to cyclin D1 promoter via activation of Stat3. In the present study, we found a novel bidirectional crosstalk between IGF-1 and leptin signaling that promotes invasion and migration of triple-negative (ER, PR, HER2 negative) breast cancer cells MDA-MB-231, MDA-MB-468, MDA-MB-435, and HCC-1806. Methods and Results: IGF-1 induced significant tyrosine phosphorylation of leptin receptor (Ob-Rb) and leptin induced tyrosine phosphorylation of IGF-1 receptor (IGF-1R). Combined treatment of leptin and IGF-1 induced synergistic activation of both Ob-Rb and IGF-1R along with activation of Akt and ERK. Furthermore, IGF-1 and leptin synergistically transactivated epidermal growth factor receptor (EGFR) and induced proliferation of triple negative breast cancer cells. We also found that tyrosine phosphorylation of EGFR induced by combined treatment of leptin and IGF-1 was significantly inhibited not only by EGFR tyrosine kinase inhibitor AG1478 but also with a broad-spectrum matrix metalloproteinase inhibitor, GM6001, indicating that leptin and IGF-1 induced EGFR transactivation is dependent on proteolytic release of EGFR ligands. Intriguingly, we also found that combined treatment of leptin and IGF-1 potently induced invasion of triple negative breast cancer cells in Matrigel invasion and quantitative Electric Cell-Substrate Impedance Sensing invasion assays. Inhibition of leptin and IGF-1 mediated EGFR activation using a highly potent, reversible inhibitor of HER1/EGFR tyrosine kinase (erlotinib) or dual EGFR/HER2 kinase inhibitor (lapatinib) effectively inhibited leptin and IGF-1 induced invasion. Also, inhibition of EGFR activation using erlotinib and lapatinib reduced leptin- and IGF-1 induced migration of triple negative breast cancer cells. Conclusions: Taken together, these data indicate a novel bidirectional crosstalk between leptin and IGF-1 signaling that transactivates EGFR and promotes metastatic properties, invasion, and migration of triple negative breast carcinoma cells. Our novel findings indicate the possibility of using EGFR inhibitors erlotinib and lapatinib to counter the pro-cancerous effects of leptin and IGF-1 signaling in triple negative breast cancers.
Risk of Serious Infection in Patients Receiving Systemic Medications for the Treatment of Psoriasis
Authors: Erica D. Dommasch, Seoyoung C. Kim, Moa P. Lee, Joshua J. Gagne
Journal: JAMA Dermatology (2019)

There is a need for better understanding of the comparative safety of systemic medications used in the treatment of psoriasis.To compare the risk of serious infection associated with biologic and nonbiologic systemic medications in patients with psoriasis.An observational cohort study was conducted using medical and outpatient pharmacy claims from 2 large US health insurance claims databases from January 1, 2003, through September 30, 2015. We included patients with a diagnosis of psoriasis who were new users of systemic medications for psoriasis.Prescription claims for acitretin, adalimumab, apremilast, etanercept, infliximab, methotrexate, or ustekinumab.The primary outcome was serious infection, defined by inpatient discharge diagnosis International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Cox proportional hazards regression was used to compare rates of serious infection for each exposure (acitretin, adalimumab, apremilast, etanercept, infliximab, and ustekinumab) with the referent group (methotrexate). We used pairwise 1:1 propensity score (PS) matching to adjust for potential confounders, which were assessed during a 180-day baseline period prior to study drug initiation. Results from the 2 databases were pooled via fixed-effects analysis.The databases included 31 595 patients in the Optum Clinformatics Data Mart and 76 112 patients in Truven MarketScan who were new users of acitretin, adalimumab, apremilast, etanercept, infliximab, methotrexate, and ustekinumab. Users of acitretin, apremilast, infliximab, and methotrexate were older and had higher baseline comorbidity scores than subcutaneous biologic users (adalimumab, etanercept, and ustekinumab). The pooled PS-matched analysis yielded a decreased rate of overall serious infection in users of apremilast (hazard ratio [HR], 0.50; 95% CI, 0.26-0.94), etanercept (HR, 0.75; 95% CI, 0.61-0.93), and ustekinumab (HR, 0.65; 95% CI, 0.47-0.89) compared with methotrexate. We did not find a different rate of overall serious infection among users of acitretin, adalimumab, and infliximab compared with methotrexate. Subanalysis by type of serious infection showed a significantly increased risk of cellulitis among users of acitretin compared with methotrexate (PS-adjusted HR, 1.76; 95% CI, 1.11-2.80).Among patients with psoriasis treated with systemic medications in 2 large US claims databases, new users of apremilast, etanercept, and ustekinumab had a decreased rate of serious infection compared with methotrexate.
Alterations in DNA Damage Repair Genes in Primary Liver Cancer
Authors: Jianzhen Lin, Junping Shi, Honglin Guo, Xu Yang, Yan Jiang, Junyu Long, Yi Bai, Dongxu Wang, Xiaobo Yang, Xueshuai Wan, Lei Zhang, Jie Pan, Ke Hu, Mei Guan, Li Huo, Xinting Sang, Kai Wang, Haitao Zhao
Journal: Clinical Cancer Research (2019)

Alterations in DNA damage repair (DDR) genes produce therapeutic biomarkers. However, the characteristics and significance of DDR alterations remain undefined in primary liver cancer (PLC).Patients diagnosed with PLC were enrolled in the trial (PTHBC, NCT02715089). Tumors and matched blood samples from participants were collected for a targeted next-generation sequencing assay containing exons of 450 cancer-related genes, including 31 DDR genes. The OncoKB knowledge database was used to identify and classify actionable alterations, and therapeutic regimens were determined after discussion by a multidisciplinary tumor board.A total of 357 patients with PLC were enrolled, including 214 with hepatocellular carcinoma, 122 with ICC, and 21 with mixed hepatocellular-cholangiocarcinoma. A total of 92 (25.8%) patients had at least one DDR gene mutation, 15 of whom carried germline mutations. The most commonly altered DDR genes were ATM (5%) and BRCA1/2 (4.8%). The occurrence of DDR mutations was significantly correlated with a higher tumor mutation burden regardless of the PLC pathologic subtype. For DDR-mutated PLC, 26.1% (24/92) of patients possessed at least one actionable alteration, and the actionable frequency in DDR wild-type PLC was 18.9% (50/265). Eight patients with the BRCA mutation were treated by olaparib, and patients with BRCA2 germline truncation mutations showed an objective response.The landscape of DDR mutations and their association with genetic and clinicopathologic features demonstrated that patients with PLC with altered DDR genes may be rational candidates for precision oncology treatment.
Abstract 4014: The therapeutic potential of ICG-001 and β-catenin specific RNAi in liver cancer development.
Authors: Anketse D. Kassa, Vivian G. Medina, Ni Zeng, Lina He, Cu Nguyen, Goar Smbatyan, Megan Rieger, Michael Kahn, Bangyan L. Stiles
Journal: Cancer Research (2013)

Abstract Liver cancer is one of the most common malignant tumors. It is reported to be the third most lethal malignancy worldwide. Recent studies including our own identified CD133+ cell population as the tumor initiating cells for liver cancer. Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome ten) is aberrantly expressed in liver cancers. Liver specific Pten (Pm) null mice develop liver cancer following an extensive phase of chronic lipid accumulation and demonstrate escalating levels of hepatic injury markers from 6-12M, prior to hepatic progenitor cell proliferation. Concomitantly, expression of mRNA levels for Wnt ligands and receptors also increased progressively. Wnt/β-Catenin signaling pathway has various roles in regulating embryonic development and tumorigenesis. In Pten null liver progenitor cell line and tissues; we observed high levels of βcatenin, a downstream target component of the Wnt signaling pathway compared to control cells. In this study, we investigate the role of the Wnt/β-Catenin pathway in the activation of hepatic progenitor cells in the Pten deletion liver cancer model using two methods: a novel Wnt/β-Catenin inhibitor ICG-001 and β-Catenin specific RNAi. ICG-001 is a small molecule, which specifically inhibits β-Catenin/CBP interaction. Coactivator CBP/β-Catenin/T cell factor (TCF) mediated transcription has been reported as critical for stem cell/progenitor cell proliferation. ICG-001 significantly attenuates the proliferation of hepatic cancer stem cells in vitro and in vivo. Our preliminary results demonstrate inhibition of Wnt/β-Catenin pathway using sh-β-Catenin in vitro can effectively inhibit the proliferation of CD133+ hepatic cancer stem cells. These observations indicate that Wnt/β- Catenin pathway likely mediates proliferation of hepatic cancer stem cell. Targeting this pathway using ICG-001 and/or β-Catenin directed shRNA holds promise for the treatment and eradication of liver cancer. Citation Format: Anketse D. Kassa, Vivian G. Medina, Ni Zeng, Lina He, Cu Nguyen, Goar Smbatyan, Megan Rieger, Michael Kahn, Bangyan L. Stiles. The therapeutic potential of ICG-001 and β-catenin specific RNAi in liver cancer development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4014. doi:10.1158/1538-7445.AM2013-4014
Abstract P5-07-14: CCL18 signaling from breast tumor-associated macrophages fosters the activation of fibroblasts into a chemoresistance-inducing phenotype
Authors: E Song, S Su, J Chen
Journal: Cancer Research (2019)

Abstract Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment critically involved in cancer progression. Our recent study identified a specific CAFs subset by two cell-surface molecules, CD10 and GPR77. We proved that CD10+GPR77+ CAFs could promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). However, their origin and underlying activating initiation mechanism are unclear. Tumor-associated macrophages (TAMs) are the most abundant immune-related stromal cells and the important source of inflammatory cytokine. Here, we demonstrated that CCL18 secreted by TAMs could induces the activation of normal breast fibroblasts into a CD10+GPR77+ CAFs phenotype, which are not only resistant to chemotherapy themselves, but also can induce chemoresistance in cancer cells by abundantly producing IL-8 and IL-6 and enriching the population of cancer stem cells. In conclusion, our studies have identified an inflammatory signaling network in the interaction of different kind of stroma cells in tumor microenvironment and highlighted its potential values as predictive markers and therapeutic targets to abrogate tumor formation and improve chemotherapeutic efficacy. Citation Format: Song E, Su S, Chen J. CCL18 signaling from breast tumor-associated macrophages fosters the activation of fibroblasts into a chemoresistance-inducing phenotype [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-14.
Patrolling monocytes scavenge endothelial-adherent sickle RBCs: a novel mechanism of inhibition of vaso-occlusion in SCD
Authors: Yunfeng Liu, Hui Zhong, Weili Bao, Avital Mendelson, Xiuli An, Patricia Shi, Stella T. Chou, Deepa Manwani, Karina Yazdanbakhsh
Journal: Blood (2019)
Abstract P1-07-02: Withdrawn
Authors: M Di Nicola, T Volpari, G Fucà, S Romero Cordoba, F De Santis, O Rondinone, S Faraci, F Ferris, C Puricelli, L Castagnoli, R Marullo, L Cerchietti, S Pupa
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Di Nicola M, Volpari T, Fucà G, Romero Cordoba S, De Santis F, Rondinone O, Faraci S, Ferris F, Puricelli C, Castagnoli L, Marullo R, Cerchietti L, Pupa S. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-07-02.
Association of Industry and Academic Sponsorship With Negative Phase 3 Oncology Trials and Reported Outcomes on Participant Survival
Authors: Alfredo Addeo, Glen J. Weiss, Bishal Gyawali
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Only 3.4% of cancer drugs evaluated in phase 1 trials are approved by the US Food and Drug Administration, with most failing in phase 3 trials. <h3>Objective</h3> To investigate whether an association exists between the sponsorship and conduct of a negative phase 3 randomized clinical trial (RCT) investigating a cancer drug that lacked supporting phase 2 trial evidence for that drug, and to evaluate the association with overall survival among patients randomized to the experimental arm of such phase 3 trials. <h3>Data Sources</h3> Articles in the<i>Lancet</i>,<i>Lancet Oncology</i>,<i>JAMA</i>,<i>JAMA Oncology</i>, and<i>Journal of Clinical Oncology</i>published between January 2016 and June 2018 were searched. <h3>Study Selection</h3> Phase 3 RCTs of cancer drugs that failed to improve the primary end point were selected and any prior phase 2 trial of the same drug that supported the phase 3 trial was selected without any date or journal restrictions. <h3>Data Extraction and Synthesis</h3> Percentages of negative phase 3 RCTs of cancer drugs that lacked any phase 2 evidence, had a negative phase 2 trial, or had a positive phase 2 study were extracted. Associations were assessed using the Fisher exact test. Pooled hazard ratios and 95% CIs for the overall survival of patients enrolled in these negative phase 3 RCTs were estimated using a random-effects model. <h3>Main Outcomes and Measures</h3> Negative phase 3 RCTs with a lack of a phase 2 trial or the presence of a negative phase 2 trial and overall survival of enrolled patients in the phase 3 RCTs. <h3>Results</h3> In this meta-epidemiological study, 67 negative phase 3 RCTs on cancer drugs, which included 64 600 patients, met the criteria of being sponsored by industry or academic groups, of which 42 RCTs (63%) were industry sponsored and the remaining 25 RCTs (37%) were academic. A phase 2 trial was not available for 28 of these trials (42%). Of 29 trials (43%) with a phase 2 trial available, 8 trials (28%) failed to meet their primary end points and 5 of those were industry sponsored. There was no association with overall survival for patients participating in these negative phase 3 RCTs (pooled hazard ratio, 0.99; 95% CI, 0.96-1.02). When the pooled analysis was limited to the 27 RCTs with a hazard ratio above 1.00, the overall pooled hazard ratio for overall survival was 1.11 (95% CI, 1.06-1.16). No association between having a negative or undefined phase 2 trial and trial sponsorship was found using the Fisher exact test. <h3>Conclusions and Relevance</h3> More than 40% of the negative phase 3 RCTs in oncology published in these 5 journals were conducted without a supporting phase 2 trial and were sponsored by both academia and industry. Running such trials not only may risk loss of resources owing to a failed trial but also may be associated with decreased patient survival. Further research and regulations in this area appear warranted.
A pint too far?
Authors: Hannah Barton
Journal: BMJ (2010)

It was all the way back in January, the beginning of a new decade, a time when many people were re-examining their lifestyles, making resolutions, and generally recovering from the excesses of the festive season. And so I found it an interesting contrast, that at the same time that I read about the latest report from the parliamentary Health Select Committee, on alcohol, and the ongoing debates about the low cost of supermarket booze, I was also receiving emails from the student union at my medical school publicising £1 (€1; $1.60) tequila shots and their latest drinks deals to kick …
Abstract P5-07-04: Not presented
Authors: S Chatterjee, P Basak, S Tan, S Lefort, D Pellacani, J Safneck, E Buchel, S Aparicio, CJ Eaves, A Raouf
Journal: Cancer Research (2019)

Abstract This abstract was not presented at the conference. Citation Format: Chatterjee S, Basak P, Tan S, Lefort S, Pellacani D, Safneck J, Buchel E, Aparicio S, Eaves CJ, Raouf A. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-04.
Impacts of Subchronic, High-Level Noise Exposure on Sleep and Metabolic Parameters: A Juvenile Rodent Model
Authors: Aymar Bosquillon de Jenlis, Flavia Del Vecchio, Stéphane Delanaud, Jérôme Gay-Queheillard, Véronique Bach, Amandine Pelletier
Journal: Environmental Health Perspectives (2019)

Noise is an environmental factor that has been associated with metabolic and sleep disorders. Sleep is a vital function, since it underpins physiologic processes and cognitive recovery and development. However, the effects of chronic noise exposure on the developing organism are still subject to debate.The objective of the present study was to assess the effects of subchronic, high-level noise exposure on sleep, apnea, and homeostasis in juvenile rats.Twenty-four 3-wk-old male Wistar rats were exposed to noise [[Formula: see text], [Formula: see text]] for 5 wk and 2 d during the 12-h rest period. Data on sleep stages, food and water intake, apnea, and body and organ weight were recorded.Five weeks of high-level noise exposure were associated with hyperphagia ([Formula: see text]), body weight gain ([Formula: see text]), a heavier thymus ([Formula: see text]), and heavier adrenal glands ([Formula: see text]). A sleep analysis highlighted microstructural differences in the active period: in particular, the mean daily amount of rapid eye movement (REM) sleep as a proportion of total sleep time (TST) was higher. The mean daily amount of non-REM (NREM) sleep was lower in the exposed group, meaning that the intergroup difference in the TST was not significant. During a 1-h, noise-free plethysmographic recording during the rest period, the mean total amount of active wakefulness (AW) was lower in the exposed group (by 9.1 min), whereas the mean duration of an episode of REM sleep was higher (by 1.8 min), and the TST was higher (by 10.7 min).Subchronic exposure of juvenile rats to high-intensity noise during the rest period was associated with some small but significant sleep disturbances, greater food and water intakes, greater body weight gain, and greater thymus and adrenal gland weights. The main effects of noise exposure on sleep were also observed in the 1-h plethysmography session after 5 wk of exposure. https://doi.org/10.1289/EHP4045.