tbuckley/cabot-search huggingface dataset:
IL13Rα2 Promotes Proliferation and Outgrowth of Breast Cancer Brain Metastases
Authors: R. Alejandro Márquez-Ortiz, Maria J. Contreras-Zárate, Vesna Tesic, Karen L.F. Alvarez-Eraso, Gina Kwak, Zachary Littrell, James C. Costello, Varsha Sreekanth, D. Ryan Ormond, Sana D. Karam, Peter Kabos, Diana M. Cittelly
Journal: Clinical Cancer Research (2021)

Abstract Purpose: The survival of women with brain metastases (BM) from breast cancer remains very poor, with over 80% dying within a year of their diagnosis. Here, we define the function of IL13Rα2 in outgrowth of breast cancer brain metastases (BCBM) in vitro and in vivo, and postulate IL13Rα2 as a suitable therapeutic target for BM. Experimental Design: We performed IHC staining of IL13Rα2 in BCBM to define its prognostic value. Using inducible shRNAs in TNBC and HER2+ breast–brain metastatic models, we assessed IL13Rα2 function in vitro and in vivo. We performed RNAseq and functional studies to define the molecular mechanisms underlying IL13Rα2 function in BCBM. Results: High IL13Rα2 expression in BCBM predicted worse survival after BM diagnoses. IL13Rα2 was essential for cancer-cell survival, promoting proliferation while repressing invasion. IL13Rα2 KD resulted in FAK downregulation, repression of cell cycle and proliferation mediators, and upregulation of Ephrin B1 signaling. Ephrin-B1 (i) promoted invasion of BC cells in vitro, (ii) marked micrometastasis and invasive fronts in BCBM, and (iii) predicted shorter disease-free survival and BM-free survival (BMFS) in breast primary tumors known to metastasize to the brain. In experimental metastases models, which bypass early tumor invasion, downregulation of IL13Rα2 before or after tumor seeding and brain intravasation decreased BMs, suggesting that IL13Rα2 and the promotion of a proliferative phenotype is critical to BM progression. Conclusions: Non-genomic phenotypic adaptations at metastatic sites are critical to BM progression and patients' prognosis. This study opens the road to use IL13Rα2 targeting as a therapeutic strategy for BM.
Emerging Technologies for In Vitro Inhalation Toxicology (Adv. Healthcare Mater. 18/2021)
Authors: Ajay Vikram Singh, Anthony Romeo, Kassandra Scott, Sandra Wagener, Lars Leibrock, Peter Laux, Andreas Luch, Pranali Kerkar, Shidin Balakrishnan, Sarada Prasad Dakua, Byung‐Wook Park
Journal: Advanced Healthcare Materials (2021)

Inhalation Toxicology In article number 2100633 by Ajay Vikram Singh, Byung-Wook Park, and co-workers, a systematic approach is taken to discuss the bottleneck, pros and cons of current technologies pertaining to organ-on-a-chip systems for inhalation toxicology. Design processes inspired from soft robotics actuation with attention to the inhalation exposure, lung cells, and materials used are presented.
Endothelial Poldip2 regulates sepsis-induced lung injury via Rho pathway activation
Authors: Elena V Dolmatova, Steven J Forrester, Keke Wang, Ziwei Ou, Holly C Williams, Giji Joseph, Sandeep Kumar, Alejandra Valdivia, Andrew P Kowalczyk, Hongyan Qu, Hanjoong Jo, Bernard Lassègue, Marina S Hernandes, Kathy K Griendling
Journal: Cardiovascular Research (2021)

Abstract Aims Sepsis-induced lung injury is associated with significant morbidity and mortality. Previously, we showed that heterozygous deletion of polymerase δ-interacting protein 2 (Poldip2) was protective against sepsis-induced lung injury. Since endothelial barrier disruption is thought to be the main mechanism of sepsis-induced lung injury, we sought to determine if the observed protection was specifically due to the effect of reduced endothelial Poldip2. Methods and results Endothelial-specific Poldip2 knock-out mice (EC−/−) and their wild-type littermates (EC+/+) were injected with saline or lipopolysaccharide (18 mg/kg) to model sepsis-induced lung injury. At 18 h post-injection mice, were euthanized and bronchoalveolar lavage (BAL) fluid and lung tissue were collected to assess leucocyte infiltration. Poldip2 EC−/− mice showed reduced lung leucocyte infiltration in BAL (0.21 ± 0.9×106 vs. 1.29 ± 1.8×106 cells/mL) and lung tissue (12.7 ± 1.8 vs. 23 ± 3.7% neutrophils of total number of cells) compared to Poldip2 EC+/+ mice. qPCR analysis of the lung tissue revealed a significantly dampened induction of inflammatory gene expression (TNFα 2.23 ± 0.39 vs. 4.15 ± 0.5-fold, IκBα 4.32 ± 1.53 vs. 8.97 ± 1.59-fold), neutrophil chemoattractant gene expression (CXCL1 68.8 ± 29.6 vs. 147 ± 25.7-fold, CXCL2 65 ± 25.6 vs. 215 ± 27.3-fold) and a marker of endothelial activation (VCAM1 1.25 ± 0.25 vs. 3.8 ± 0.38-fold) in Poldip2 EC−/− compared to Poldip2 EC+/+ lungs. An in vitro model using human pulmonary microvascular endothelial cells was used to assess the effect of Poldip2 knock-down on endothelial activation and permeability. TNFα-induced endothelial permeability and VE-cadherin disruption were significantly reduced with siRNA-mediated knock-down of Poldip2 (5 ± 0.5 vs. 17.5 ± 3-fold for permeability, 1.5 ± 0.4 vs. 10.9 ± 1.3-fold for proportion of disrupted VE-cadherin). Poldip2 knock-down altered expression of Rho-GTPase-related genes, which correlated with reduced RhoA activation by TNFα (0.94 ± 0.05 vs. 1.29 ± 0.01 of relative RhoA activity) accompanied by redistribution of active-RhoA staining to the centre of the cell. Conclusion Poldip2 is a potent regulator of endothelial dysfunction during sepsis-induced lung injury, and its endothelium-specific inhibition may provide clinical benefit.
P03.04 Primary CNS lymphoma of the corpus callosum: presentation and neurocognitive prognosis. Study of a monocentric cohort of 27 patients
Authors: C Nilles, D Delgadillo, N Martin Duverneuil, K Mokhtari, B Mathon, K Hoang-Xuan, A Duran-Pena, A Morales, C Houillier
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The corpus callosum (CC) is frequently involved in primary central nervous system lymphomas (PCNSL). The aim of our study was to describe the impact of these lesions on neurocognition of patients presenting with PCNSL of the CC (PCNSL-CC) and their post-therapeutic evolution. MATERIAL AND METHODS This is a retrospective single-center study. Patients newly diagnosed at Pitié Salpêtrière Hospital from (1999–2018) were included in this study according to the following criteria: age &amp;gt;18, immunocompetent patient, pathological confirmation (Diffuse Large B cell lymphoma) and CC as main location of the tumor on MRI. Clinical, neuroradiological and neuropsychological data of the patients were collected. In addition, prognostic factors for the neurocognitive outcome of the patients were investigated. RESULTS 27 patients were included (median age: 67 years, median KPS: 70). At the time of diagnosis, 74% of patients had cognitive impairment and 59% of patients had balance disorders. The cognitive functions most frequently affected were memory and executive functions. Tumor lesions in the CC had a median maximum diameter of 5 cm with a so called “butterfly pattern” in 92% of cases. All patients received a high dose methotrexate based polychemotherapy, including one with radiation therapy, and 67% of patients achieved a complete remission (CR). Median PFS and OS were 33.3 months and 177.9 months respectively. With a median follow-up of 48 months (range 6–156), despite CR, there were still abnormal values in 17% of patients on overall efficiency, 17–55% of patients on executive function tests, 45–55% of patients on memory tests. No significant impaired values were found for visuo-spatial and language tests. Splenial location and age ≥ 60 years were significantly associated with worse episodic memory scores throughout the follow-up. CONCLUSION PCNSL-CC are associated with frequent cognitive dysfunctions, especially memory impairment, which may recover only partially despite CR, that warrant specific rehabilitation. Older age (≥ 60) and splenial location have worse neurocognition outcome.
Less Sitting for Preventing Type 2 Diabetes
Authors: David W. Dunstan, Neville Owen
Journal: Diabetes Care (2021)

The findings reported by Li et al. (1) in this issue of Diabetes Care are a welcome contribution to the body of evidence informing type 2 diabetes prevention. They focus on sedentary behavior (put simply, too much sitting), which has adverse health consequences that are distinct from those of too little exercise (2). These new findings, from a prospective study with long-term follow-up of 475,502 adults with 18,619 type 2 diabetes cases, represent strong evidence pointing to causality in the relationships of sedentary behavior with the development of type 2 diabetes. To this end, the study by Li et al. has strengths of method and analytical approach, employing measures of both physical activity and sedentary behavior as exposures, and examining their interrelationships as predictors of the diagnosis of type 2 diabetes over an 11-year median follow-up interval. Importantly, their analyses used iso-temporal substitution methods, which allow statistical estimation of the benefits of reallocating time in one behavior for time in another behavior. Although iso-temporal substitution has previously been used to model the putative impacts of substituting physical activity for sedentary time, such evidence has come predominantly from cross-sectional studies (3).

Sedentary behaviors—primarily television (TV) viewing and other screen use, time sitting in cars, and desk-based working—occupy the largest proportion of adults’ waking hours. Over the past 10 years, sedentary time, characterized by a sitting posture in the absence of skeletal muscle contractile activity (4,5), has increased by ∼1 h/day (6). The coronavirus disease 2019 pandemic has further exacerbated the pervasiveness of prolonged periods of time spent sitting in people’s lives (7). The widespread implementation of infection-risk mitigation strategies has seen daily time spent sitting increase by a staggering 3 h/day (8). Because sedentary behavior displaces time spent engaging in …
KS01.5.A Allergic airway inflammation impacts tumor take and delays experimental glioblastoma progression
Authors: A Poli, A Oudin, A Muller, O Hunewald, O Domingues, P V Nazarov, V Puard, V Baus, F Azuaje, G Dittmar, J Zimmer, T Michel, S P Niclou, M Ollert
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Numerous epidemiological studies have highlighted the protective role of immunoglobulin E-mediated allergic diseases on glioblastoma (GBM) susceptibility and prognosis. However, the mechanistic explanations behind these phenomena remain unexplored. Our objective was to set up a preclinical model and investigate the mechanisms underlying such protection to improve our understanding of the crosstalk between immune system and brain tumor development. MATERIAL AND METHODS A mouse model of allergic airway inflammation (AAI) induced by repeated nasal instillation of House Dust Mite extract was initiated before intracranial implantation of GL261 glioma cells, in both immunocompetent (C57BL/6) and immunodeficient (RAG-KO) mice. Tumor take and tumor growth were monitored by MRI. Central (microglia) and peripheral (spleen, bone marrow) immune cells were characterized by flow cytometry. The response of microglia was further assessed by RNA sequencing. Impact of candidate genes on patient survival was characterized by Cox regression analysis using data from TCGA and CGGA. RESULTS Following AAI induction in C57BL/6 mice, engraftment of GL261 cells in the brain was delayed and tumor growth rate was reduced. This correlated with an increase in survival of the mice and was accompanied by increased effector memory T-cells in the circulation. Of note, the survival benefit was lost in RAG-KO mice devoid of adaptive immunity. At the level of the brain, we observed enhanced secretion of TNFα and IL6 in microglia ex vivo. AAI induced a transcriptional reprogramming of microglia towards a pro-inflammatory-like state. We identified an allergy-related microglia gene signature that is associated with improved prognosis of glioma patients. CONCLUSION Our results demonstrate that AAI limits both tumor take and GBM progression in mice, providing a preclinical model to study the role of allergic inflammation in GBM susceptibility and prognosis, respectively. At the functional level, we identify a potentiation of microglial and adaptive anti-tumoral immunity. Further investigations are warranted to shed light on the reciprocal crosstalk between microglial reprogramming and peripheral immunity in the context of allergies and brain tumors.
Barriers to participation and success in value-based care (VBC) models.
Authors: Ajeet Gajra, Dewilka Simons, Yolaine Jeune-Smith, Amy W. Valley, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2021)

70 Background: The enactment of the Medicare Access and CHIP Reauthorization Act (MACRA) in 2015 initiated the transition from a fee-for-service to a fee-for-value payment system in healthcare. Two government-sponsored VBC models (Oncology Care Model [OCM] and Merit-Based Incentive Payment System [MIPS]) were introduced in 2016 and 2017. Several commercial payers followed suit with similar value-based contracts. Implementing and complying with the performance metrics of these models comes with challenges. This qualitative research study sought to assess participation in both government-sponsored and commercial-insurance-sponsored VBC models among oncology providers and their perceptions regarding the ability to perform successfully. Methods: Between February and April 2021, medical oncologists/hematologists (mO/H) from across the U.S. were invited to complete a web-based survey about various trends and critical issues in oncology care. Demographics about the physicians and characteristics of their practices were captured as well in the survey. Responses were aggregated and analyzed using descriptive statistics. Results: A total of 307 mO/H across the U.S. completed the survey: 73% practice in a community setting; 47% identify as hospital employees. The participants spend a median of 90% of their working time in direct patient care, have a median of 16 years of clinical experience, and see a median of 20 patients per day on clinic days. Half participate in a government-sponsored VBC model (21% MIPS and 28% OCM), and 20% participate in a commercial VBC model. A third reported that it is difficult to perform favorably in VBC models (37% government and 35% commercial). Primary challenges deterring favorable performance were navigating the payer landscape and reimbursements (27%), identifying cost-reduction opportunities (20%), tracking costs across an episode (18%), and clinical decision support and compliance (17%). One-third are not satisfied with currently available technology to effectively support their performance in VBC models. Almost half would like to see more seamless integration into practice workflows (49%) and interoperability across platforms including EHRs (42%), and 24% would like artificial intelligence or machine learning features integrated into solutions tools. Conclusions: Oncology practices find it challenging to perform favorably in government and private payer-sponsored VBC models. They are generally dissatisfied with current technology and see an unmet need for interoperability and artificial intelligence to better support their performance in these programs. Further research is needed to determine how best to design and implement VBC programs.
Risk factors and outcome of sars-cov-2 infection in hematologic patients - A single center experience
Authors: M. Narancic, M. Mikulić, S. Basic-Kinda, J. Batinic, A. Ostojic, D. Dujmovic, B. Dreta, M. Vodanovic, L. Desnica, V. R. Vranjes, G. Pavlisa, Z. Peric, P. Roncevic, P. Pulanic, D. Sertic, I. Aurer
Journal: HemaSphere (2021)

Background: Reports on outcomes of COVID-19 in hematologic patients vary. Aims: To describe outcomes and risk factors of SARS-CoV2 infection in patients treated in a large university medical center. Methods: We analyzed the outcomes of our patients diagnosed with COVID-19 between July 2020 and January 2021. The diagnosis was made by PCR from nasopharyngeal/oral swabs or bronchoalveolar lavage. Outcomes were classified as: recovered, persistently positive, died. Results: We identified 116 patients. Median age was 59 years (range 20-92);55% were male. 13% had no symptoms;49% had mild disease with no need for oxygen therapy;14% with moderately severe disease were treated with low flow oxygen therapy;25% had severe COVID-19 with respiratory failure and/or septic shock. Except for seven palliative patients, severe cases were treated with noninvasive ventilation (3%), mechanical ventilation (13%) and ECMO (1%). 27% received no treatment for COVID-19;38% were treated with antibiotics, corticosteroids and/or anticoagulant therapy;34% received remdesivir, 6% in combination with convalescent plasma;5% were treated with extracorporeal blood purification. 65 patients recovered (56%), 17 are still positive (15%) and 34 (29%) died. All 4 untreated and 16 patients that were off treatment for more than 3 months recovered. The outcome of those on treatment is presented in Table 1. Allotransplanted patients had the worst outcome, 5 died, 3 are persistently positive and 1 recovered. Untransplanted patients with acute lymphoblastic and chronic myeloid leukemia fared best, 3 out of 3 in each group recovered. Treatment with anti-CD20 monoclonal antibodies (MoAbs) resulted in an increase in persistent positivity, frequently longer than 8 weeks. Of the 34 patients, 9 died, 12 have persistent infection and 13 recovered. There was no clear-cut correlation between outcome and other types of treatment within diagnostic groups. Summary/Conclusion: COVID19 in hematologic patients, who are currently on treatment, follows a significantly worse course than in the general population or other cancer types. Allotransplanted patients have the highest mortality, while those treated with anti-CD20 MoAbs frequently have a persistent infection with dubious outcome.
Simple and effective bacterial-based intratumoral cancer immunotherapy
Authors: Christina S E Carroll, Erin R Andrew, Laeeq Malik, Kathryn F Elliott, Moira Brennan, James Meyer, Alexander Hintze, Andrew A Almonte, Cassandra Lappin, Philip MacPherson, Klaus-Martin Schulte, Jane E Dahlstrom, Rohit Tamhane, Teresa Neeman, Elizabeth W Herbert, Maurice Orange, Desmond Yip, Rachel Allavena, Aude M Fahrer
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background We describe intratumoral injection of a slow-release emulsion of killed mycobacteria (complete Freund’s adjuvant (CFA)) in three preclinical species and in human cancer patients. Methods Efficacy and safety were tested in mammary tumors in mice, in mastocytomas in mice and dogs, and in equine melanomas. In mice, survival, tumor growth, and tumor infiltration by six immune cell subsets (by flow cytometry) were investigated and analyzed using Cox proportional hazards, a random slopes model, and a full factorial model, respectively. Tumor growth and histology were investigated in dogs and horses, as well as survival and tumor immunohistochemistry in dogs. Tumor biopsies were taken from human cancer patients on day 5 (all patients) and day 28 (some patients) of treatment and analyzed by histology. CT scans are provided from one patient. Results Significantly extended survival was observed in mouse P815 and 4T1 tumor models. Complete tumor regressions were observed in all three non-human species (6/186 (3%) of mouse mastocytomas; 3/14 (21%) of canine mastocytomas and 2/11 (18%) of equine melanomas). Evidence of systemic immune responses (regression of non-injected metastases) was also observed. Analysis of immune cells infiltrating mastocytoma tumors in mice showed that early neutrophil infiltration was predictive of treatment benefit. Analysis of the site of mastocytoma regression in dogs weeks or months after treatment demonstrated increased B and T cell infiltrates. Thus, activation of the innate immune system alone may be sufficient for regression of some injected tumors, followed by activation of the acquired immune system which can mediate regression of non-injected metastases. Finally, we report on the use of CFA in 12 human cancer patients. Treatment was well tolerated. CT scans showing tumor regression in a patient with late-stage renal cancer are provided. Conclusion Our data demonstrate that intratumoral injection of CFA has major antitumor effects in a proportion of treated animals and is safe for use in human cancer patients. Further trials in human cancer patients are therefore warranted. Our novel treatment provides a simple and inexpensive cancer immunotherapy, immediately applicable to a wide range of solid tumors, and is suitable to patients in developing countries and advanced care settings.
P12.05 Pulmonary embolism in neuroncological patients: Monoistitutional experience
Authors: P Gaviani, G Simonetti, V Redaelli, A Botturi, E Corsini, A Silvani
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Venous thromboembolism (VTE) is a frequent and potentially fatal event in cancer patients. Patients with brain tumors in particular have one of the highest risk of developing VTE among cancer patients (25–39%), contributing significantly to mortality and morbidity. VTE is particularly high in the postoperative period, with almost half of the events occurring at that time, but it also persists in the first 12 months, with a risk ranging between 7–28%. Despite the high incidence of VTE in patients with brain tumors, to date there are no sufficient data to predict teh real risk or to lead to a standardized approach in the management of these patients. We conducted a retrospective analysis to assess the prevalence of pulmonary embolism complication in patients with brain tumors treated by our Institution in the last 3 years. MATERIAL AND METHODS Clinical data, treatment modalities, and patients outcome were analyzed and described. In particular, In particular, the dosages of D-dimer performed in the clinical suspicion of thromboembolic complication were reviewed, and the data of patients with pulmonary embolism confirmed by chest CT scan were recorded. RESULTS Overall 372 patients were treated at our Institute in the last 3 years for brain tumors. 14 patients (3.7%) 9 males and 5 females, with a median age of 62 years and a median KPS of 80, affected by glioblastoma (69%), cerebral lymphoma (23%) and low-grade gliomas (8%) had pulmonary embolism during the course of treatment. None of the 14 patients was on prophylactic anticoagulant treatment. One patient developed the embolic event during radio and chemotherapy concomitant treatment, 5 patients during chemotherapy only (2 with PCV scheme and 3 with fotemustine scheme), 2 patients with primary nervous system lymphoma during methotrexate infusion. Six patients were not receiving any chemotehrapy treatment at the onset of pulmonary embolism. At the time of pulmonary embolism diagnosis, more than half of the patients had clinical signs suggestive of deep venous thrombosis, confirmed by echocolor Doppler, 10/14 patients were treated with high-dose enoxaparin, the others with fondaparinux and calcium nadroparin. CONCLUSION Despite the high incidence of VTE in patients with brain tumors, there is currently no gold standard in the prevention and treatment of this complication. In fact, many questions are still open, for example the efficacy of low molecular weight heparins vs oral anticoagulants as a prophylactic treatment, the timing of onset and the real risk of bleeding. Future prospective studies should be designed to identify parameters for optimize stratification of thrombotic / haemorrhagic risk in this group of patients. This could allow patients at high risk to undergo more aggressive prophylactic therapy or closer clinical-instrumental surveillance, without incurring the opposite risk of bleeding.