tbuckley/cabot-search huggingface dataset:
Ventilation following established ARDS: a preclinical model framework to improve predictive power
Authors: Charlotte Oakley, Marissa Koh, Rhianna Baldi, Sanooj Soni, Kieran O'Dea, Masao Takata, Michael Wilson
Journal: Thorax (2019)

Background Despite advances in understanding the pathophysiology of acute respiratory distress syndrome, effective pharmacological interventions have proven elusive. We believe this is a consequence of existing preclinical models being designed primarily to explore biological pathways, rather than predict treatment effects. Here, we describe a mouse model in which both therapeutic intervention and ventilation were superimposed onto existing injury and explored the impact of β-agonist treatment, which is effective in simple models but not clinically. Methods Mice had lung injury induced by intranasal lipopolysaccharide (LPS), which peaked at 48 hours post-LPS based on clinically relevant parameters including hypoxaemia and impaired mechanics. At this peak of injury, mice were treated intratracheally with either terbutaline or tumour necrosis factor (TNF) receptor 1-targeting domain antibody, and ventilated with moderate tidal volume (20 mL/kg) to induce secondary ventilator-induced lung injury (VILI). Results Ventilation of LPS-injured mice at 20 mL/kg exacerbated injury compared with low tidal volume (8 mL/kg). While terbutaline attenuated VILI within non-LPS-treated animals, it was ineffective to reduce VILI in pre-injured mice, mimicking its lack of clinical efficacy. In contrast, anti-TNF receptor 1 antibody attenuated secondary VILI within pre-injured lungs, indicating that the model was treatable. Conclusions We propose adoption of a practical framework like that described here to reduce the number of ultimately ineffective drugs reaching clinical trials. Novel targets should be evaluated alongside interventions which have been previously tested clinically, using models that recapitulate the (lack of) clinical efficacy. Within such a framework, outperforming a failed pharmacologic should be a prerequisite for drugs entering trials.
Conceptual model of chronic lymphocytic leukemia.
Authors: Helena Chung, Matthew Blowfield, Calvin Krogh, Daniel Eek
Journal: Journal of Clinical Oncology (2019)

e19001 Background: The study aimed to create a conceptual model (CM) of disease- and treatment-related signs, symptoms and impacts in patients with first-line (1L) or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Methods: The CM was based on literature searches, review of CLL patient blogs/forums, interviews with expert hematologists, and semi-structured concept elicitation interviews with 40 patients with CLL (20 1L, 20 R/R; with fatigue, weight loss, fever and/or night sweats in previous week). To identify salient concepts, the number of patients mentioning each concept and the concept’s mean disturbance rating (from 0 [not at all] to 10 [very]) were mapped. Results: Literature searches identified 32 prevalent concepts, with the most common being fatigue/tiredness. Patient blogs/forums revealed further symptoms (muscle/joint aches, headaches, weakness) and impacts (stress, fear of death, uncertainty). Clinicians reported recurrent infections and swollen lymph nodes as key signs of CLL and noted that fatigue is related to both symptoms (e.g. tiredness) and impacts (e.g. needing to rest and limit daily activities). In patient interviews, 50 concepts were revealed, with 42 present in both 1L and R/R; fatigue was the most prominent and impactful. Fatigue-related sub-concepts were identified, covering symptoms (tiredness/need to sleep, lack of energy, weakness, cognitive fatigue) and impacts (decreased ability to maintain social/familial/professional role, decreased physical functioning, frustration). Three versions of the CM were created: an overall model with all identified concepts, and two models highlighting the most salient concepts in 1L and R/R. Muscle/joint aches, night sweats, bruising, fatigue-related symptoms, fever and recurrent infections/illness were salient symptoms in both 1L and R/R, as were impacts such as anxiety/worry, stress, depression, financial difficulty, and fear of death. Shortness of breath and coughing were salient in 1L only, and swollen lymph nodes, headaches, pain/discomfort, weight loss, nausea/vomiting, and infusion reactions were salient in R/R only. Conclusions: The three versions of the CM can help to inform patient-centered end points to evaluate new treatments for 1L and/or R/R CLL.
Abstract 1199: Identification of candidate regulators of genomic instability in human lung adenocarcinoma through a new cross-species <i>in silico</i> analysis
Authors: Chinthalapally V. Rao, Mudassir Farooqui, Yuting Zhang, Gaurav Kumar, Janani Panneerselvam, Nagendra Yarla, Adam S. Asch, Hiroshi Y. Yamada
Journal: Cancer Research (2019)

(a) Chromosome instability (CIN), a type of genomic instability that is mitotic error-driven, has a deep impact on carcinogenesis and cancer recurrence. High CIN is a marker for poor prognosis in various cancers, including lung adenocarcinoma. In the tumor genome, CIN can be indicated with Copy Number Alterations (CNA) as its surrogate indicator. Although a diverse array of genes can cause CIN at the cellular level, genes responsible for tumor CNA remain elusive. In this study, we set out to identify genes whose expression shows correlation with CNA in human lung adenocarcinoma.(b) We employed a novel cross-species in silico analysis. Our previous lung RNAseq results from lung cancer-prone CIN mice indicated 348 misregulated genes (92 up-regulated, 256 down-regulated; 2-fold cutoff, P<0.05). We hypothesized that some of the genes misregulated in CIN mice are involved in genomic instability in tumors. With in silico analysis with a human cancer genome database, we identified five human genes as candidate regulators of CNA in human lung adenocarcinoma: MMP13, NUF2, CCL22, ZNF366, and GPR114. High expression of MMP13, CCL22, ZNF366, and GPR114 was correlated with low CNA, suggesting their role in suppressing CIN. High expression of NUF2 was correlated with high CNA, suggesting its role in increasing CIN.(c) MMP13 (Matrix Metalloprotease 13) is a protease involved in the breakdown of extracellular matrix. NUF2 (yeast NUF2 Kinetochore Protein homolog) is involved in the mitotic process, the misregulation of which directly leads to CIN. CCL22 (C-C Motif Chemokine Ligand 22), ZNF366 (Zinc Finger Protein 366), and GPR114 (G protein-coupled receptor 114, aka ADGRG5) are generally markers for subsets of immune cells (likely dendritic cells). This result led us to further hypothesize that infiltration of CCL22-, ZNF336-, and/or GPR114-positive immune cells inhibits pre-tumor cells and tumor cells with high CNA.(d) The removal mechanism of cells with genomic instability is poorly understood. This is the first time that candidate markers for the immune cells directly or indirectly involved in removal of CIN cells have been identified. This study may aid in fine-tuning cancer-preventive immunotherapy that targets lung cells with genomic instability.Citation Format: Chinthalapally V. Rao, Mudassir Farooqui, Yuting Zhang, Gaurav Kumar, Janani Panneerselvam, Nagendra Yarla, Adam S. Asch, Hiroshi Y. Yamada. Identification of candidate regulators of genomic instability in human lung adenocarcinoma through a new cross-species in silico analysis [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 1199.
Abstract 4368: Investigating the role of IDH in normal metabolic and cancer pathways
Authors: Nicholas DiDuca, Sarah H. Roberts, Shane Sturtevant, Marla Tipping
Journal: Cancer Research (2019)

Abstract Isocitrate dehydrogenase (IDH) has gained much attention due its frequent mutation in acute myeloid leukemia (AML) and glioblastomas. This enzyme is responsible for converting isocitrate into α-ketoglutarate (α-KG); when this gene is mutated it further converts α-KG into another metabolite, D-2-HG, that competes with α-KG. Production of D-2-HG causes diversion to a new metabolic pathway, as well as inhibits the activity of other enzymes in the cell. We have created flies that express the IDH mutant protein to investigate the other metabolic changes. One of these changes results in an embryo lethality. Additional model systems investigating larval and adult brains have shown glial cell inhibition. We hypothesize that harboring the IDH mutation will have a negative impact on the stable development of progeny. Note: This abstract was not presented at the meeting. Citation Format: Nicholas DiDuca, Sarah H. Roberts, Shane Sturtevant, Marla Tipping. Investigating the role of IDH in normal metabolic and cancer pathways [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 4368.
Abstract 3455: TNFAIP8 increases drug resistance and steatosis in liver cancer by inducing autophagy
Authors: Suresh Niture, Maxwell A. Gyamfi, Deepak Kumar
Journal: Cancer Research (2019)

Abstract Tumor necrosis factor-α-inducible protein 8 (TNFAIP8) is a TNF-α inducible anti-apoptotic protein which facilitates tumor growth and progression in several cancers. The molecular mechanisms how TNFAIP8 modulates the progression of liver cancer remain elusive. The present study investigated the role of TNFAIP8 in the liver cancer cell growth, drug resistance/survival and cell steatosis. Tissue microarray data from patients demonstrated an increased expression of TNFAIP8 protein during development of different stages of liver cancer compared with normal liver tissues. To test the correlation between TNFAIP8 expression and liver cancer progression, we transiently/stably expressed TNFAIP8 protein in liver cancer cell lines. Expression of TNFAIP8 in liver cancer cells HepG2 and SK-Hep1 increased both cell growth/survival and drug resistance against anti-liver cancer drugs sorafenib and regorafenib by inhibition of apoptosis. In addition, TNFAIP8 knockdown sensitized tumor cell lines to sorafenib and regorafenib. Expression of TNFAIP8 modulates AKT/mTOR pathway and induced autophagy and thus increased drug resistance. Moreover, TNFAIP8 induced liver cancer cell steatosis by increasing the expression of L-FABP1, SCD1, ACC, and PPARγ proteins which involved in lipid synthesis. We also demonstrate that chronic EtOH induced steatosis in mice liver was associated with increased TNFAIP8 expression and autophagy suggesting that TNFAIP8 mediate EtOH induced steatosis. In addition, increased expression of TNFAIP8 and hepatic steatosis was observed in patients with a history of alcohol use compared with no history of alcohol use. Taken together our data suggested that TNFAIP8 increases drug resistance/survival, EtOH-induced cell steatosis and early liver cancer development by the induction of autophagy. Citation Format: Suresh Niture, Maxwell A. Gyamfi, Deepak Kumar. TNFAIP8 increases drug resistance and steatosis in liver cancer by inducing autophagy [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 3455.
Migrant charging policy is incompatible with good healthcare
Authors: Rayah A Feldman
Journal: BMJ (2019)

Torjesen’s article on charging migrants for care in the NHS is misleading about who is eligible for free NHS care and glosses over implications of the United Kingdom’s charging policy for “overseas visitors” that make it fundamentally incompatible with the principles of good healthcare.1

People on visitor visas and undocumented migrants are likely to be charged or refused non-urgent care even if …
Abstract 3903: Acute toxicity studies of ethanolic fruit-skin extract of <i>Annona muricata</i>
Authors: Wisdom O. Iyanda-Joel, Sandra O. Israel-Ovirih, Shalom N. Chinedu, Emeka EJ Iweala
Journal: Cancer Research (2019)

Abstract Recent reports have shown that the currently high demand for Annona muricata fruits and plant products is most likely due to their selective cytotoxic activity, where extracts and subsequent pure compounds exhibited more toxicity to cancer cell lines than standard drugs and even increased the viability of normal cells at certain concentrations. The current study explored the phytochemical screening and acute toxicity profile of ethanolic fruit-skin extract of Annona muricata (ESA) in female Wistar rats. Phytochemical screening were carried out following stipulated protocols while twenty-five female Wistar albino rats were treated with 2000 mg kgbwt-1and 5000 mg kgbwt-1 ESA for 24 - 72 hours and after 14 days to evaluate their toxicity against biochemical (ALT, AST, ALP, urea, creatinine, triglycerides, cholesterol, albumin and total protein), hematological (RBC, WBC, PCV, platelet count, MCV, MCH and MCHC, neutrophil, lymphocyte and monocyte) and histopathological parameters. The phytochemical screening of extract collectively revealed the presence of alkaloids, flavonoids, phenols, quinones, saponins, steroids, tannins and terpenoids. No sign of toxicity was observed in animals treated with ESA in the first critical four hours of dosage neither any mortality recorded. Toxicological assessment of ESA showed significant difference in values of extract-treated animals mostly at 5000 mg kgbwt-1 compared to normal control on ALT, ALP, WBC, M, N, PCV, MCH, MCV and platelet count within 72 hours of treatment compared to normal control but mostly later reversed after 14 days. Histopathology results also showed significant differences in morphology of certain organs compared to control with reversal of some lesions after 14 days. Ultimately, ethanolic fruit-skin extract of Annona muricata is non-toxic at moderate concentrations and may serve as a huge potential for nature-friendly antiproliferative and antitumour agents. Note: This abstract was not presented at the meeting. Citation Format: Wisdom O. Iyanda-Joel, Sandra O. Israel-Ovirih, Shalom N. Chinedu, Emeka EJ Iweala. Acute toxicity studies of ethanolic fruit-skin extract of Annona muricata [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 3903.
Vitamin D for secondary prevention of acute wheeze attacks in preschool and school-age children
Authors: Christos Stefanidis, Adrian R Martineau, Chinedu Nwokoro, Christopher J Griffiths, Andrew Bush
Journal: Thorax (2019)

Introduction Vitamin D is best known for its role in bone health; however, the discovery of the vitamin D receptor and the expression of the gene encoding the vitamin D 1α-hydroxylase (CYP27B1) enzyme in a wide variety of tissues including immune cells and respiratory epithelium has led to the discovery of potential roles for vitamin D in the prevention of acute wheeze. Methods We review here the literature concerning the relationships between circulating 25-hydroxyvitamin D (25(OH)D) concentration and secondary prevention of acute wheeze attacks in preschool and school-age children. Results Epidemiological data suggest that vitamin D insufficiency (25(OH)D &lt;75 nmol/L) is highly prevalent in preschool and school-age children with wheeze. Preschool age children with a history of wheeze attacks and circulating 25(OH)D &lt;75 nmol/L are at increased risk and frequency of future acute wheeze. However, no consistent association between low vitamin D status and risk of acute wheeze is reported in school-age children. Seven randomised controlled trials (RCTs) with relatively small sample sizes (30–430) and variable quality showed inconsistent results regarding the effect of oral vitamin D supplementation during childhood on the risk of asthma attacks, asthma symptom control, inhaled corticosteroid requirements, spirometry and unscheduled healthcare attendances for wheeze. A RCT showed that vitamin D supplementation had no effect on the frequency of unplanned healthcare attendances due to acute wheeze in 22 preschool children. Discussion An evidence-based recommendation for the use of vitamin D as a preventive therapy for wheeze attacks cannot be made until results of further trials are available. The assessment of circulating 25(OH)D concentration and the optimisation of vitamin D status to prevent acute respiratory tract infections, and to maintain skeletal and general health in preschool and school-age children with acute wheeze is worthwhile in its own right, but whether this will reduce the risk of acute wheeze attacks is unclear.
Abstract 4273: Inhibition of autophagy increases HNSCC sensitivity to cancer therapies
Authors: Yong-Syu Lee, Justin Skiba, Jaimee Kubatzke, Kwangok P. Nickel, Randall Kimple
Journal: Cancer Research (2019)

Abstract Background: Radiation and EGFR-targeted therapies are commonly used in the treatment of head and neck squamous cell carcinoma (HNSCC). These treatments fail to control a significant number of cancers resulting in a 5-year survival rate that remains around 40-50%. We have shown that both cetuximab and radiation induce autophagy, a pro-survival cellular stress response, in head and neck cancer. In this study, we examine the consequence of autophagy inhibition and investigate the molecular mechanism underlying therapy-induced autophagy. Methods: Autophagy was assessed using a nano-Luc LC3 reporter (Promega), immunofluorescence for LC3, p62, and acridine orange in HNSCC cell lines. RNAi knockdown of EGFR and LAPTM4B were used to test the involved signaling molecules. Radiation was delivered using a RS225 cabinet irradiator at a dose rate of approximately 3 Gy/min with dose validation by TLD using custom phantoms. Cetuximab was delivered via intraperitoneal injection. Vps34 inhibitor SAR405 and ULK1 inhibitor SBI-0206965 were used to determine whether inhibition of autophagy reduces cell survival or represses cancer cell growth in the clonogenic assay. A flank xenograft model using A253 cells was used to test the combination of autophagy inhibitors and current therapies in vivo. Results: As previously shown, both cetuximab and radiation induced autophagy by two times. Knockdown of EGFR and LAPTM4B decreased autophagy (62.5% and 65%, respectively) when assessed using the nano-Luc reporter assay. Similar results were seen using IF. Using a clonogenic survival assay, the combination of SAR405 and radiation resulted in complete loss of cell survival suggesting a radiosensitizing effect. In vivo, SAR405 treatment improved tumor control when combined with radiation or cetuximab when compared to either treatment alone. Conclusions: Therapy induced autophagy is dependent upon expression of both EGFR and LAPTM4B. Inhibition of autophagy resulted decreased cell survival in vitro and resulted in decreased in vivo tumor growth. These results suggest that inhibition of autophagy may be a viable approach to sensitize HNSCC to anti-cancer treatments. Citation Format: Yong-Syu Lee, Justin Skiba, Jaimee Kubatzke, Kwangok P. Nickel, Randall Kimple. Inhibition of autophagy increases HNSCC sensitivity to cancer therapies [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 4273.
Abstract 1504: Characterization of a MC38 mouse syngeneic tumor model expressing human PD-L1 in the transgenic C57BL/6 mouse system expressing human PD-1 and PD-L1
Authors: Michael Koratich, Ted Green, Jie Liu, Charlotte Hammond, LaJuana Durbin, Jerry Zhou, Anna Chen, Murray Stackhouse
Journal: Cancer Research (2019)

Abstract The human checkpoint targets PD-1 and PDL-1 continue to demonstrate great promise in the clinic. With much of the current focus turning toward combination regiments, an animal model using the human clinical antibodies will be beneficial for evaluating new combination strategies. Here we continue characterization of a C57BL/6 transgenic mouse model expressing both the human PD-1 and PD-L1 combined with a modified murine MC38 colon tumor cell line expressing human PD-L1. Both PD-1 and PD-L1 expression of the transgenic mice were verified in ex vivo stimulated splenocytes by flow cytometry analysis. Expression of PD-L1 on the genetically modified MC38 cells was also demonstrated by flow cytometry. For in vivo efficacy evaluation, tumor-implanted mice were treated with the clinical agents nivolumab and pembrolizumab at 100 µg and atezolizumab at 1 mg on Days 3, 7, 10, and 14 post implant. Treatment with nivolumab and pembrolizumab initiated tumor regression by Day 17. Complete tumor regressions were seen at Day 28 in nivolumab, 62.5% complete regression, and pembrolizumab, 71.4% complete regression. Growth inhibition was 83.9%, 69.7%, and 95.0% on Day 28 for nivolumab, atezolizumab, and pembrolizumab, respectively, compared to the control animals. There was no significant body weight loss and no signs of toxicity in any of the treated animals. To compare the human anti-PD-1 and PD-L1 clinical agent specificity, the non-transgenic parent C57BL/6 mouse strain was implanted with the unmodified MC38 colon tumor cells. Treatment with pembrolizumab and atezolizumab was conducted as with the transgenic animals. Through 28 days no growth inhibition, tumor size 105.9% of control, was seen in the pembrolizumab treated group, demonstrating lack of cross reactivity of the human therapeutic in the standard mouse model. Atezolizumab did demonstrate a 56.9% growth inhibition compared to controls and is consistent with the known cross reactivity of atezolizumab between human and mouse. We have shown a genetically modified MC38 colon tumor expressing human PD-L1 in transgenic mice expressing both human PD-1 and PD-L1 to be a suitable model for checkpoint inhibitor evaluation of the human form of the particular checkpoint therapeutic. Further research will involve combining each of the checkpoint antibodies with various chemotherapeutic agents. Citation Format: Michael Koratich, Ted Green, Jie Liu, Charlotte Hammond, LaJuana Durbin, Jerry Zhou, Anna Chen, Murray Stackhouse. Characterization of a MC38 mouse syngeneic tumor model expressing human PD-L1 in the transgenic C57BL/6 mouse system expressing human PD-1 and PD-L1 [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 1504.