tbuckley/cabot-search huggingface dataset:
Natural history of growth and anaemia in children with epidermolysis bullosa: a retrospective cohort study*
Authors: A. Reimer, M. Hess, A. Schwieger‐Briel, D. Kiritsi, F. Schauer, H. Schumann, L. Bruckner‐Tuderman, C. Has
Journal: British Journal of Dermatology (2019)

Impaired growth and anaemia are major extracutaneous complications of epidermolysis bullosa (EB), but data on their development are lacking. To determine the clinical course of growth and anaemia in children with EB and clarify the impact of nutritional compromise, inflammation and genetic factors. A retrospective study was conducted of 200 children, 157 with recessive dystrophic EB (RDEB) and 43 with junctional EB (JEB)‐generalized intermediate, followed at the main referral centre in Germany. Growth charts were calculated using the modified LMS method and were correlated with parameters of anaemia, nutrition, inflammation and the molecular defect in a linear model. In our cohort of patients with RDEB, weight impairment started at 12–18 months old; by the age of 10 years, 50% showed wasting. The predicted median weight at age 20 years was 35·2 kg for men and 40·1 kg for women. In JEB, growth resembled that of healthy children. Anaemia was present from the second year of life onwards in RDEB and JEB. Low levels of haemoglobin, iron, vitamin D, zinc and albumin, high levels of C‐reactive protein, and absence of collagen VII correlated significantly with low weight in RDEB. No correlation was observed in JEB. The results highlight that nutritional compromise occurs early in children with RDEB and therefore may require interventions as of the first year or two of life. What's already known about this topic? Children with epidermolysis bullosa (EB) suffer from failure to thrive and anaemia as major extracutaneous complications. The course of growth and the development of anaemia in EB are poorly characterized. What does this study add? A molecularly well characterized cohort of 200 children with EB was followed with regard to anthropometrics, anaemia and inflammation. We demonstrate early onset of growth failure and anaemia, most pronounced in the subset of recessive dystrophic EB. Awareness of early growth delay and nutritional deficiencies will improve EB care in daily practice.
Hyaluronic acid-targeted and pH-responsive drug delivery system based on metal-organic frameworks for efficient antitumor therapy
Authors: Qianqian Sun, Huiting Bi, Zhao Wang, Chunxia Li, Xuwei Wang, Jiating Xu, Hui Zhu, Ruoxi Zhao, Fei He, Shili Gai, Piaoping Yang
Journal: Biomaterials (2019)
Development of a novel RT-PCR assay for the detection of EML4-ALK fusion products in FFPE speciments.
Authors: Eirini Papadopoulou, Samuel Murray, George Nasioulas
Journal: Journal of Clinical Oncology (2012)

e21087 Background: EML4-ALK is a fusion-type protein tyrosine kinase identified recently in a subset of human lung carcinomas and seems to be a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC. To date, several EML4-ALK variants have been identified in lung cancer samples. Three methods have been used for the detection of these fusions, including IHC, FISH, and RT-PCR, which is the only method that can distinguish between different variants. Existing RT-PCR methods, are designed to amplify large cDNA fragments and are inadequate for the analysis of formalin-fixed paraffin-embedded (FFPE) tissues which produce cDNA fragments of limited size. Thus, we designed an RT-PCR assay that can detect all published EML4-ALK variants and is suitable for use with this commonly available material. Methods: Synthetic DNA fragments for each variant were cloned using the pCR2.1 cloning vector and used as positive controls. Specific primers that enhance specifically EML4-ALK transcripts 1, 2, 3a, 3b, 4, 5a, 5b, 6, 7, "4", and "5" were designed. Detection of all EML4-ALK fusions was achieved using RT-PCR. DNA sequencing analysis was performed to confirm the specificity of the obtained PCR products. The sensitivity of the method was calculated by adding to 1μg RNA serial dilutions of the synthetic DNA fragments. It was found that up to 22 copies of the translocation can be detected per μg of RNA. The study included FFPE specimens from NSCLC patients without EGFR and K-RAS mutations. Pathological review was obtained for all samples and macro-dissection was used to ensure a tumor cell content of &gt;75%. We are currently increasing our sample size of Greek patients and are in collaboration with other centers to further understand the clinical impact of the variant spectrum. Results: Three control EML4-ALK FISH positive samples were positively subtyped using RT-PCR and sequencing. None of the 96 FFPE specimens tested so far was positive for the EML4-ALK fusion. Conclusions: We designed a robust multiplex RT-PCR assay that permits the sensitive detection of all published EML4-ALK variants. It’s suitable for use with commonly available materials such as FFPE specimens, cytological specimens and other aspirates.
P11.52 Reduced expression of proteolipid protein 2 increases ER-stress-induced apoptosis and autophagy in glioblastoma
Authors: Z Feng, W Zhou, J Wang, B Huang, A Chen, D Zhang, R Bjerkvig, J Wang, F Thorsen, X Li
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The PLP2 gene encodes for the Proteolipid protein 2 (PLP2) which is an integral ion channel membrane protein of the endoplasmic reticulum. The protein has been shown to be involved in several human cancers, but the importance of PLP2 in gliomas is poorly understood. In the present study, we therefore investigated the role of PLP2 in human glioma development. MATERIAL AND METHODS Immunohistochemistry was carried out for paraffin-embedded glioma samples, and changes in protein level were detected by western blot analysis. Small interfering RNA transfections were used for knockdown of specific genes. Cell viability and proliferation was then assessed by CCK-8 assay and EdU assay. Transmission electron microscopy was used to observe the ultrastructure of the cells and flow cytometry for the evaluation of apoptosis. Finally, U87 and U251 cells were treated with lentiviral transduction to obtain stably PLP2-knockdown cell lines, which were used for an in vivo study. RESULTS Data from publicly available datasets (Rembrandt, TCGA and CGGA) showed a correlation between up-regulation of PLP2 levels and increased malignancy. This was confirmed by IHC staining of sections from our own clinical glioma samples. Mechanistically, down-regulation of PLP2 in U87 and U251 glioma cell lines decreased the proliferation and increased apoptosis and autophagy, mediated by ER-stress. In PLP2 knockdown U87 and U251 cells, autophagy inhibition by chloroquine (CQ) augmented apoptotic cell death. Finally, orthotopic U87-shPLP2 and U251-shPLP2 intracranial xenograft models revealed that down-regulating of PLP2 inhibited glioma development in vivo. CONCLUSION In conclusion, the results indicate that PLP2 expression is related to glioma progression, and could be a potential target for future treatment strategies.
P14.91 Study glycolytic metabolism in 1H-MRS monovoxel in the most aggressive part of 62 glioblastomas before and after 18 months of treatment
Authors: A Heintz, S Boussida, Z Saida, J Chombar, M Lefranc, C Desenclos, A Galmiche, B Chauffert, M Boone, J Constans
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND To study the relationship between glycolytic metabolism, tumor proliferation, survival and treatment response in patients with glioblastoma (GBM). MATERIAL AND METHODS Patients: 62 patients with glioblastoma, all having a STUPP Protocol (radiotherapy and concomitant chemotherapy), were selected and separated into 2 groups: Biopsies (30) and resections (32). In total, 269 NMR spectra (PRESS at GE 1.5T and 3T; multi-TEs TE=35ms and TE=144ms) were acquired. Processing: MRS data were processed with jMRUI software and quantitated using HLSVD and QUEST algorithms. Statistical analysis of longitudinal MRS data (every 3 months) RESULTS 1H-MRS glucose (Glc/tCr) and lactate (Lac/tCr) measurements are highly correlated before the beginning of treatment. This correlation is less obvious after 3, 6, 9 and 12 months of treatment. Proliferation is also strongly correlated with Lactate and Glucose before the beginning of treatment in both groups, whereas these correlations decrease in resected patients.The variability of ratios follow-up is higher in biopsied patients. Tumoral proliferation (tCho/tCr) and Glucose ratio (Glc/tCr) levels decreased along the follow-up. Although, the Lac/tCr ratio progressively decreased, its level remains high until 6 months. After 15 months of treatment, glucose increased although the lactate decreased. CONCLUSION The study of glycolytic metabolism in GBM could be used to evaluate the response to treatment. Being able to have a treatment response biomarker at 3 months, especially for patients who could not be resected could help to monitor and adapt treatment. The increase of Glucose at the end of the follow-up shows the interest of spectral and metabolic follow-up of glioblastoma after 18 months of treatment.
Charcot-Leyden crystals promote neutrophilic inflammation in patients with nasal polyposis
Authors: Elien Gevaert, Tim Delemarre, Joyceline De Volder, Nan Zhang, Gabriele Holtappels, Natalie De Ruyck, Emma Persson, Ines Heyndrickx, Kenneth Verstraete, Helena Aegerter, Hans Nauwynck, Savvas N. Savvides, Bart N. Lambrecht, Claus Bachert
Journal: Journal of Allergy and Clinical Immunology (2019)
P14.112 Long-term application of TTFields in glioblastoma: a multiple-case study
Authors: A Lawson McLean, R Kalff, J Walter
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Tumor treating fields (TTFields) is an antimitotic cancer therapy that utilizes low-intensity, intermediate-frequency alternating electrical fields to treat glioblastoma (GBM). Increased compliance with TTFields is independently prognostic for improved survival and was correlated with significantly improved overall and progression-free survival versus temozolomide (TMZ) alone. We present two exemplary cases of primary GBM treated with TTFields on long-term and adjuvant chemotherapy to explore treatment adherence, feasibility and safety issues. MATERIAL AND METHODS We present case details of two patients from our comprehensive cancer center, both of whom have primary GBM and are long-term TTFields users. One patient began TTFields at first diagnosis whilst the other had already survived to two years at the time of TTFields commencement. Their histories and disease status under continuous, ongoing TTFields therapy with concomitant, extended chemotherapy are explored. RESULTS Patient A is a 52-year-old male with IDH1-wildtype, MGMT promoter-methylated GBM. He began TTFields 24 months after initial diagnosis. Before starting TTFields, he had two resections, one owing to early locoregional progression, and had underwent standard, dual radiochemotherapy and started adjuvant TMZ. He has now completed 931 days of treatment with an average daily usage of 82% and has survived 55 months from first diagnosis. Since beginning TTFields, he has undergone a further two resections and another radiotherapy course. His chemotherapy regime has been modified several times, from standard-dose to dose-intensified TMZ, then later switched to lomustine and irinotecan-containing protocols. Patient B is a 68-year-old male, also with IDH1-wildtype, MGMT promoter-methylated GBM. He began TTFields six months after first diagnosis and after one tumor resection, concomitant radiochemotherapy and initiation of long-term TMZ therapy. He has now undergone 636 days of TTFields treatment with an average daily usage of 74%. In addition, 28 cycles of TMZ have been completed. CONCLUSION During a mean treatment duration of 784 days and alongside extended-course adjuvant chemotherapy, TTFields was well tolerated. Both patients are alive and still receiving treatment. Compliance has remained within the target range. Significant adverse events or treatment interruptions have not occurred. The patients have remained symptomatically stable and their quality of life has been maintained.
Actor network theory to map planetary health interconnections: a clinical case study
Authors: Enrique Falceto de Barros, Tatiana Souza de Camargo, Diogo Onofre de Souza
Journal: The Lancet Planetary Health (2019)

BackgroundIn 2017, the World Organization of Family Doctors (WONCA) officially stated "[it is] imperative that planetary health be included in the core curriculum of medical schools, family medicine residencies and further professional development". In 2019 WONCA urged "family doctors around the world to commit to acting on planetary health". Despite positive repercussions from major medical journals, the integration of planetary health into medical education remains a challenge. In this context it seems relevant to search for and develop tools to facilitate planetary health medical teaching. We aimed to apply actor-network theory (ANT) to describe interconnections between a patient with a clinical problem and planetary health proximal and distal issues.MethodsUsing ANT anthropological methodology, we describe the human and non-human actors involved in the interdependent network around the visit of a patient with obesity, hypertension, and diabetes to a community health clinic in southern Brazil. Perceived relevant proximal and distal planetary health issues involved in the clinical case were described, then organised into one diagram. This ANT clinical case diagram was subsequently used as a teaching tool.FindingsThis ANT clinical case diagram was presented to medical students and other health professionals in a few conferences and lectures in Brazil during the second semester of 2018 and initial months of 2019. Informal feedback from students and peers has been positive so far. The ANT diagram seemed to significantly facilitate comprehension of the planetary health framework to address clinical issues.InterpretationANT methodology could potentially be used in different clinical cases in diverse scenarios. Further formal quantitative and qualitative assessment of the utility of this teaching tool is required.FundingNone.
P11.20 Assessing TTFields-response and associated gene expression in various human cancer cell lines
Authors: A Kinzel, G Lavy-Shahaf, M Giladi, R Schneiderman, K Gotlib, E Zeevi, Y Porat, M Munster, U Weinberg, E Kirson, Y Palti
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Various cancer cell lines were reported to be affected in an inhibitory manner of varying magnitude by tumor treating fields (TTFields). Here, we aimed to detect response markers for TTFields treatment by analyzing specific properties of cell lines according to their response pattern to these alternating electric fields of intermediate frequency and low intensity. MATERIAL AND METHODS We treated 45 cell lines of diverse types of human cancer with TTFields at their specific optimal frequency and equal nominal intensity of 1.7 V/cm for 72 h. In addition to investigating cytotoxicity and clonogenic potential, we used the Cancer Cell Line Encyclopedia (CCLE) database for further analysis: First, to functionally examine patterns of differentially expressed genes or mutations associated with response to TTFields; and second, to compare sensitivity to TTFields using pharmacological profiling (CCLE). RESULTS TTFields had a cytotoxic effect on tested cell lines of 50 % on average (range: 14–86% reduced cell counts), whereas the clonogenic effect varied between no effect and 88 % reduction in the number of colonies. With regard to differential gene expression and mutation analysis, our analysis detected upregulated pathways associated with migration, DNA damage repair response, oxidative stress, and hypoxia. Further, cells identified as having a better response to TTFields were also more sensitive to lapatinib, PHA-665752 and PLX-4720. CONCLUSION In this study, we determined the optimal frequency for maximum response to TTFields in numerous human cancer cell lines. Our results argue strongly for a vast effectiveness of TTFields treatment in cancer cells, and synergistic effects in combination with other therapeutic agents might be revealed in future studies using pharmacological profiling. Beyond that, further research is needed on the role of identified response-associated mutations.
P05.01 the efficacy of donepezil on cognitive function in postoperative brain tumor patients
Authors: Y Diansari, Y Harun, S Marisdina, Y Felistia
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Cognitive impairment is frequently found in brain tumor patients. More than 90% of patients with brain tumor have at least one cognitive domain disturbance. Decline in cognitive function could happen before due to the tumor or after the treatment because of surgery, radiotherapy or chemotherapy. Until now there is no available standard treatment for patients with cognitive impairment due to brain tumor. Moreover, Donepezil is an acetylcholinesterase inhibitor known to be useful for improving cognitive function in patients with dementia. This clinical study aims to determine the cognitive effects of donepezil therapy in patients with brain tumors following surgery. MATERIAL AND METHODS This is a pilot study with total of 20 adult brain tumor patients were double blinded randomly assigned to receive a single daily dose (5mg for 12 weeks) of donepezil or placebo. The inclusion criteria were patients with primary brain tumor who had undergone surgery with cognitive impairment at the initial evaluation and age range 18 to 65 years old. Patients with previous cognitive problem, other diseases that can cause cognitive decline e.g. stroke and history of taking donepezil, memantine, methylphenidate, ginkgo biloba, and modafinil were excluded. A cognitive test using Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment Indonesia Version (MoCA-INA) assessing memory, attention, language, visuospatial, verbal fluency, and executive functions were administered before random assignment and at 4, 8 and 12 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated. Furthermore, side effects and adverse events were also recorded. RESULTS Of this mostly middle-age (30–60 years old), female, meningioma as primary brain tumor with frontal and temporal lobe are the most frequent locations. After 12 weeks of treatment, the composite scores did differ significantly between groups (MMSE P=0.027, MoCA-INA P=0.024). Furthermore, the significant differences favouring donepezil were observed for orientation and recall domains using MMSE with p value 0.017 and 0.006 respectively. Visuospatial (P=0.034) and delayed recall domains (P=0.004) were significant through MoCA-INA evaluation. In addition, Mean MMSE score for pre-donepezil administration was 14.60 ± 4.47 and after 3 months was 20.40 ± 4.24 (P=0.000). Mean MoCA-INA score for pre-donepezil administration was 9.30 ± 3.65 and after 3 months was 15.30 ± 4.24 (P=0.000). However, there was no differences in the placebo group (MMSE P= 0.066, MoCA-INA P=0.313). CONCLUSION Three months treatment with donepezil significantly improve the cognitive functions among post-operative brain tumor patients with no reported side effect. Moreover, further research is needed for longer duration of follow-up and possibility of increased doses.
P14.25 Venous thromboembolic events in patients with brain metastases: the PICOS score
Authors: F Wolpert, B Grossenbacher, A Lareida, P Roth, M C Neidert, N Andratschke, E Le Rhun, M Weller
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Venous thromboembolic events are significant complications in patients and possibly associated with an unfavorable outcome. Thrombosis risk is poorly defined for patients with brain metastasis, and available risk calculation scores are not validated for these patients. MATERIAL AND METHODS We identified 811 patients with brain metastasis followed at our institution and screened electronic charts retrospectively for the occurrence of venous thromboembolic events, along with candidate risk factors. Risk factors were tested in uni- and multivariate analyses and finally integrated in a score model for risk prediction. RESULTS Venous thromboembolic events were documented in 97 of 811 patients (12.0%). Primary tumors with high thrombogenicity (p=0.02, odds ratio 1.7, 95% CI 1.1–2.8), dexamethasone (p=0.011, odds ratio 2.27, 95% CI 1.5–4.5), chemotherapy (p=0.005, odds ratio 3.4, 95% CI 1.6–7.5), BMI &gt; 35 kg/m2 (p=0.002, odds ratio 3.4, 95% CI 1.6–7.5) and immobilization (p=0.003, odds ratio 2.4, 95% CI 1.3–4.3) were confirmed as independent predictors of VTE. We derived a score model for venous thromboembolic event prediction, the PICOS (thrombogenic Primary, Immobilization, Chemotherapy, Obesity, Steroids) score (0–7 points). Receiver Operating Characteristic Curve Analysis demonstrated its prognostic accuracy (AUC=0.71, 95% CI 0.64–0.77), and its predictive capability was superior to that of other scores proposed for the evaluation of venous thromboembolic event risk such as the Khorana (AUC=0.51) or CONKO (AUC=0.52) scores. CONCLUSION We report a rate of venous thrombotic events of 12.0% in our cohort of 811 patients with brain metastasis. We define a risk model for prediction in of venous thrombotic events in patients with BM, the PICOS score. It may become a valuable tool for the identification of brain metastasis patients at high risk for venous thromboembolic events and be helpful for guidance of clinicians towards decision whether to start thrombosis prophylaxis. Further, the PICOS score might be used for stratification in controlled studies.
Proteasome Inhibitor Drugs
Authors: Lloyd D. Fricker
Journal: The Annual Review of Pharmacology and Toxicology (2019)

Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms.
NICE recommends gene therapy for inherited retinal dystrophy
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Draft guidance from the National Institute for Health and Care Excellence (NICE) has recommended licensed gene therapy for people with vision loss caused by RPE65 mediated inherited retinal dystrophy who have enough viable retinal cells, after a deal between NICE and the manufacturer Novartis.1

RPE65 mediated inherited retinal dystrophies are rare and involve progressive vision loss that leads to near total blindness. So far treatment has been limited to supportive care.

NICE’s review of clinical trial data …