tbuckley/cabot-search huggingface dataset:
Chimeric antigen receptor T cell therapy targeting NKG2D ligand.
Authors: Tetsuhiko Asao, Rie Ishibashi, Moeko Inoue, Masafumi Fuse, Yoshie Miura, Hidenobu Ishizaki, Kiyoshi Yoshimura
Journal: Journal of Clinical Oncology (2016)

e14523 Background: Chimeric antigen receptor T cell (CAR-T) therapy is promising immunotherapy for cancer. While CAR-T therapy has shown encouraging results against CD19 in acute lymphoblastic lymphoma and other hematologic malignancies, CAR-T therapy targeting solid tumors is having problem with shortage of appropriate target antigens. NKG2D ligand (NKG2DL) is a ligand of NKG2D, which is expressed mainly on NK and γδ T cells, could be an attractive target of CAR-T therapy. NKG2DL such as MICA, MICB, and ULBP1 (UL16 binding protein 1) to ULBP3 are reported to be expressed on several kinds of tumors. Expression of MICA/MICB on tumor cells are reported to correlate with poor prognosis. Here we demonstrate that co-expressions of ULBP1 in cancer and NKG2D in peripheral blood mononuclear cells are associated with better prognosis in gastric cancer. For further analysis, we are investigating whether NKG2DL is appropriate target and which one among NKG2DL is able to be a target for the CAR-T therapy. Methods: We retrospectively reviewed the ULBP1 expression on tumor cells and the NKG2D expression on tumor infiltrating mononuclear cells by immunohistochemical staining in 98 specimens of surgically resected gastric cancer with cases of MP or deeper invasion depth. We also evaluated the correlation of ULBP1 and/or NKG2D expressions and its clinical outcome. Anti-tag(AT)-CAR-T therapy system which our group has been developing was used for this analysis. AT-CAR gene is transferred to activated T cells. ULBP1 and MICA expression vector was made by pcDNA 3.1. This vector was transfected to the SW480 human colon cancer cell line and A549 human lung cancer cell line by lipofection. Cytotoxicity by AT-CAR-T against tumor cells are evaluated using Terascan-VPC and EVOS. Results: Cases with both ULBP1 and NKG2D positive (n = 12) had better clinical outcome than those with doubly negative (n = 21) (5-year survival rate 90% vs 34%; Log-rank P < 0.05). We successfully set up cytotoxic assay for AT-CAR-T system. We also made the ULBP1 and MICA expression vector and tumor cells lines expressing ULBP1 and MICA in SW480. Conclusions: We are analyzing the cytotoxicity against tumor cell line targeting ULBP1 and/or MICA using CAR-T therapy.
Double incision and snare resection in symptomatic Zenker’s diverticulum: a modification of the stag beetle knife technique
Authors: Stefan Gölder, Juliane Brueckner, Alanna Ebigbo, Helmut Messmann
Journal: Endoscopy (2017)

Relief from dysphagia and regurgitation are the main goals of therapy in symptomatic Zenker's diverticulum. Flexible endoscopic treatment has proved to be an effective and safe method in control of these symptoms. The aim of our study was to further improve the resection of the cricopharyngeal muscle using a new technique, the double incision and snare resection (DISR) procedure, to reduce the recurrence rate.From February 2016 to April 2017, 16 patients were treated with 18 DISR procedures at our institution. The symptoms of the patients were recorded by a seven-item questionnaire prior to treatment, and re-evaluation was scheduled at 1 and 6 months after treatment.The median age was 70 years (range 55 - 85), and 10 patients were men (62 %). The median size of the diverticulum was 20 mm (range 5 - 40 mm), and the DISR procedure was performed in 28 minutes (range 20 - 47 minutes), with no major postinterventional complications. All patients re-started oral nutrition on the day after the intervention; a gastric tube was not required. The median follow-up was 3 months (range 1 - 15 months). Two patients received a planned second-step procedure, one because of a very large cricopharyngeal muscle and one because of a cyst inside the Zenker's bridge. Although one patient suffered from mild recurrence of symptoms, she refused a second treatment. All other patients were free of symptoms after treatment.The DISR procedure is a new endoscopic treatment technique that safely and reproducibly offers relief from symptomatic Zenker's diverticulum.
Effect of neoadjuvant chemoradiation on the tumor microenvironment in rectal cancer.
Authors: Prashant Mukesh Jani, Paul Renz, Candice Brem, Stephen Abel, Moses S. Raj, Dulabh K. Monga, James McCormick, Jan F Silverman, Alexander V. Kirichenko, Gene Grant Finley
Journal: Journal of Clinical Oncology (2017)

e15115 Background: Chemoradiotherapy (CRT) followed by surgery is standard treatment for most rectal cancers. This creates an inflammatory reaction which recruits and enhances T-cell mediated killing. Tumors can evade destruction by expressing immune modulating proteins such as PD-L1. Inhibitors of PD-L1 can circumvent immune evasion potentially enhancing neoadjuvant treatment. We assessed CD8+ infiltrates and PD-L1 expression before and after neoadjuvant CRT. We correlated these changes with clinical and pathological endpoints. Methods: We obtained tissue from 22 patients treated with neoadjuvant CRT followed by primary surgery for rectal adenocarcinoma from 2005-2015. Patients received 5FU based chemotherapy with concurrent radiation (mean 51.2 Gy in 27 fractions). Pre- and post-CRT samples were stained with VENTANA PD-L1 (SP263) Rabbit Monoclonal Primary Antibody to quantitate PD-L1 expression. CD8 + lymphocytes were assessed over one high power field (40x objective) in the area of densest expression. Analysis of 8 patients was completed at the time of this submission. Results: 37.5% of cases had upregulated PD-L1 expression post-CRT. 62.5% maintained similar PD-L1 expression in the biopsy and resection specimen. All patients had a CD8+ infiltrate after CRT with 87.5% demonstrating an increase in CD8+ lymphocytes. Patients without increased PD-L1 expression had a trend toward improved pathologic response. Conclusions: A majority of patients had an increased inflammatory infiltrate post-CRT indicating immune activation within the tumor microenvironment. A subset of tumors had increased PD-L1 expression. This population might benefit from neoadjuvant PD-L1 inhibition, which could translate to better pathological response and clinical outcomes. We will present the results from 22 patients currently under study. [Table: see text]
The sex‐shift in single disease and multimorbid asthma and rhinitis during puberty ‐ a study by MeDALL
Authors: T. Keller, C. Hohmann, M. Standl, A. H. Wijga, U. Gehring, E. Melén, C. Almqvist, S. Lau, E. Eller, U. Wahn, E. S. Christiansen, A. von Berg, J. Heinrich, I. Lehmann, D. Maier, D. S. Postma, J. M. Antó, J. Bousquet, T. Keil, S. Roll
Journal: Allergy (2017)

Cross-sectional studies suggested that allergy prevalence in childhood is higher in boys compared to girls, but it remains unclear whether this inequality changes after puberty. We examined the sex-specific prevalence of asthma and rhinitis as single and as multimorbid diseases before and after puberty onset in longitudinal cohort data.In six European population-based birth cohorts of MeDALL, we assessed the outcomes: current rhinitis, current asthma, current allergic multimorbidity (ie, concurrent asthma and rhinitis), puberty status and allergic sensitization by specific serum antibodies (immunoglobulin E) against aero-allergens. With generalized estimating equations, we analysed the effects of sex, age, puberty (yes/no) and possible confounders on the prevalence of asthma and rhinitis, and allergic multimorbidity in each cohort separately and performed individual participant data meta-analysis.We included data from 19 013 participants from birth to age 14-20 years. Current rhinitis only affected girls less often than boys before and after puberty onset: adjusted odds ratio for females vs males 0.79 (95%-confidence interval 0.73-0.86) and 0.86 (0.79-0.94), respectively (sex-puberty interaction P = .089). Similarly, for current asthma only, females were less often affected than boys both before and after puberty onset: 0.71, 0.63-0.81 and 0.81, 0.64-1.02, respectively (sex-puberty interaction P = .327). The prevalence of allergic multimorbidity showed the strongest sex effect before puberty onset (female-male-OR 0.55, 0.46-0.64) and a considerable shift towards a sex-balanced prevalence after puberty onset (0.89, 0.74-1.04); sex-puberty interaction: P < .001.The male predominance in prevalence before puberty and the "sex-shift" towards females after puberty onset were strongest in multimorbid patients who had asthma and rhinitis concurrently.
<i>In Utero</i> Exposure to Select Phenols and Phthalates and Respiratory Health in Five-Year-Old Boys: A Prospective Study
Authors: Céline Vernet, Isabelle Pin, Lise Giorgis-Allemand, Claire Philippat, Meriem Benmerad, Joane Quentin, Antonia M. Calafat, Xiaoyun Ye, Isabella Annesi-Maesano, Valérie Siroux, Rémy Slama
Journal: Environmental Health Perspectives (2017)

Phenols and phthalates may have immunomodulatory and proinflammatory effects and thereby adversely affect respiratory health.We estimated the associations between gestational exposure to select phthalates and phenols and respiratory health in boys.Among 587 pregnant women from the EDEN (Etude des Déterminants pré et post natals du développement et de la santé de l'Enfant) cohort who delivered a boy, 9 phenols and 11 phthalates metabolites were quantified in spot pregnancy urine samples. Respiratory outcomes were followed up by questionnaires until age 5, when forced expiratory volume in 1 s (FEV1) was measured by spirometry. Adjusted associations of urinary metabolites log-transformed concentrations with respiratory outcomes and FEV1 in percent predicted (FEV1%) were estimated by survival and linear regression models, respectively.No phenol or phthalate metabolite exhibited clear deleterious associations simultaneously with several respiratory outcomes. Ethyl-paraben was associated with increased asthma rate [hazard rate (HR)=1.10; 95% confidence interval (CI): 1.00, 1.21] and tended to be negatively associated with FEV1% (beta=-0.59; 95% CI: -1.24, 0.05); bisphenol A tended to be associated with increased rates of asthma diagnosis (HR=1.23; 95% CI: 0.97, 1.55) and bronchiolitis/bronchitis (HR=1.13; 95% CI: 0.99, 1.30). Isolated trends for deleterious associations were also observed between 2,5-dichlorophenol and wheezing, and between monocarboxynonyl phthalate, a metabolite of di-isodecyl phthalate (DIDP), and wheezing.Ethyl-paraben, bisphenol A, 2,5-dichlorophenol, and DIDP tended to be associated with altered respiratory health, with ethyl-paraben and bisphenol A exhibiting some consistency across respiratory outcomes. The trends between bisphenol A pregnancy level and increased asthma and bronchiolitis/bronchitis rates in childhood were consistent with a previous cohort study. https://doi.org/10.1289/EHP1015.
MANF Promotes Differentiation and Migration of Neural Progenitor Cells with Potential Neural Regenerative Effects in Stroke
Authors: Kuan-Yin Tseng, Jenni E. Anttila, Konstantin Khodosevich, Raimo K. Tuominen, Maria Lindahl, Andrii Domanskyi, Mikko Airavaara
Journal: Molecular Therapy (2017)

Cerebral ischemia activates endogenous reparative processes, such as increased proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and migration of neural progenitor cells (NPCs) toward the ischemic area. However, this reparative process is limited because most of the NPCs die shortly after injury or are unable to arrive at the infarct boundary. In this study, we demonstrate for the first time that endogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) protects NSCs against oxygen-glucose-deprivation-induced injury and has a crucial role in regulating NPC migration. In NSC cultures, MANF protein administration did not affect growth of cells but triggered neuronal and glial differentiation, followed by activation of STAT3. In SVZ explants, MANF overexpression facilitated cell migration and activated the STAT3 and ERK1/2 pathway. Using a rat model of cortical stroke, intracerebroventricular injections of MANF did not affect cell proliferation in the SVZ, but promoted migration of doublecortin (DCX)+ cells toward the corpus callosum and infarct boundary on day 14 post-stroke. Long-term infusion of MANF into the peri-infarct zone increased the recruitment of DCX+ cells in the infarct area. In conclusion, our data demonstrate a neuroregenerative activity of MANF that facilitates differentiation and migration of NPCs, thereby increasing recruitment of neuroblasts in stroke cortex.
Targeting the PI3K/mTOR Pathway in Lymphoma with PQR309 and PQR620: Single Agent Activity and Synergism with the BCL2 Inhibitor Venetoclax
Authors: Chiara Tarantelli, Eugenio Gaudio, Petra Hillmann, Filippo Spriano, Ivo Kwee, Andrea Rinaldi, Anastasios Stathis, Emanuele Zucca, Doriano Fabbro, Vladimir Cmiljanovic, Francesco Bertoni
Journal: Blood (2016)
Integrated Analysis of Whole-Genome ChIP-Seq and RNA-Seq Data of Primary Head and Neck Tumor Samples Associates HPV Integration Sites with Open Chromatin Marks
Authors: Dylan Z. Kelley, Emily L. Flam, Evgeny Izumchenko, Ludmila V. Danilova, Hildegard A. Wulf, Theresa Guo, Dzov A. Singman, Bahman Afsari, Alyza M. Skaist, Michael Considine, Jane A. Welch, Elena Stavrovskaya, Justin A. Bishop, William H. Westra, Zubair Khan, Wayne M. Koch, David Sidransky, Sarah J. Wheelan, Joseph A. Califano, Alexander V. Favorov, Elana J. Fertig, Daria A. Gaykalova
Journal: Cancer Research (2017)

Chromatin alterations mediate mutations and gene expression changes in cancer. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been utilized to study genome-wide chromatin structure in human cancer cell lines, yet numerous technical challenges limit comparable analyses in primary tumors. Here we have developed a new whole-genome analytic pipeline to optimize ChIP-Seq protocols on patient-derived xenografts from human papillomavirus-related (HPV+) head and neck squamous cell carcinoma (HNSCC) samples. We further associated chromatin aberrations with gene expression changes from a larger cohort of the tumor and normal samples with RNA-Seq data. We detect differential histone enrichment associated with tumor-specific gene expression variation, sites of HPV integration in the human genome, and HPV-associated histone enrichment sites upstream of cancer driver genes, which play central roles in cancer-associated pathways. These comprehensive analyses enable unprecedented characterization of the complex network of molecular changes resulting from chromatin alterations that drive HPV-related tumorigenesis. Cancer Res; 77(23); 6538-50. ©2017 AACR.
A Reloadable Self‐Healing Hydrogel Enabling Diffusive Transport of C‐Dots Across Gel–Gel Interface for Scavenging Reactive Oxygen Species
Authors: Jing Chen, Shuya Li, Ye Zhang, Wei Wang, Xiang Zhang, Yangyang Zhao, Yucai Wang, Hong Bi
Journal: Advanced Healthcare Materials (2017)

Abstract While reloadable drug delivery platforms are highly prized for the treatment of a broad spectrum of diseases, the gel–gel interface between hydrogels hinders the intergel diffusive transport of drugs and thus limits the application of hydrogels as reloadable depots. Here, this study reports the circumvention of this barrier by employing a self‐healing hydrogel prepared from N ‐carboxyethyl chitosan and sodium alginate dialdehyde, which are cross‐linked via a reversible Schiff base linkage. The injectable and bioadhesive hydrogel shows a rapid gelation time of 47 s. The dynamic self‐healing process enables the efficient diffusive transport of carbon quantum dots (C‐dots) into an adjacent hydrogel, and thus, the C‐dots can be used to scavenge reactive oxygen species from a remote inflammation site. Specifically, the diffusive transport of the C‐dots in the self‐healing hydrogel after three sequential reloading steps is sevenfold greater than that in the non‐self‐healing counterpart. In vivo, hematoxylin and eosin staining of the murine skin at the injection site shows no apparent symptoms of inflammation in the group treated with the reloadable self‐healing hydrogel. The current strategy represents a promising and straightforward route for the design of a reloadable drug delivery system for future use in clinical application.
Recurrent scarring papulovesicular lesions on sun-exposed skin in a 22-year-old man
Authors: Melissa A. Levoska, Jeffrey I. Cohen, Irini Manoli, Chyi-Chia Richard Lee, Steven S.T. Ching, Jessica Shand, Deborah Tamura, Kenneth H. Kraemer, John J. DiGiovanna
Journal: Journal of the American Academy of Dermatology (2017)
Are radical changes to health and social care paving the way for fewer services and new user charges?
Authors: Shailen Sutaria, Peter Roderick, Allyson M Pollock
Journal: BMJ (2017)

Current reforms to health and social care services, and radical redesign of the local government finance system, may signal the end of the NHS and local government in England as we know them, argue <b>Shailen Sutaria, Peter Roderick, and Allyson M Pollock</b>
Epigenetic inactivation to target the arginine biosynthetic pathway in multiple myeloma.
Authors: Eleftheria Hatzimichael, Aggeliki Dasoula, Nelofer Syed, Peter Wojciech Szlosarek, George Dranitsaris, Tim Crook, Evangelos C. Briasoulis
Journal: Journal of Clinical Oncology (2012)

e18567 Background: Argininoosuccinate synthetase-1 (ASS1) catalyses the rate-limiting step in arginine biosynthesis, the conversion of citruline to arginine. Argininosuccinate lyase (ASL) is an enzyme that catalyses the reversible breakdown of arginosuccinate producing arginine and fumerate. Arginine deprivation using arginine deiminase (ADI-PEG20) is currently considered as a novel therapeutic intervention for cancer. In this perspective, we investigated the methylation status of the ASS1 and ASL CpG islands in multiple myeloma (MM) and analyzed for clinical relevance. Methods: Genomic DNA was extracted from bone marrow aspirate samples from 46 MM patients (28 male, 18 female, median age 64 years) obtained at diagnosis. Methylation-specific PCR was employed to study the methylation in the ASS1 and ASL CpG islands. DNA was isolated and bisulphite modified using commercially available kits. Logistic regression analyses were used to measure the association between gene methylation and sex, age&gt;65, ISS stage, presence of extramedullary disease, renal failure and bone disease. Kaplan-Meier curves were used to estimate the probabilities of survival and the Log-rank test to assess the statistical significance of differences in event rates. Results: Methylation in the CpG island of ASS1 was detected in 71.7% patients and of ASL in 37% patients, while simultaneous methylation in both genes was present in 10 patients. None of the two genes was detectably methylated in the control group. Patients with ASS1 methylation were less likely to have bone disease (p=0.04, OR=0.22) and extramedullary disease (p=0.05, OR=0.22) and a trend was also noted that these patients were less likely to be &gt;65 years of age (p=0.2, OR=0.37). We did not detect any statistically significant difference in overall survival by methylation status of the studied genes in this small study size. Conclusions: We demonstrate for the first time that arginine biosynthesis genes ASS1 and ASL are methylated in MM.Methylation of ASS1 was found to be more frequent and negatively associated with bone or extramedullary disease. Further evaluation of ASS1 and ASL is warranted in MM and supports the expansion of arginine deprivation trials in these patients
The Wound Microenvironment Reprograms Schwann Cells to Invasive Mesenchymal-like Cells to Drive Peripheral Nerve Regeneration
Authors: Melanie P. Clements, Elizabeth Byrne, Luis F. Camarillo Guerrero, Anne-Laure Cattin, Leila Zakka, Azhaar Ashraf, Jemima J. Burden, Sanjay Khadayate, Alison C. Lloyd, Samuel Marguerat, Simona Parrinello
Journal: Neuron (2017)

Schwann cell dedifferentiation from a myelinating to a progenitor-like cell underlies the remarkable ability of peripheral nerves to regenerate following injury. However, the molecular identity of the differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled Schwann cells acutely purified from intact nerves and from the wound and distal regions of severed nerves. Our analysis reveals novel facets of the dedifferentiation response, including acquisition of mesenchymal traits and a Myc module. Furthermore, wound and distal dedifferentiated Schwann cells constitute different populations, with wound cells displaying increased mesenchymal character induced by localized TGFβ signaling. TGFβ promotes invasion and crosstalks with Eph signaling via N-cadherin to drive collective migration of the Schwann cells across the wound. Consistently, Tgfbr2 deletion in Schwann cells resulted in misdirected and delayed reinnervation. Thus, the wound microenvironment is a key determinant of Schwann cell identity, and it promotes nerve repair through integration of multiple concerted signals.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIyZDRhMGVmOGMwNWE4NTMyZjY1NWE0MjQxYzVjMjNiZSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc5MzcwNjQwfQ.AfYB5fSBspHtjZFqBE_scYGtkZtRYZ3eTM3uJX6Y5qrXPhcmOvd84VzR_KgH-G3FfIixuQqXM0KpRHexmBAvMvDpnP6KR-xjAYXQCIzxl_He357fVckWVZ07xPbBHxTEWom0i_62fSDea--EMO6kzTrMoc8DPIu6lMgoKArduS7tgsQylewAvRi3y8JQRGQvcOHYKJORBz7mrdbjpW6NictvJjjTKZxQkU3G7QNfBGxO3FaGGIxXD7Stt7JTN8j8LtoH7Ft8gMXSQ0pGx1DYhUN3L3RzUYLtNg-tpJNOHchgNVIJLEDAhK5p0HT4LPkR5C24Ocr83RZ_yqAkBnCLVA(mp4, (12.16 MB) Download video
Metronomic methotrexate and cyclophosphamide after carboplatin included adjuvant chemotherapy in triple-negative breast cancer: A phase III study.
Authors: Mohammad Sabry El Kady, Khalid El Nasr, Mohammed A Moneam Osman, Mahmoud Ellithy
Journal: Journal of Clinical Oncology (2015)

e12087 Background: Despite being chemosensetive, the majority of triple-negative breast cancer (TNBC) patients recur. The primary study objectives of the current phase III trial were to compare disease free survival (DFS), and overall survival (OS) for TNBC after adjuvant chemotherapy, who underwent maintenance metronomic chemotherapy versus no maintenance therapy. Methods: TNBCpatients were eligible for enrolment if they had TNM stages II-III and fit with our inclusion criteria. For their adjuvant chemotherapy, patients were assigned to either; Group1; 3cycles FEC-100 then 3 cycles docetaxel, carboplatin, followed by maintenance metronomic chemotherapy for 1 year, and group2; 3cycles FEC-100 then 3cycles docetaxel. Results: Between November 2008 and December 2014, 158 patients (78 group1, and 80 group2) were enrolled. The mean age was 46 years. The median performance status was 0. The median DFS for group 1, 2 were 26 months, 24 months respectively. The median OS for group 1, 2 were 34 months, 28 months respectively. Additionally, during the follow-up period, the overall distant metastasis recurrence rates for group 1, 2 were 26%, 37% respectively. Finally, treatment protocol was tolerated well in both groups with mild toxicity profiles. Conclusions: Extended adjuvant metronomic chemotherapy achieved significant improvement in the OS, DFS, and further they were well tolerated. Clinical trial information: 40267.
Gene expression profiling in 5q-syndrome and myelodysplastic syndromes.
Authors: A Pellagatti, N Esoof, F Watkins, C F Langford, D Vetrie, L Campbell, C Fidler, J D Cavenagh, H Eagleton, B Pushkaran, M Kwan, J S Wainscoat, J Boultwood
Journal: Blood (2003)