tbuckley/cabot-search huggingface dataset:
Novel binding pattern of chlorotoxin (TM-601) in glioma cells in vitro.
Authors: Marzenna Wiranowska, Gathline Etienne, Sharron Ladd, Vernon L. Alvarez
Journal: Cancer Research (2006)

5488  These studies are focused on evaluating the cellular target(s) and cellular effects of chlorotoxin (also called TM-601), a scorpion-derived, 36-amino acid peptide with specificity to tumor cells including glioma. TM-601 is a new experimental drug currently in Phase II clinical trials for treatment of adult recurrent glioma. Here we used the biotinylated version of TM-601, called TM-602, to evaluate binding to human U373 MG and mouse G-26 glioma cells. The glioma cell cultures were seeded on tissue culture chamber slides at 5000 cells per chamber for 24 hours at 37° C. Some cultures were fixed with 1% glutaraldehyde or 10% neutral buffered formalin (NBF) and reacted with TM-602 at 1 or 50 micromolar concentrations. Other cell cultures were incubated live at 37° C in the presence of either growth medium alone, 1.2 mM D-biotin or TM-602 (1 or 50 micromolar concentrations) for 5 minutes, 1 hour or 24 hours, followed by fixation with 1% glutaraldehyde or 10% NBF. Next, all cell preparations were treated with Vectastain Elite ABC Reagent followed by diaminobenzidine. Slides were dehydrated, cleared and coverslipped with Cytoseal and the brown reaction product was evaluated under a light microscope. We found that cell cultures which were fixed first and then exposed to TM-602 displayed a wide range of morphologically distinct stages of glioma cell division captured after fixation. Intensely dark stained cells at all stages of the cell division were clearly visible because of the TM-602 present in the nucleus and/or the microtubules of the mitotic spindle. The remaining majority of the cells exhibited strong brown filamentous staining in the cytoplasm, often concentrated adjacent to the nucleus, with darkly stained round structures visible within the nucleus. This suggested that TM-602 may have bound to the microtubules within the cell and concentrated around the centrosome, as well as to the kinetochore microtubules visible in the nucleus at S phase of the cell cycle. However, when live glioma cells were incubated with TM-602 for longer periods of time such as 1 hour or 24 hours (but not 5 minutes), the majority of cells exhibited nuclear staining but cells undergoing cell division were not found. In all cultures, the intensity of the staining following exposure to TM-602 increased in a dose and time dependent manner, but there was no staining displayed in the controls. The current study suggests that TM-602 binds to the microtubular structures known to be involved in cell division and cell motility and consequently inhibits glioma proliferation. Ongoing studies in our laboratory will further define cellular targets for TM-601 to aid in current and future clinical trials of adult recurrent glioma.
Diversification of Retinoblastoma Protein Function Associated with Cis and Trans Adaptations
Authors: Rima Mouawad, Jaideep Prasad, Dominic Thorley, Pamela Himadewi, Dhruva Kadiyala, Nathan Wilson, Philipp Kapranov, David N Arnosti
Journal: Molecular Biology and Evolution (2019)

Retinoblastoma proteins are eukaryotic transcriptional corepressors that play central roles in cell cycle control, among other functions. Although most metazoan genomes encode a single retinoblastoma protein, gene duplications have occurred at least twice: in the vertebrate lineage, leading to Rb, p107, and p130, and in Drosophila, an ancestral Rbf1 gene and a derived Rbf2 gene. Structurally, Rbf1 resembles p107 and p130, and mutation of the gene is lethal. Rbf2 is more divergent and mutation does not lead to lethality. However, the retention of Rbf2 >60 My in Drosophila points to essential functions, which prior cell-based assays have been unable to elucidate. Here, using genomic approaches, we provide new insights on the function of Rbf2. Strikingly, we show that Rbf2 regulates a set of cell growth-related genes and can antagonize Rbf1 on specific genes. These unique properties have important implications for the fly; Rbf2 mutants show reduced egg laying, and lifespan is reduced in females and males. Structural alterations in conserved regions of Rbf2 gene suggest that it was sub- or neofunctionalized to develop specific regulatory specificity and activity. We define cis-regulatory features of Rbf2 target genes that allow preferential repression by this protein, indicating that it is not a weaker version of Rbf1 as previously thought. The specialization of retinoblastoma function in Drosophila may reflect a parallel evolution found in vertebrates, and raises the possibility that cell growth control is equally important to cell cycle function for this conserved family of transcriptional corepressors.
Preliminary analysis of risk factors associated with peritoneal carcinomatosis (PC) after prophylactic bilateral salpingoophorectomy (PBSO) in patients with a BRCA mutation.
Authors: Neda Stjepanovic, Estela Carrasco, Neus Gadea, Antonio Gil, M. Assumpcio Perez, Berta Diaz, Silvia Franco, Silvia Cabrera, Angel Garcia, Josep Castellvi, Orland Díez, Marta Vilaro, Judith Balmaña
Journal: Journal of Clinical Oncology (2013)

1509 Background: Women with a BRCA1 or BRCA2 mutation are at high risk of developing ovarian carcinoma (OC) and a residual risk of PC after PBSO has been reported. We aimed to analyze the incidence of PC after PBSO and the clinical, pathological and molecular risk factors associated to PC in our series. Methods: Between April 2005 and December 2012, 100 patients with BRCA1 or BRCA2 mutation (50 each) underwent PBSO and were followed in the High Risk Clinics for the development of PC. PBSO pieces were submitted to pathological examination for presence of pathological and molecular risk factors like in situ or invasive Fallopian Tube Carcinoma (isFTC, inFTC) and p53 signature. Patients’ medical charts included in the High Risk Clinics Database were revised retrospectively for clinical, pathological and molecular characteristics. We analyzed the incidence of PC and the odds ratio (OR) for PC after PBSO in univariate analysis. Results: Overall, 2 patients (2%, 1 BRCA1, 1 BRCA2) were found to have isFTC, while 5 out 34 had a positive p53 signature (15%, 1 BRCA1, 4 BRCA2). With a median follow-up of 40 months (1-90) since PBSO, 2 patients developed PC (2%, both BRCA2). They underwent PBSO at age of 63 and 64 years and developed the PC 2 and 9 years after. One had a history of isFTC with p53 signature and 5 children, while the other had a prior history of bilateral breast cancer and no children. None had a family history of OC. Performing PBSO at an age older than 50 years was associated with an OR 8.56 (3.29-22.27) of PC. Conclusions: Fifteen and 2% percent of our patients had a positive p53 signature or an occult isFTC in the PBSO piece. Our analysis suggests that delaying PBSO to women older than 50 years may be associated with a higher risk of PC. Further analysis in a larger cohort is warranted.
Strategies to Adjust Positive End-Expiratory Pressure in Patients With ARDS
Authors: Stefan Lundin, Per Persson, Anders Larsson
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Nanomedicine as a putative approach for active targeting of hepatocellular carcinoma
Authors: Muhammed H. Elnaggar, Abdelrahman I. Abushouk, Ahmed H.E. Hassan, Hadeer M. Lamloum, Amira Benmelouka, Shurouk A. Moatamed, Hossam Abd-Elmegeed, Somia Attia, Aya Samir, Nouran Amr, Dina Johar, Samy Zaky
Journal: Seminars in Cancer Biology (2019)
<i>Notes from the Field</i>: A Multipartner Response to Prevent a Binational Rabies Outbreak — Anse-à-Pitre, Haiti, 2019
Authors: Joane Adrien, Yvenel Georges, Pierre D. Augustin, Benjamin Monroe, Andrew D. Gibson, Natael Fenelon, Ludder Fleurinord, Kelly Crowdis, Anna Mandra, Haim C. Joseph, Melissa D. Etheart, Ryan M. Wallace, Jesse Blanton, Julie Cleaton, Rene Edgar Condori, Brett Petersen, Yasmeen Ross, David Moran, Joanne Tataryn, Luke Gamble, Fred Lohr, Alasdair King
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Response Team
A Versatile Biosynthetic Hydrogel Platform for Engineering of Tissue Analogues
Authors: Barbara J. Klotz, Loes A. Oosterhoff, Lizette Utomo, Khoon S. Lim, Queralt Vallmajo‐Martin, Hans Clevers, Tim B. F. Woodfield, Antoine J. W. P. Rosenberg, Jos Malda, Martin Ehrbar, Bart Spee, Debby Gawlitta
Journal: Advanced Healthcare Materials (2019)

For creating functional tissue analogues in tissue engineering, stem cells require very specific 3D microenvironments to thrive and mature. Demanding (stem) cell types that are used nowadays can find such an environment in a heterogeneous protein mixture with the trade name Matrigel. Several variations of synthetic hydrogel platforms composed of poly(ethylene glycol) (PEG), which are spiked with peptides, have been recently developed and shown equivalence to Matrigel for stem cell differentiation. Here a clinically relevant hydrogel platform, based on PEG and gelatin, which even outperforms Matrigel when targeting 3D prevascularized bone and liver organoid tissue engineering models is presented. The hybrid hydrogel with natural and synthetic components stimulates efficient cell differentiation, superior to Matrigel models. Furthermore, the strength of this hydrogel lies in the option to covalently incorporate unmodified proteins. These results demonstrate how a hybrid hydrogel platform with intermediate biological complexity, when compared to existing biological materials and synthetic PEG-peptide approaches, can efficiently support tissue development from human primary cells.
Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G<sub>4</sub> Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial
Authors: Xinan Sheng, Xieqiao Yan, Zhihong Chi, Lu Si, Chuanliang Cui, Bixia Tang, Siming Li, Lili Mao, Bin Lian, Xuan Wang, Xue Bai, Li Zhou, Yan Kong, Jie Dai, Kai Wang, Xiongwen Tang, Huaning Zhou, Hai Wu, Hui Feng, Sheng Yao, Keith T. Flaherty, Jun Guo
Journal: Journal of Clinical Oncology (2019)

Metastatic mucosal melanoma responds poorly to anti-programmed cell death-1 (PD-1) monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. The combination of VEGF inhibition and PD-1 blockade provides therapeutic opportunities for patients refractory to either therapy alone.We conducted a single-center, phase IB trial evaluating the safety and preliminary efficacy of toripalimab, a humanized immunoglobulin G4 monoclonal antibody against PD-1 in combination with the VEGF receptor inhibitor axitinib in patients with advanced melanoma, including patients with chemotherapy-naïve mucosal melanomas (88%). Patients received toripalimab at 1 or 3 mg/kg via intravenous infusion every 2 weeks, in combination with axitinib 5 mg orally twice a day, in a dose-escalation and cohort-expansion study until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary objective was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and tumor tissue biomarkers.Thirty-three patients were enrolled. No dose-limiting toxicities were observed. Ninety-seven percent of patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were mild (grade 1 or 2) and included diarrhea, proteinuria, hand and foot syndrome, fatigue, AST or ALT elevation, hypertension, hypo- or hyperthyroidism, and rash. Grade 3 or greater TRAEs occurred in 39.4% of patients. By the cutoff date, among 29 patients with chemotherapy-naïve mucosal melanoma, 14 patients (48.3%; 95% CI, 29.4% to 67.5%) achieved objective response, and the median progression-free survival time was 7.5 months (95% CI, 3.7 months to not reached) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.The combination of toripalimab plus axitinib was tolerable and showed promising antitumor activity in patients with treatment-naïve metastatic mucosal melanoma. Patients enrolled in this study were all Asian, and this combination therapy must be validated in a randomized phase III trial that includes a non-Asian population before it can become a standard of care.
PTU-080 Upper gastrointestinal bleeding: the role of a dedicated inpatient list
Authors: M Hussein, C Podesta, M Carpani, K Tang, A Alisa, S Musa
Journal: Gut (2017)

Introduction  United Kingdom guidelines recommend all upper gastrointestinal bleed (UGIB) patients have endoscopy within 24 hours (h). The 2015 National Confidential Enquiry into Patient Outcome and Death (NCEPOD) audit reported a rate of 65%. In addition to a well-established out of hours rota, a dedicated weekday afternoon inpatient endoscopy list was introduced at Barnet Hospital, Royal Free London NHS Trust, in 2016. We sought to assess the early impact of the service on UGIB patients.  Method  A single centre retrospective study involving all inpatients with an UGIB at a large district general hospital (445 beds) serving a population >500,000, during a 5 month period (January-May 2016). The endoscopy procedure log was interrogated to identify UGIB patients, defined by haematemesis/coffee ground vomit, malaena and haemoglobin drop. Additional data were collected via electronic patient records and ‘Unisoft GI Reporting Tool’. Patient demographics, sedation dose, procedural time, endoscopy diagnosis, endoscopic intervention, time from presentation to endoscopy and hospital discharge within 24 hour of endoscopy, were evaluated.  Results  In total, UGIB accounted for 152/439 (35%) of all inpatient endoscopies. Median age was 73 [interquartile range (IQR) 58–86], 53% were female. Median midazolam dose was 2 mg (IQR 1–3 mg) and fentanyl 50mcg (IQR 31.25-50mcg). Median procedure time was 15 min (IQR 10–20 min), 110/152 (73%) patients underwent endoscopy within 24 hour of presentation. Endoscopic findings included hiatus hernia 58/152 (38%), oesophagitis 41/152 (27%), gastritis 37/152 (24%), duodenitis 25/152 (16%), duodenal ulcer 17/152 (11%), portal hypertensive gastropathy 17/152 (11%), oesophageal varices 15/152 (10%), gastric ulcer 8/152 (5%), Mallory Weiss tear 2/152 (1%). Endoscopic therapeutic intervention was required in 21/152 (14%). Six (4%) patients had a normal endoscopy. 38/152 (25%) patients were discharged within 24 hour. Only 1/38 (2.6%) patient was re-admitted within 30 days. Overall 30 day mortality was 20/152 (13%).  Conclusion  A dedicated inpatient endoscopy list can improve UGIB patient flow with a majority scoped within 24 hour and a quarter being discharged within 24 hour. Our rate was greater than reported by the NCEPOD audit. The timing of the list requires further validation as does the prospect of extending the service to achieve national recommendations.  Disclosure of Interest  None Declared
Characterization of the DNA ligase IV BRCT domains and their role in DNA double strand break repair
Authors: Chinonye C. Nnakwe, Karen Frank
Journal: Cancer Research (2004)

2656  DNA ligase IV (Lig4) is an indispensable component of the DNA double strand break repair pathway known as nonhomologous end-joining (NHEJ). Lig4 is also an indispensable component of V(D)J recombination, a process used to generate antigen-specific lymphocyte receptors. These pathways are essential for maintaining genomic integrity and developing a functional immune system. The overall goal of this project is to study the Lig4 BRCT (BRCA1 C-terminal) domains and their role in coordinating Lig4 activities with other components of the NHEJ complex. All homologs of Lig4 contain two BRCT domains; however their function has not yet been identified. BRCT domains are commonly found in proteins that participate in DNA damage repair and cell cycle signaling. Two recent studies identified a class of BRCT domains that interact with phosphorylated peptides and make phosphorylation-dependent protein interactions. BRCT domains share a common folding pattern despite their divergent sequence homology and phosphorylation is a key regulatory event in DNA damage signaling. This recent discovery may provide a link between DNA damage-induced phosphorylation and the function of BRCT domains. It has been shown that a Lig4 protein without BRCT domains can ligate DNA substrates in vitro yet cannot recombine substrates in vivo. To test the hypothesis that the Lig4 BRCT domains play an in vivo role in DNA end ligation, the Lig4 BRCT domains will be characterized in two projects. First, we are identifying residues critical to BRCT domain function by evaluating BRCT deletion and point mutants. Our point mutant design incorporated the use of comparative protein modeling to identify surface-exposed, structure-independent amino acids. Second, we are identifying interactions potentially made by the Lig4 BRCT domains within the NHEJ complex. DNA polymerase μ, γ-H2AX and additional NHEJ components will be assessed for their ability to interact with the Lig4 BRCT domains. Potential interactions will be analyzed using co-immunoprecipitation and immunofluorescence analysis. To characterize interactions, these assays will be performed using BRCT mutants to define critical residues, and using EtBr to assay for DNA dependence. Kinetics of the interaction will also be determined. Our findings will determine the function of the Lig4 BRCT domains and further define interactions between the multiple protein complexes involved in DNA double strand break repair. Our findings will also improve our understanding of mechanisms that result in the development of immunodeficiency syndromes and cancer formation in lymphoid and non-lymphoid cells.
Integrin-α3 Is a New Marker of Long-Term Hematopoietic Stem Cells in Ex Vivo Expanded Cells
Authors: Elisa Tomellini, Iman Fares, Bernhard Lehnertz, Jalila Chagraoui, Nadine Mayotte, Tara MacRae, Sophie Corneau, Guy Sauvageau
Journal: Blood (2018)
Antizyme inhibits N-nitrosomethylbenzylamine-induced mouse forestomach carcinogenesis in a p53-independent manner
Authors: David J. Feith, Louise Y.Y. Fong, Anthony E. Pegg
Journal: Cancer Research (2005)

3887  Esophageal squamous cell carcinoma (ESCC) can be modeled in mice using a zinc deficient (ZD) diet to induce hyperproliferation followed by a single dose of the carcinogen N-nitrosomethylbenzylamine (NMBA). Zinc deficiency is prevalent in geographic regions with high incidence of ESCC and environmental exposure to N-nitrosamines such as NMBA is also associated with increased risk for the disease. In the mouse ZD/NMBA model the primary region of tumor development is the forestomach, a stratified epithelium considered a dilation of the lower esophagus. p53 mutations are common in human ESCC and p53+/− or p53-/- animals subjected to ZD/NMBA carcinogenesis exhibit a greatly enhanced tumor induction and progression compared to wild-type mice. Antizyme (AZ) is a negative regulator of cellular polyamine levels that inhibits ornithine decarboxylase (ODC) activity, stimulates ODC degradation and suppresses exogenous polyamine uptake into the cell. Transgenic AZ expression from the keratin 5 promoter directs expression to the forestomach epithelium and protects mice from NMBA-induced forestomach carcinogenesis by reducing cell proliferation and stimulating apoptosis. To examine the ability of AZ to suppress tumor induction in ZD/NMBA-treated p53 mutant mice, four experimental groups (p53+/−, AZ/p53+/−, p53-/- and AZ/p53-/-; n=17 to 37 mice/group) were placed on a ZD diet (1.5 ppm) at four weeks of age and treated with a single intra-gastric dose of NMBA (2 mg/kg body weight) 25 days later. Mice were maintained on the ZD diet for 44 days, then sacrificed. On the p53+/− background, tumor incidence was 21% for AZ/p53+/− mice compared to 70% for p53+/− in the forestomach, and 39% compared to 81% in the squamocolumnar junction (SCJ) between the forestomach and glandular stomach. AZ/p53+/− mice developed 0.4 tumors/forestomach and 0.6 tumors/SCJ compared to 3.3 and 2.5, respectively, for p53+/− mice, which represents an 87% and 76% reduction in tumor multiplicity. While AZ/p53+/− mice exhibited a thin epithelium or slight thickening, the forestomach and SCJ of p53+/− mice was dramatically thickened. On the p53-/- background, only 65% of AZ/p53-/- animals had forestomach tumors and 76% had SCJ tumors while 100% of p53-/- mice had tumors in both regions. AZ/p53-/- mice developed 3.1 tumors/forestomach and 3.1 tumors/SCJ compared to p53-/- mice with 11.7 and 6.3, respectively. AZ/p53-/- mice had a thickened epithelium with mainly solitary tumors, whereas both regions were very thick with multiple fused tumors in p53-/- mice. Forestomach samples from all groups are being analyzed for proliferation and apoptosis markers by immunohistochemistry. These studies demonstrate that the tumor suppressive effects of AZ are not dependent on wild-type p53 function and support the concept of chemoprevention of ESCC through modulation of cellular polyamine content.
Polypectomy of a giant sessile polyp in the hepatic flexure using scissor-type forceps and a gravity traction method to create a pseudo-peduncle
Authors: Felipe Ramos-Zabala, Alejandra Alzina-Pérez, Jorge Vásquez-Guerrero, Marian García-Mayor, Ana Domínguez-Pino, Irene Rodríguez-Pérez, Luis Moreno-Almazán
Journal: Endoscopy (2019)

A 60-year-old man with abdominal discomfort was referred to our hospital. Abdominal computed tomography (CT) revealed a tumor in the hepatic flexure and colonoscopy showed a giant protruding polyp ([Fig. 1]). The biopsies were interpreted as adenoma with areas of high grade dysplasia.