tbuckley/cabot-search huggingface dataset:
Targeting Wee1 for the treatment of pediatric high-grade gliomas
Authors: Sabine Mueller, Rintaro Hashizume, Xiaodong Yang, Ilan Kolkowitz, Aleksandra K. Olow, Joanna Phillips, Ivan Smirnov, Maxwell W. Tom, Michael D. Prados, C. David James, Mitchel S. Berger, Nalin Gupta, Daphne A. Haas-Kogan
Journal: Neuro-Oncology (2013)

We investigated the efficacy of the Wee1 inhibitor MK-1775 in combination with radiation for the treatment of pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine gliomas (DIPGs).Gene expression analysis was performed for 38 primary pediatric gliomas (3 grade I, 10 grade II, 11 grade III, 14 grade IV) and 8 normal brain samples using the Agilent 4 × 44 K array. Clonogenic survival assays were carried out in pediatric and adult HGG cell lines (n = 6) to assess radiosensitizing effects of MK-1775. DNA repair capacity was evaluated by measuring protein levels of γ-H2AX, a marker of double strand DNA breaks. In vivo activity of MK-1775 with radiation was assessed in 2 distinct orthotopic engraftment models of pediatric HGG, including 1 derived from a genetically engineered mouse carrying a BRAF(V600E) mutation, and 1 xenograft model in which tumor cells were derived from a patient's DIPG.Wee1 is overexpressed in pediatric HGGs, with increasing expression positively correlated with malignancy (P = .007 for grade III + IV vs I + II) and markedly high expression in DIPG. Combination treatment of MK-1775 and radiation reduced clonogenic survival and increased expression of γ-H2AX to a greater extent than achieved by radiation alone. Finally, combined MK-1775 and radiation conferred greater survival benefit to mice bearing engrafted, orthotopic HGG and DIPG tumors, compared with treatment with radiation alone (BRAF(V600E) model P = .0061 and DIPG brainstem model P = .0163).Our results highlight MK-1775 as a promising new therapeutic agent for use in combination with radiation for the treatment of pediatric HGGs, including DIPG.
CADM1 Expression and Stepwise Downregulation of CD7 Are Closely Associated with Clonal Expansion of HTLV-I–Infected Cells in Adult T-cell Leukemia/Lymphoma
Authors: Seiichiro Kobayashi, Kazumi Nakano, Eri Watanabe, Tomohiro Ishigaki, Nobuhiro Ohno, Koichiro Yuji, Naoki Oyaizu, Satomi Asanuma, Makoto Yamagishi, Tadanori Yamochi, Nobukazu Watanabe, Arinobu Tojo, Toshiki Watanabe, Kaoru Uchimaru
Journal: Clinical Cancer Research (2014)

Cell adhesion molecule 1 (CADM1), initially identified as a tumor suppressor gene, has recently been reported to be ectopically expressed in primary adult T-cell leukemia-lymphoma (ATL) cells. We incorporated CADM1 into flow-cytometric analysis to reveal oncogenic mechanisms in human T-cell lymphotrophic virus type I (HTLV-I) infection by purifying cells from the intermediate stages of ATL development.We isolated CADM1- and CD7-expressing peripheral blood mononuclear cells of asymptomatic carriers and ATLs using multicolor flow cytometry. Fluorescence-activated cell sorted (FACS) subpopulations were subjected to clonal expansion and gene expression analysis.HTLV-I-infected cells were efficiently enriched in CADM1(+) subpopulations (D, CADM1(pos)CD7(dim) and N, CADM1(pos)CD7(neg)). Clonally expanding cells were detected exclusively in these subpopulations in asymptomatic carriers with high proviral load, suggesting that the appearance of D and N could be a surrogate marker of progression from asymptomatic carrier to early ATL. Further disease progression was accompanied by an increase in N with a reciprocal decrease in D, indicating clonal evolution from D to N. The gene expression profiles of D and N in asymptomatic carriers showed similarities to those of indolent ATLs, suggesting that these subpopulations represent premalignant cells. This is further supported by the molecular hallmarks of ATL, that is, drastic downregulation of miR-31 and upregulation of abnormal Helios transcripts.The CADM1 versus CD7 plot accurately reflects disease progression in HTLV-I infection, and CADM1(+) cells with downregulated CD7 in asymptomatic carriers have common properties with those in indolent ATLs.
FACTORS CONTROLLING SERUM γ-GLOBULIN CONCENTRATION
Authors: John L. Fahey, Alan G. Robinson
Journal: The Journal of Experimental Medicine (1963)

Both synthetic and catabolic processes determine the serum gamma-globulin level. The rate of gamma-globulin synthesis appears to be the primary factor determining the amount of serum gamma-globulin. Increase of gamma-globulin synthesis (as may occur following immunization or development of plasma cell tumor) elevates the serum gamma-globulin level. This, in turn, accelerates the fractional rate of gamma-globulin catabolism. The change in catabolic rate reduces the dimensions of the serum change from that which would occur if synthesis alone determined the serum gamma-globulin level. The present studies indicate the existence of a homeostatic mechanism controlling the rate of gamma-globulin catabolism. The mechanisms of gamma-globulin catabolism are specific and selective. Marked serum increase of other immunoglobulin components (beta(2A)-globulins and gamma(1)-macroglobulins) do not accelerate gamma-globulin catabolism. Similarly, serum albumin increases do not influence gamma-globulin catabolism. The site determining gamma-globulin catabolism is restricted to a part of the gamma-globulin molecule; i.e., on the F piece obtained by papain digestion and, by inference, on the H chains obtained by reduction and alkylation of gamma-globulin molecules.
Informed Decisions Regarding Microsatellite Instability Testing: Need for an Intention-to-Screen Analysis
Authors: Stefania Sciallero, Alberto Sobrero
Journal: Journal of Clinical Oncology (2010)

informed consent on microsatellite instability (MSI) testing in patients with colorectal cancer (CRC) who have suspected Lynch syndrome met the primary end point: a CD-ROM–assisted intervention had a positive impact on the education of patients. However, in our opinion, the authors’ conclusions on the secondary outcomes suffer from a substantial selection bias. They suggest that decisional and emotional distress were negligible among patients who accepted to be randomly assigned, which ignores that more than one third of patients denied participation in the study. Although this regards secondary end points, it is relevant for medical oncologists, because it pertains to daily practice. We think that the logical hierarchy of the issues related to advising patients with CRC about MSI testing is as follows: whether to do that; when to do that; who should do that; and how to do that. Testing for MSI is becoming more and more popular. Some experts suggest to perform universal MSI testing on all patients with newly diagnosed CRC, regardless of age and family history. 2 This is because regular surveillance is of clinical benefit for relatives at risk. 3 In contrast, the benefit of such testing for individual patients with CRC has not been definitively proven: the type of surgery and chemotherapy are the same for patients with sporadic and Lynch syndrome CRC, 4 but the follow-up may be different (ie, the issue of whether to do that). Mastering the clinical implications of MSI testing and sharing them with our patients constitute prohibitive challenges for the oncologists. The patients themselves, who often want to concentrate on the treatment of their cancer, present a challenge as well (ie, the issues of when and who). Recent guidelines and policy statements from both the United
Chloride/Bicarbonate Exchanger SLC26A7 Is Localized in Endosomes in Medullary Collecting Duct Cells and Is Targeted to the Basolateral Membrane in Hypertonicity and Potassium Depletion
Authors: Jie Xu, Roger T. Worrell, Hong C. Li, Sharon L. Barone, Snezana Petrovic, Hassane Amlal, Manoocher Soleimani
Journal: Journal of the American Society of Nephrology (2006)

SLC26A7 is a Cl(-)/HCO(3)(-) exchanger that is expressed on the basolateral membrane and in the cytoplasm of two distinct acid-secreting epithelial cells: The A-intercalated cells in the kidney outer medullary collecting duct and the gastric parietal cells. The intracellular localization of SLC26A7 suggests the possibility of trafficking between cell membrane and intracellular compartments. For testing this hypothesis, full-length human SLC26A7 cDNA was fused with green fluorescence protein and transiently expressed in MDCK epithelial cells. In monolayer cells in isotonic medium, SLC26A7 showed punctate distribution throughout the cytoplasm. However, in medium that was made hypertonic for 16 h, SLC26A7 was detected predominantly in the plasma membrane. The presence of mitogen-activated protein kinase inhibitors blocked the trafficking of SLC26A7 to the plasma membrane. Double-labeling studies demonstrated the localization of SLC26A7 to the transferrin receptor-positive endosomes. A chimera that was composed of the amino terminal fragment of SLC26A7 and the carboxyl terminal fragment of SLC26A1, and a C-terminal-truncated SLC26A7 were retained in the cytoplasm in hypertonicity. In separate studies, SLC26A7 showed predominant localization in plasma membrane in potassium-depleted isotonic medium (0.5 or 2 mEq/L KCl) versus cytoplasmic distribution in normal potassium isotonic medium (4 mEq/L). It is concluded that SLC26A7 is present in endosomes, and its targeting to the basolateral membrane is increased in hypertonicity and potassium depletion. The trafficking to the cell surface suggests novel functional upregulation of SLC26A7 in states that are associated with hypokalemia or increased medullary tonicity. Additional studies are needed to ascertain the role of SLC26A7 in enhanced bicarbonate absorption in outer medullary collecting duct in hypokalemia and in acid-base regulation in conditions that are associated with increased medullary tonicity.
Effects of a K <sup>+</sup> Channel Opener to Reduce Transmural Dispersion of Repolarization and Prevent Torsade de Pointes in LQT1, LQT2, and LQT3 Models of the Long-QT Syndrome
Authors: Wataru Shimizu, Charles Antzelevitch
Journal: Circulation (2000)

Background —This study examines the effects of nicorandil, a K + channel opener, on transmural dispersion of repolarization (TDR) and induction of torsade de pointes (TdP) under conditions mimicking the LQT1, LQT2, and LQT3 forms of the congenital long-QT syndrome (LQTS). Methods and Results —Transmembrane action potentials of epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle together with a transmural ECG. Chromanol 293B (30 μmol/L) was used to block I Ks (LQT1 model). Isoproterenol (50 to 100 nmol/L) was used to mimic an increase in β-adrenergic tone, d -sotalol (100 μmol/L) to block I Kr (LQT2 model), and ATX-II (20 nmol/L) to augment late I Na (LQT3 model). Isoproterenol+chromanol 293B, d -sotalol, and ATX-II produced preferential prolongation of the action potential duration at 90% repolarization (APD 90 ) of the M cell, an increase of TDR, and spontaneous as well as stimulation-induced TdP (LQT1, 3/6; LQT2, 3/6; LQT3, 5/6). Nicorandil (2 to 20 μmol/L) abbreviated the QT interval and APD 90 of the 3 cell types in the 3 models. High concentrations (10 to 20 μmol/L) completely reversed the effects of 293B±isoproterenol and those of d -sotalol to increase APD 90 and TDR and to induce TdP in LQT1 and LQT2 models. Nicorandil 20 μmol/L reversed only 50% of the effect of ATX-II and failed to completely suppress TdP in the LQT3 model (5/6 to 3/6). Conclusions —Our data suggest that K + channel openers may be capable of abbreviating the long QT interval, reducing TDR, and preventing spontaneous and stimulation-induced TdP when congenital or acquired LQTS is secondary to reduced I Kr or I Ks but less so when it is due to augmented late I Na .
Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS)
Authors: Annick Delvigne, Serge Rozenberg
Journal: Human Reproduction Update (2003)

The ovarian hyperstimulation syndrome (OHSS) is a rare iatrogenic complication of ovarian stimulation occurring during the luteal phase or during early pregnancy. This complication is unusual as it is not the consequence of a treatment which is vital or mandatory for the patient's health. Nevertheless, it can be accompanied by severe morbidity and may even be fatal. Data pertaining to the clinical course and consequences of OHSS in women and its treatment were searched using Medline, Current Contents and PubMed. To date, only a few studies have collected a large number of cases of OHSS. The clinical course of OHSS may involve, according to its severity and the occurrence of pregnancy, electrolytic imbalance, neurohormonal and haemodynamic changes, pulmonary manifestations, liver dysfunction, hypoglobulinaemia, febrile morbidity, thromboembolic phenomena, neurological manifestations and adnexal torsion. Treatment of the acute phase relies only on an empirical and symptomatic approach. The general approach will be adapted to the levels of severity. Specific approaches such as paracentesis, pleural puncture, surgical approach of OHSS and specific medication during OHSS were evaluated sporadically. More adequate treatment methods would require a better understanding of the underlying pathophysiological mechanisms, to promote an aetiological therapeutic approach. Properly conducted studies, including large numbers of patients are required in order to determine the best method of prevention and management.
Prospective Trial of Synchronous Bevacizumab, Erlotinib, and Concurrent Chemoradiation in Locally Advanced Head and Neck Cancer
Authors: David S. Yoo, John P. Kirkpatrick, Oana Craciunescu, Gloria Broadwater, Bercedis L. Peterson, Madeline D. Carroll, Robert Clough, James R. MacFall, Jenny Hoang, Richard L. Scher, Ramon M. Esclamado, Frank R. Dunphy, Neal E. Ready, David M. Brizel
Journal: Clinical Cancer Research (2012)

We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC).Newly diagnosed patients with stage III/IV HNC received a 2-week lead-in of bevacizumab and/or erlotinib, followed by both agents with concurrent cisplatin and twice daily radiotherapy. Safety was assessed using Common Toxicity Criteria version 3.0. The primary efficacy endpoint was clinical complete response (CR) rate after CRT.Twenty-nine patients enrolled on study, with 27 completing therapy. Common grade III toxicities were mucositis (n = 14), dysphagia (n = 8), dehydration (n = 7), osteoradionecrosis (n = 3), and soft tissue necrosis (n = 2). Feeding tube placement was required in 79% but no patient remained dependent at 12-month posttreatment. Clinical CR after CRT was 96% [95% confidence interval (CI), 82%-100%]. Median follow-up was 46 months in survivors, with 3-year locoregional control and distant metastasis-free survival rates of 85% and 93%. Three-year estimated progression-free survival, disease-specific survival, and overall survival rates were 82%, 89%, and 86%, respectively. Dynamic contrast enhanced MRI (DCE-MRI) analysis showed that patients who had failed had lower baseline pretreatment median K(trans) values, with subsequent increases after lead-in therapy and 1 week of CRT. Patients who did not fail had higher median K(trans) values that decreased during therapy.Dual VEGF/EGFR inhibition can be integrated with CRT in locally advanced HNC, with efficacy that compares favorably with historical controls albeit with an increased risk of osteoradionecrosis. Pretreatment and early DCE-MRI may prospectively identify patients at high risk of failure.
Plasma membrane vesicles decorated with glycolipid-anchored antigens and adjuvants via protein transfer as an antigen delivery platform for inhibition of tumor growth
Authors: Jaina M. Patel, Vincent F. Vartabedian, Erica N. Bozeman, Brianne E. Caoyonan, Sanjay Srivatsan, Christopher D. Pack, Paulami Dey, Martin J. D'Souza, Lily Yang, Periasamy Selvaraj
Journal: Biomaterials (2015)
Spontaneous Human Adult Stem Cell Transformation
Authors: Daniel Rubio, Javier Garcia-Castro, María C. Martín, Ricardo de la Fuente, Juan C. Cigudosa, Alison C. Lloyd, Antonio Bernad
Journal: Cancer Research (2005)

Human adult stem cells are being evaluated widely for various therapeutic approaches. Several recent clinical trials have reported their safety, showing them to be highly resistant to transformation. The clear similarities between stem cell and cancer stem cell genetic programs are nonetheless the basis of a recent proposal that some cancer stem cells could derive from human adult stem cells. Here we show that although they can be managed safely during the standard ex vivo expansion period (6-8 weeks), human mesenchymal stem cells can undergo spontaneous transformation following long-term in vitro culture (4-5 months). This is the first report of spontaneous transformation of human adult stem cells, supporting the hypothesis of cancer stem cell origin. Our findings indicate the importance of biosafety studies of mesenchymal stem cell biology to efficiently exploit their full clinical therapeutic potential.
Induction of specific immune unresponsiveness with purified mixed leukocyte culture-activated T lymphoblasts as autoimmunogen. III. Proof for the existence of autoanti-idiotypic killer T cells and transfer of suppression to normal syngeneic recipients by T or B lymphocytes.
Authors: H Binz, H Wigzell
Journal: The Journal of Experimental Medicine (1978)

Specific immune unresponsiveness against a given set of histocompatibility antigens can be induced by immunization with autologous, antigen-specific T lymphoblasts. Such unresponsiveness can be transferred by lymphoid cells from autoblast-immunized donors to normal syngeneic recipients. The cells being most efficient in transferring the selective suppression are T lymphocytes from the spleen, especially if of Ly 1-2+3+ phenotype. By using such T lymphocytes we deem it likely that the actual underlying mechanism is one of actual transfer of autoanti-idiotypic killer T cells. In support for this view is the fact that such T cells endowed with exquisite specific, cytolytic reactivity towards autologous idiotype-positive T target cells exist in autoblast immune animals. Significant suppression may also be transferred with T cells of Ly 1+2-3- phenotype or with B cells. Here, we consider the suppressive mechanism to be one of production of autoanti-idiotypic antibodies. By using affinity fraction procedures, it was finally possible to prove that all T-cell suppressive activity resides in a population with true antigen-binding-specific receptors for the relevant idiotypes.
Can a Metastatic Gene Expression Profile Outperform Tumor Size as a Predictor of Occult Lymph Node Metastasis in Oral Cancer Patients?
Authors: Eduardo Méndez, Pawadee Lohavanichbutr, Wenhong Fan, John R. Houck, Tessa C. Rue, David R. Doody, Neal D. Futran, Melissa P. Upton, Bevan Yueh, Lue Ping Zhao, Stephen M. Schwartz, Chu Chen
Journal: Clinical Cancer Research (2011)

To determine the differential gene expression between oral squamous cell carcinoma (OSCC) with and without metastasis to cervical lymph nodes and to assess prediction of nodal metastasis by using molecular features.We used Affymetrix U133 2.0 plus arrays to compare the tumor genome-wide gene expression of 73 node-positive OSCCs with 40 node-negative OSCCs (≥ 18 months). Multivariate linear regression was used to estimate the association between gene expression and nodal metastasis. Stepwise logistic regression and receiver operating characteristics (ROC) analysis were used to generate predictive models and to compare these with models by using tumor size alone.We identified five genes differentially expressed between node-positive and node-negative OSCCs after adjusting for tumor size and human papillomavirus status: REEP1, RNF145, CTONG2002744, MYO5A, and FBXO32. Stepwise regression identified a four-gene model (MYO5A, RFN145, FBXO32, and CTONG2002744) as the most predictive of nodal metastasis. A leave-one-out ROC analysis revealed that our model had a higher area under the curve (AUC) for identifying occult nodal metastasis compared with that of a model by tumor size alone (respective AUC: 0.85 and 0.61; P = 0.011). A model combining tumor size and gene expression did not further improve the prediction of occult metastasis. Independent validation using 31 metastatic and 13 nonmetastatic cases revealed a significant underexpression of CTONG2002744 (P = 0.0004).These results suggest that our gene expression markers of OSCC metastasis hold promise for improving current clinical practice. Confirmation by others and functional studies of CTONG2002744 is warranted.
Gln27Glu and Arg16Gly polymorphisms of the β2-adrenergic receptor gene are not associated with obesity in Japanese men
Authors: Tetsuo Hayakawa, Yukihiro Nagai, Toshio Kahara, Haruhisa Yamashita, Toshinari Takamura, Toshio Abe, Gakuji Nomura, Ken-ichi Kobayashi
Journal: Metabolism (2000)
Intravitreal triamcinolone acetonide for refractory diabetic macular oedema
Authors: A. I Fernando
Journal: Journal of the Royal Society of Medicine (2005)

Diabetic macular oedema is caused by hyperpermeability of the retinal vasculature and results in retinal thickening due to intraretinal fluid accumulation between the inner and outer plexiform layers. The Early Treatment Diabetic Retinopathy Study defined clinically significant macular oedema (CSMO) by the presence of one or more of the following: retinal thickening at or within 500 mm of the centre of the macula; hard exudates at or within 500 m mo f the macular centre, if associated with adjacent retinal thickening; retinal thickening greater than or equal to one disc area, any part of which is within one disc diameter of the centre of the macular centre.1 Focal argon laser photocoagulation is beneficial in non-ischaemic CSMO but less so in diffuse macular oedema.2 A treatment now used for macular oedema in various diseases is intravitreal triamcinolone acetonide.