tbuckley/cabot-search huggingface dataset:
Design of inhibitors of the protein tyrosine phosphatase Shp2 as novel anticancer agents
Authors: Harshani Lawrence, Roberta Pireddu, Liwei Chen, Yunting Luo, Shen-shu Sung, Richard Yip, Wayne Guida, Said Sebti, Jie Wu, Nicholas Lawrence
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

1307 

Shp2, encoded by PTPN11 gene, is a protein tyrosine phosphatase (PTP) that mediates growth factor- and cytokine-stimulated cellular activities essential for oncogenesis. It is a positive regulator of Src family kinases (SFKs), Ras, and Erk MAP kinases. Shp2 mutations have been found in juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, and solid tumors such as neuroblastoma, lung cancer, colon cancer, and melanoma. In particular, PTPN11 is the most frequently mutated gene in JMML, accounting for 35-50% of cases. All Shp2 mutations found in human malignancies are gain-of-function mutations, resulting in constitutively active Shp2. Thus, Shp2 PTP is an important target for new cancer therapy.    The structure of the Shp2 phosphatase has been determined by X-ray crystallography at 2.0 A resolution. Shp2 contains two Src homology-2 (SH2) domains (N-SH2, C-SH2) at its N-terminal region. In the absence of a tyrosine-phosphorylated binding partner, the N-SH2 domain blocks the catalytic domain until the upstream signaling effectors bind to Shp2. Consequently, Shp2 is basally inactive due to autoinhibition and inhibition of Shp2 by a small molecule is not predicted to affect resting cells, making it an attractive target for drug design. A challenge of this approach is the design of a small molecule that does not bind to the phosphotyrosine binding sites that control the dynamic (on/off) binding of the N-SH2 domain to the PTP pocket.    Screening of a small library has led to the identification of an inhibitor of the signaling protein tyrosine phosphatase (PTP) Shp2. A focused library was designed incorporating the isatin scaffold was screened for Shp2 and Shp1 activity. Several compounds were identified that selectively inhibit Shp2 with low to sub-micromolar activity. A model for the selective binding of the active compounds will be presented.
Guidelines for the management of aneurysmal subarachnoid hemorrhage. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association.
Authors: M R Mayberg, H H Batjer, R Dacey, M Diringer, E C Haley, R C Heros, L L Sternau, J Torner, H P Adams, W Feinberg
Journal: Circulation (1994)
Subepidermal Calcified Nodule in the Periocular Region: A Report of 6 Cases
Authors: Carol L. Shields, Molly R. Marous, Mairghread G. Casey, Alexzandra M. Douglass, Chloe T.L. Khoo, Jurij R. Bilyk, Jerry A. Shields, Ralph C. Eagle
Journal: Ophthalmology (2015)
Helicobacter Pylori and Gastroduodenal Disease
Authors: T L Cover, M J Blaser
Journal: Annual Review of Medicine (1992)

Helicobacter pylori infection is now recognized as the primary cause of active chronic gastritis in humans. Most infected persons remain asymptomatic, but are at increased risk for the development of peptic ulcer disease and possibly gastric cancer. The pathogenesis of this infection is not well understood, but motility and urease activity are virulence factors in an animal model. The eradication of H. pylori infection is associated with resolution of gastritis and a decreased rate of duodenal ulcer recurrence.
Blood coagulation during adjuvant epirubicin/cyclophosphamide chemotherapy in patients with primary operable breast cancer.
Authors: G F von Tempelhoff, M Dietrich, G Hommel, L Heilmann
Journal: Journal of Clinical Oncology (1996)

Influences of adjuvant epirubicin/cyclophosphamide (EC) chemotherapy on blood coagulation were investigated in patients with operable breast cancer and the incidence of thromboembolic events was recorded.In 50 consecutive node-positive breast cancer patients, serial coagulation studies (fibrinogen method of Clauss, antithrombin III, protein C amidolytic methods, D dimer enzyme-linked immunoadsorbent assay [ELISA] techniques, and plasminogen activator inhibitor [PAI] activity u-PA inhibition test) and impedance plethysmography (IPG) for screening of deep vein thrombosis (DVT) were performed preoperatively and postoperatively, before each of six cycles of adjuvant chemotherapy (60 mg/m2 epirubicin and 600 mg/m2 cyclophosphamide) and 3 months thereafter. Seventy-two healthy women served as controls.During chemotherapy, the phlebographically proven DVT incidence was 10% (n = 2 after second cycle; n = 3 after third cycle). Preoperative levels of D-dimer, fibrinogen, and the PAI activity were significantly higher than in healthy women and only mean levels of the D-dimer were significantly higher in patients with DVT compared with patients without DVT. Postoperatively, only D-dimer and fibrinogen levels significantly increased, while in the course of chemotherapy, these levels were significantly decreased. Mean D-dimer levels and PAI increased steadily in patients with DVT. Preoperatively and during chemotherapy, levels of antithrombin III and protein C were within the normal range. Only one patient with DVT had decreased protein C levels throughout chemotherapy.Monitoring with sophisticated coagulation tests during adjuvant EC chemotherapy for breast cancer does not identify patients at higher risk for DVT development. Preoperatively, in patients with later DVT, an imbalance of hemostasis is already present; thus, thrombosis might predominantly be initiated by malignancy-induced hypercoagulability and secondarily by the influence of EC chemotherapy. Prospective randomized trials must determine whether prophylactic anticoagulation during EC chemotherapy reduces the incidence of DVT.
Data mining in gene expression datasets reveals new potential loops of signaling in ovarian cancer
Authors: Castellano Giancarlo, James F. Reid, Antonella Tomassetti, Silvana Canevari
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1561 

Recent technological developments that enable simultaneous measurement of many parameters (“omic” approaches) hold the promise of identifying new molecular prognostic and predictive markers. Accordingly the field of functional genomics has progressed rapidly due in large part to the development of microarray technology. We applied and implemented an algorithm for extracting information from the published gene expression microarray datasets. The approach is based on the hypothesis that gene products involved in the same biological process would be coupled at transcriptional level and was applied to the identification of correlated gene expression of ligands and receptors, as possible activators of signaling in ovarian cancer. By using, as resources, the Database of Ligand-Receptor Patterns (DLRP), the Human Protein Reference Database and PubMed, and selecting proteins whose interaction is at the cell surface we compiled a list of 535 ligand-receptor (L-R) pairs. For each pair, gene expression profiles were extracted from eight microarray ovarian cancer datasets and the Pearson correlation coefficient was calculated. Eighty-four L-R pairs showed a statistically significant correlation, after Bonferroni correction, in at least one dataset, and 12 were significantly correlated in 3 or more datasets. L-R pairs, previously implicated in ovarian cancer signaling, such as the colony-stimulating factor 1 (CSF1) ligand and its receptor (CSF1R), the hepatocyte growth factor (HGF) ligand and its receptor (MET) and the plasminogen activator urokinase (PLAU) ligand and its receptor (PLAUR), significantly correlated in 3/5, 6/6 and 5/7 datasets respectively, thus demonstrating the validity of this approach. Beside that, new L-R pairs were identified as potentially implicated in signaling in EOC. Subsequently, we calculated the correlation coefficients in patient samples subdivided according to the survival length. This analysis extracted four L-R pairs with significantly correlated gene expression patterns in two out of three datasets. One of L-R pairs, associated with short-term survival, is involved in motility and angiogenesis. The coordinated expression of this L-R was analyzed by western blot and immunohistochemistry using in vitro cell lines and surgical specimens from ovarian cancer. In conclusion, this study highlights the feasibility of analyzing large scale gene expression data to identify L-R signaling loops in ovarian cancer and, once supported and validated by biological assays, opens the way to the design of specifically targeted new diagnostic and therapeutic tools.
Phase II diaziquone-based chemotherapy trials in patients with anaplastic supratentorial astrocytic neoplasms.
Authors: S C Schold, M S Mahaley, N A Vick, H S Friedman, P C Burger, E R DeLong, R E Albright, D E Bullard, J D Khandekar, J G Cairncross
Journal: Journal of Clinical Oncology (1987)

We treated 103 patients with histologically confirmed anaplastic supratentorial astrocytic neoplasms with either diaziquone (AZQ) and carmustine (BCNU) or AZQ and procarbazine. There were 74 patients with glioblastoma multiforme (GBM) and 29 patients with anaplastic astrocytoma (AA). AZQ plus BCNU produced partial (PR) or unequivocal responses in seven of 32 (21.9%) patients with GBMs and three of ten (30%) patients with AAs. Two patients with GBMs (6.3%) and five patients with AAs (50%) showed stable disease (SD). AZQ plus procarbazine produced PRs or unequivocal responses in five of 42 (11.9%) patients with GBMs and nine of 19 (47.4%) patients with AAs. Eight patients with GBMs (19%) and one patient with an AA (5.2%) showed SD. In addition to histologic diagnosis, only the Karnofsky performance-status (KPS) rating independently influenced response and survival. Differences in response rates between the two regimens were not significant, although estimated median survival after adjusting for performance status was slightly better with AZQ plus BCNU than with AZQ plus procarbazine (P = .031). Neither age nor prior chemotherapy were significant independent risk factors. Toxicity was mild and primarily hematologic. We conclude that these AZQ-based regimens have activity in patients with recurrent anaplastic gliomas, but that they are not clearly superior to other agents in current use. The histologic diagnosis of GBM is associated with a significantly worse prognosis than AA, and we believe that this important distinction must be recognized in phase II as well as phase III trials.
Molecular Imaging of the Chemokine Receptor CXCR4 After Acute Myocardial Infarction
Authors: James T. Thackeray, Thorsten Derlin, Arash Haghikia, L. Christian Napp, Yong Wang, Tobias L. Ross, Andreas Schäfer, Jochen Tillmanns, Hans J. Wester, Kai C. Wollert, Johann Bauersachs, Frank M. Bengel
Journal: JACC. Cardiovascular imaging (2015)
Epidermal necrolysis: 60 years of errors and advances
Authors: Y.K. Heng, H.Y. Lee, J.-C. Roujeau
Journal: British Journal of Dermatology (2015)

Journal Article Epidermal necrolysis: 60 years of errors and advances Get access Y.K. Heng, Y.K. Heng National Skin Centre 1 Mandalay Road Singapore 308205 Correspondence Yee Kiat Heng. E‐mail: ykheng@nsc.gov.sg Search for other works by this author on: Oxford Academic Google Scholar H.Y. Lee, H.Y. Lee Department of Dermatology Singapore General Hospital Singapore Search for other works by this author on: Oxford Academic Google Scholar J.‐C. Roujeau J.‐C. Roujeau Université Paris Est Créteil Créteil France Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 173, Issue 5, 1 November 2015, Pages 1250–1254, https://doi.org/10.1111/bjd.13989 Published: 01 November 2015
Abstract 9736: Identification of Phenotypes at Risk of Transition from Systo-Diastolic Hypertension to Isolated Systolic Hypertension
Authors: Raffaele Izzo, Giovanni De Simone, Marina De Marco, Renata Giudice, Teresa Migliore, Valentina Trimarco, Gianni Luigi Iovino, Bruno Trimarco, Nicola De Luca
Journal: Circulation (2011)

Background: Isolated Systolic Hypertension (ISH) is the most frequent subtype of uncontrolled hypertension in elderly patients and is associated with high cardiovascular (CV) risk. Little is known about the natural evolution towards this type of hypertension and the CV phenotype associated with its appearance. Aim of the present study was to detect predictors of evolution towards ISH in subjects with initial systo-diastolic hypertension (SDH). Methods: 6,027 individuals with SDH (age 53±11 years, 57% men, systolic blood pressure [SBP] 159±21, diastolic blood pressure [DBP] 99±10), without prevalent CV disease, MDRD-estimated glomerular filtrate ratio (eGFR)&gt;30mL/mmHg/1.73 m2 , and with at least 6 month-follow up were selected from the CampaniaSalute registry. Echocardiography and carotid ultrasound were performed. The diagnosis of ISH was made at the end of follow up according to the ESH/ESC and JNCVII Guidelines (SBP ≥140 mmHg with DBP&lt;90 mmHg). Results: After a mean follow up period of 55±44 months, 19% of the study population exhibited ISH (n=1122). Patients with ISH were older, more often women and more often diabetic, and exhibited higher initial SBP, HDL-cholesterol, left ventricular (LV) mass, relative wall thickness, pulse pressure/stroke index ratio (PP/SVi), more severe carotid atherosclerosis and lower values of eGFR (all p&lt;0.001). These differences were studied using a multivariate proportional hazard model (Cox) including all variables that were found different at the descriptive analysis. Presence of ISH at follow up was independently predicted by older age (p&lt;0.0001; HR=1.20/5 years; CI=1.12-1.28), female gender (p&lt;0.004; HR=1.22; CI=1.06-1.40), baseline higher LV mass index (p=0.04;HR=1.04/5g*m-2.7; CI=1.01-1.05), higher carotid intima-media thickness (p=0.02; HR=1.12/mm; CI=1.02-1.22) and higher PP/SVi (p&lt;0.0001;HR=1.35/Unit); CI=1.23-1.48). Conclusion: Factors influencing the transition from SDH to ISH are older age, female gender and signs of CV target organ damage. Thus, a prompt and aggressive therapy for arterial hypertension before the onset of target organ damage appears desirable to help lowering the prevalence of ISH especially in elderly female patients.
<i>In vivo</i> single human sweat gland activity monitoring using coherent anti-Stokes Raman scattering and two-photon excited autofluorescence microscopy
Authors: X. Chen, P. Gasecka, F. Formanek, J.-B. Galey, H. Rigneault
Journal: British Journal of Dermatology (2015)

Eccrine sweat secretion is of central importance for control of body temperature. Although the incidence of sweat gland dysfunction might appear of minor importance, it can be a real concern for people with either hypohidrosis or hyperhidrosis. However, sweat gland function remains relatively poorly explored.To investigate the function of single human sweat glands.We describe a new approach for noninvasive imaging of single sweat gland activity in human palms in vivo up to a depth of 100 μm, based on nonlinear two-photon excited autofluorescence (TPEF) and coherent anti-Stokes Raman scattering (CARS).These techniques appear to be useful compared with approaches already described for imaging single sweat gland activity, as they allow better three-dimensional spatial resolution of sweat pore inner morphology and real-time monitoring of individual sweat events. By filling the sweat pore with oil and tuning the CARS contrast at 2845 cm(-1) , we imaged the ejection of sweat droplets from a single sweat gland when oil is pushed out by sweat flow. On average, sweat events lasted for about 30 s every 3 min under the conditions studied. On the other hand, about 20% of sweat glands were found inactive. TPEF and CARS were also used to study, at the single pore level, the antiperspirant action of aluminium chlorohydrate (ACH) and to reveal, for the first time in vivo, the formation of a plug at the pore entrance, in agreement with reported ACH antiperspirant mechanisms.Although data were acquired on human palms, these techniques show great promise for a better understanding of sweat secretion physiology and should be helpful to improve the efficacy of antiperspirant formulations.
Salvage chemotherapy with paclitaxel for recurrent primary brain tumors.
Authors: M C Chamberlain, P Kormanik
Journal: Journal of Clinical Oncology (1995)

PURPOSE To assess the safety and efficacy of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) given at a dose of 175 mg/m2 every 3 weeks as a 3- to 4-hour outpatient infusion to patients with recurrent malignant primary brain tumors who had received prior radiotherapy and at least one chemotherapy regimen containing nitrosoureas and who were no longer responding to therapy. PATIENTS AND METHODS Twenty patients (12 men and eight women), ages 19 to 69 years (median, 35), with recurrent primary brain tumors were treated according to a phase II protocol with intravenous Taxol. Tumor histologies included the following: anaplastic astrocytoma (n = 8), glioblastoma multiforme (n = 8), and anaplastic oligodendroglioma (n = 4). All patients had been previously treated with subtotal resection, limited-field radiotherapy (median dose, 60 Gy; range, 54 to 78 Gy), and nitrosourea-based chemotherapy. Taxol was administered intravenously at a dose of 175 mg/m2/d every 3 weeks with neurologic and neuroradiographic evaluation every 8 to 9 weeks. Complete blood cell counts were performed weekly. RESULTS A median of six cycles of Taxol (range, two to 12) were administered to 20 assessable patients. Toxicities included partial alopecia (n = 10), thrombocytopenia (n = 4), rate of Taxol administration-dependent bradycardia (n = 3), and nondisabling peripheral neuropathy (n = 1). No patient developed neutropenic fever or sepsis or required cytokine support. Two patients required blood-product support (platelet transfusions in both). Four patients (20%) demonstrated a partial response (PR) and seven (35%) had stable disease (SD) for a total response plus SD rate of 55%. The median time to tumor progression was 6 months (range, 2 to 20). CONCLUSION Taxol demonstrated modest efficacy with minimal toxicity in this heavily pretreated cohort of young patients with recurrent primary brain tumors.
Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma
Authors: Jennifer R. Devlin, Katherine M. Hannan, Nadine Hein, Carleen Cullinane, Eric Kusnadi, Pui Yee Ng, Amee J. George, Jake Shortt, Megan J. Bywater, Gretchen Poortinga, Elaine Sanij, Jian Kang, Denis Drygin, Sean O'Brien, Ricky W. Johnstone, Grant A. McArthur, Ross D. Hannan, Richard B. Pearson
Journal: Cancer Discovery (2015)

Abstract Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I–mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K–AKT–mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYC-driven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma–bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. Significance: Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma–bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov; 6(1); 59–70. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 1
The Pathobiology of Campylobacter Infections in Humans
Authors: T L Cover, M J Blaser
Journal: Annual Review of Medicine (1989)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Carbohydrates and Carbohydrate-Binding Proteins in the Nervous System
Authors: T M Jessell, M A Hynes, J Dodd
Journal: Annual Review of Neuroscience (1990)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Effect of calcium channel blockers on human CFU-GM with cytotoxic drugs.
Authors: R L Fine, S Koizumi, G A Curt, B A Chabner
Journal: Journal of Clinical Oncology (1987)

Calcium channel blockers (CCBs) such as verapamil and nitrendipine are capable of increasing drug sensitivity in resistant murine and human tumor cells. This finding has potential value in the treatment of acquired drug resistance in human malignancies. Thus, we tested the ability of CCBs of two different structural classes to enhance the toxicity of doxorubicin (DOX), vinblastine (VBL), and vincristine (VCR) for normal myeloid and macrophage colony formation (marrow colony forming units-granulocyte-monocyte [CFU-GM]). Drug effects on colony formation from 35 normal volunteer marrows and from seven patient marrows in the recovery phase after cytotoxic chemotherapy were determined. No enhancement of toxicity was mediated by verapamil or nitrendipine when these drugs were co-incubated with the cytotoxic drugs for one hour or 24 hours before plating marrow cells in a semisolid agar system.
Phase I trial of misonidazole (NSC#261037) plus cyclophosphamide in solid tumors.
Authors: E Davila, L Klein, C L Vogel, R Johnson, F Ostroy, S Browning, E Gorowski, R L Furner, C A Presant
Journal: Journal of Clinical Oncology (1985)

Misonidazole, a hypoxic cell sensitizer, enhances the antitumor effects of cyclophosphamide in preclinical studies. Several studies also showed increased cytotoxicity for normal tissues. We undertook a phase I study of this combination. The regimen consisted of oral administration of misonidazole at one of two dose levels, 1 g/m2 and 2 g/m2, followed by an intravenous (IV) injection of cyclophosphamide four hours later. The cycle was repeated every twenty-one days. The dose of misonidazole remained constant for each regimen, but the dose of cyclophosphamide ranged from 0.4 g/m2 to 1.3 g/m2. Thirty-eight trials in 35 patients with advanced solid tumors were considered evaluable. Dose-limiting toxicity was granulocytopenia at 1 g/m2 of cyclophosphamide without significant thrombocytopenia or anemia. Peripheral neuropathy was negligible. Two patients received cumulative doses of 8 and 16 g/m2 of misonidazole without neurotoxicity. One patient developed hemorrhagic cystitis. Nausea and vomiting was mild to moderate. Possible evidence of tumor stabilization was seen in three patients, and one patient had a mixed response. The mean serum half-life for misonidazole was 11.3 hours (range, 8.4 to 20.0) and for cyclophosphamide 8.3 hours (range, 3.2 to 15.5), both within the previously reported ranges. In conclusion, it appears that this combination is well tolerated and that misonidazole does not significantly potentiate myelotoxicity caused by cyclophosphamide or alter its pharmacokinetics. The recommended starting doses for misonidazole and cyclophosphamide in phase II trials using this schedule of administration should be 2 g/m2 and 1 g/m2, respectively, with escalation for cyclophosphamide to individual tolerance.