tbuckley/cabot-search huggingface dataset:
Delivery of Therapeutics Targeting the mRNA-Binding Protein HuR Using 3DNA Nanocarriers Suppresses Ovarian Tumor Growth
Authors: Yu-Hung Huang, Weidan Peng, Narumi Furuuchi, Jacquelyn Gerhart, Kelly Rhodes, Neelanjan Mukherjee, Masaya Jimbo, Gregory E. Gonye, Jonathan R. Brody, Robert C. Getts, Janet A. Sawicki
Journal: Cancer Research (2016)

Abstract Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumor-targeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined siRNAs against HuR with FA-3DNA and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumor–bearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo–targeted delivery of a cancer therapeutic and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer. Cancer Res; 76(6); 1549–59. ©2016 AACR.
Social adjustment profiles of female drivers involved in fatal and nonfatal accidents
Authors: J W Shaffer, C W Schmidt, H I Zlotowitz, R S Fisher
Journal: American Journal of Psychiatry (1977)

Previous research by the authors has shown that male drivers involved in fatal and nonfatal accidents can be differentiated from the general population on the basis of background, behavior, and social adjustment. The results of the present study suggest that female drivers involved in serious crashes do not differ from the overall female driving population.
PROCEEDINGS OF THE TWENTY-FOURTH ANNUAL MEETING OF THE AMERICAN SOCIETY FOR CLINICAL INVESTIGATION HELD IN ATLANTIC CITY, N. J., MAY 2, 1932
Journal: Journal of Clinical Investigation (1932)

The result of five years experience of studying normal and abnormal blood by dark field illumination is given.Comparison is made of this method with that which employs supra-vital stains.Mature and immature leukocytes, as well as red blood cells, are described as viewed by dark field illumination.We believe most, if not all, circulating blood cells can be recognized in the dark field and that an accurate impression of haematological disturbances can be ar- rived at by studying fresh blood in the dark field.It is also a great help in recognizing malaria parasites with ease.The simplicity of this method, as well as the fact that it is not dependent upon dyes and staining technique, should make it available for office practice.Slides of dark field drawings are shown.Iron Metabolism Studies.By PAUL REZNIKOFF, New York, N. Y.The intake and output of iron were studied by the Elvehjem-Kennedy method in two subjects, one normal and one suffering from polycythemia vera, over a period of 8 months and blood counts were followed.Both subjects approached balance on diets ranging from 10 to 20 mgm.iron daily.The normal individual stored iron when given parenteral liver extract, when fed a "secondary'" extract, and when given 60 mgm.iron as iron am- monium citrate (the equivalent of the iron content of the latter extract).Later in the study neither high iron intake, parenteral liver, nor copper sulphate caused any storing of iron.No definite correlation was found between red blood count, hemoglobin and iron balance in this normal individual.The polycythemic patient showed little response to Fowler's solution or x-ray therapy.Phenylhydrazine caused a fall of erythocyte count from six to three million and of hemoglobin from one hundred to fifty-five per cent, but very little coincident excretion of iron.These studies, therefore, indicate that the body can store iron for long periods (382.8 mgm. in 7 months) without use by the hematopoietic system, or, in case of erythrocyte depression (852.4 mgm. in 7 months), without excretion, and this work also suggests that iron metabolism should be studied by tissue analysis.Treatment of Polycythemia Vera wpith Solution of Potassium Arsenite.By CLAUDE E. FORKNER (introduced by C. S. Keefer), Boston, Mass.Arsenic has been used for many years in the treatment of anemia and has been considered an agent favoring regeneration of erythrocytes and hemoglobin.The use of arsenic in polycythemia vera has been reported as either contra- indicated or of no value.Turk in 1904, from the result of treating one case with Fowler's solution, concluded the drug was of value.In his case the erythrocyte count was reduced from 9,000,000 to 7,000,000 cells per cu.mm.
Abstract 15274: High-Throughput, Genome-Wide siRNA Screening Identifies Novel Genes Regulating AAV Transduction of Cardiomyocytes and Other Post-Mitotic Cells
Authors: Miguel Mano, Jasmina Lovric, Rudy Ippodrino, Lorena Zentilin, Serena Zacchigna, Mauro Giacca
Journal: Circulation (2012)

Viral vectors based on AAV have gained popularity for cardiovascular gene transfer due to their safety profile, lack of inflammatory response, prolonged transgene expression, relative genetic simplicity and high efficiency of transduction of post-mitotic tissues, such as muscle, heart, brain and retina. Given the molecular simplicity of AAV particles, the determinants of permissivity to vector transduction appear to reside within the host cell. We assessed the hypothesis that the cellular proteins of the DNA Damage Response (DDR) are key players in controlling AAV permissivity and further extended our investigation by performing a high-throughput screening (HTS). We observed that cardiomyocyte and skeletal muscle permissivity to AAV transduction correlates with the loss of expression of Mre11, Rad50 and Nbs1 (the MRN complex), which are downregulated upon terminal cell differentiation. In particular, the levels of these proteins, which bind the incoming AAV genomes and block its processing, fades in cardiomyocytes at 2 weeks after birth, coinciding with increased AAV permissivity. Accordingly, in vivo treatment of relatively poorly permissive tissues with siRNAs against members of MRN markedly increases AAV permissivity. To systematically identify novel cell factors involved in AAV internalization, intracellular trafficking, genome processing and gene expression, we performed a HTS using a genome-wide siRNA library (18,175 human gene targets) using a recombinant ssAAV2 vector expressing the firefly luciferase reporter gene. We identified 1528 genes that affect transduction of AAV vectors more than 4-fold (184 genes by more than 8-fold). Of these genes, 993 are inhibitors of AAV transduction, whereas 535 are required for efficient transduction by AAV vectors. Analysis of the inhibitor genes revealed a clear overrepresentation of genes related to DNA recombination and repair and cell cycle control. Of note, the top 10 siRNAs also significantly increased AAV transduction by other serotypes (e.g. AAV1, AAV5, AAV6, AAV9) and in various cell types in cell culture and in vivo. In conclusion, these results indicate that the transient inhibition of cellular factors repressing AAV transduction in vivo can be exploited to extend vector efficacy.
A phase II trial of gefitinib in combination with 5-FU/LV/irinotecan in patients with colorectal cancer
Authors: M. Redlinger, A. Kramer, K. Flaherty, W. Sun, D. Haller, P. J. O'Dwyer
Journal: Journal of Clinical Oncology (2004)

3767 Background: Epidermal growth factor receptor is expressed in up to 70% of cases of colorectal cancer, and may be associated with more advanced disease and a poor prognosis. Preclinical and some clinical studies suggest that combining inhibitors of EGF signaling with chemotherapy agents including irinotecan may enhance therapeutic effects. Gefitinib (Iressa, ZD1839) inhibits the EGF receptor tyrosine kinase, and has single agent activity in the treatment of lung and other cancers. We performed a clinical trial of gefitinib with 5-FU/LV/irinotecan in patients with previously-untreated colorectal cancer. Methods: The initial regimen was gefitinib 250 mg/day continuously from day 1; irinotecan 180 mg/m2 as a 90-minute infusion day 1; leucovorin 400 mg/m2 over 2h, 5-FU 400 mg/m2 bolus, and 5-FU 600 mg/m2 as a 22-hour infusion on days 1 and 2. Cycles were repeated every two weeks. Dose-limiting neutropenia required a decrease in doses twice, to result in the following doses: irinotecan 120 mg/m2, bolus 5-FU 320 mg/m2, and infusion 600 mg/m2. Results: Accrual on this trial was 13 patients, median age 56 (range 47–72), PS 0–1, 6 males, 9 white/3 black/1 Asian. After 8 patients, the starting dose was reduced because of neutropenia (3 grade 4) and other dose-limiting toxicity that included dehydration\ and metabolic abnormalities (3 patients). At a reduced dose(gefitinib 250/ irinotecan 150/ 5-FU bolus-infusion 320–600), three patients were treated, and two had grade 4, one grade 2 neutropenia. The starting dose was reduced one step further (gefitinib 250/ irinotecan 120/ 5-FU bolus-infusion 320–600), and two patients tolerated this dose without significant toxicity. By virtue of dose reductions, 8/13 patients were reduced to this dose level. Of patients receiving two or more cycles, there were 1 PR (5 months), and 6 SD (median 4 months). Conclusions: These data imply an interaction between gefitinib and the chemotherapy regimen used here. The dose reductions required together with the modest activity observed led to the early cessation of this trial. PK analysis to explore a possible interaction between gefitinib and irinotecan is in progress. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Zeneca Zeneca
Prostate cancer: biopsy proven rare sites of metastases
Authors: W. Tan, K. Wu
Journal: Journal of Clinical Oncology (2005)

4794 Background: Unusual sites of prostate cancer metastases are not frequently studied. Rarely is histologic confirmation made because patients are assumed to have metastases related to the prostate cancer. Therefore, we wanted to investigate how biopsy is being utilized for this situation. Methods: We retrospectively reviewed records and pathology of all patients with biopsy proven prostate cancer metastases other than bone or lymph node at our institution (2002–2004). We reviewed the indications for biopsy, clinical course and treament. Results: 7 patients met the criteria. Indications for biopsy included: to rule out another malignancy(2), incidental finding(1), lung nodule(3)and non-response to treatment(1). Sites of metastases included lung (3), testicular(1), scrotum(1-this patient had also incidental lung metastasis), mediastinum(1), peri-rectal mass(1). PSA at the time of diagnosis of the metastases was normal in 5 patients, four patients had hormone refractory disease and Gleason score was known in 3 patients: Gleason 10(1), 9(1) and 8(1). 5 patients had no concurrent bone metastases at the time of the biopsy.Treatment included the following: luteinizing hormone releasing hormone(LHRH) -4 patients and chemotherapy/LHRH/antiandrogen (3 patients). 5 had more than 6 months followup and 2 had no available followup yet. Two patients with solitary lung metastases had wedge resection of metastases, 1 is in complete remission (1 year) and the other had stable disease(1.5 year). 1 patient with testicular metastasis subsequently had orhiectomy and biochemical remission for 2 years.On recent, followup he did develop bone and visceral metastases. The 2 other patients had progression of disease in 6 months. In all patients the biopsy helped the clinician in his therapeutic plan. Conclusions: Patients with unusual prostate metastases commonly have a normal PSA, have hormone refractory disease, and do respond to hormonal therapy intially. A subset of patients(3) with solitary metastasis might have biochemical remission with surgical excision and systemic treatment. A biopsy is often a useful tool for making therapeutic decisions in patients with unusual prostate metastases. No significant financial relationships to disclose.
Diagnostic patch testing following tuberculosis‐associated cutaneous adverse drug reactions induces systemic reactions in <scp>HIV</scp> ‐infected persons
Authors: R.J. Lehloenya, G. Todd, J. Wallace, M.R. Ngwanya, R. Muloiwa, K. Dheda
Journal: British Journal of Dermatology (2016)

The incidence of cutaneous adverse drug reactions (CADRs) to first-line antituberculosis drugs (FLTDs) is higher in HIV-tuberculosis coinfection. However, the utility of patch testing to identify the offending drug in this patient subgroup has been poorly studied.To identify drugs causing adverse drug reactions in patients with HIV-tuberculosis coinfection.Fourteen consecutive patients underwent diagnostic work-up (patch testing followed by a skin prick test and an oral rechallenge) to pinpoint the offending drug after developing FLTD-associated CADR, which included drug rash with eosinophilia and systemic symptoms (n = 12), Stevens-Johnson syndrome (SJS, n = 1) and toxic epidermal necrolysis/SJS overlap (n = 1). A positive reaction to any of the three diagnostic modalities eliminated that drug from the regimen. Once patients were clinically stable postreaction, sequential and additive rechallenge with FLTDs was initiated.Eleven of the 14 participants with FLTD-associated CADR were HIV infected (median CD4 count 149 cells mm(-3) ). In this subgroup, patch testing resulted in generalized systemic reactions in 10 of 11 patients (91%). These included rash in 10 of 13 reactions (77%), eosinophilia in eight (62%), transaminitis in seven (54%) and fever in five (38%). Isoniazid caused six of 13 (46%) generalized systemic reactions, rifampicin four (31%), ethambutol two (15%) and pyrazinamide one reaction. Using the Common Terminology Criteria for Adverse Events, five of 13 reactions were mild, six were moderate and two were severe. There were no life-threatening or fatal reactions.In HIV-infected persons with tuberculosis-associated CADR, although patch-testing reactions to FLTD are common and tend to be associated with systemic features, they are not life threatening or fatal. These data inform clinical practice in HIV-endemic settings.
Eight drugs in one day chemotherapy for brain tumors: experience in 107 children and rationale for preradiation chemotherapy.
Authors: T W Pendergrass, J M Milstein, J R Geyer, A F Mulne, E J Kosnik, J D Morris, R L Heideman, F B Ruymann, J T Stuntz, W A Bleyer
Journal: Journal of Clinical Oncology (1987)

The development of a new multidrug chemotherapy regimen for primary brain tumors was based upon the cellular heterogeneity within individual tumors, the Goldie-Coldman and Price-Goldie-Hill hypotheses, and known agonistic effects of certain drug combinations and sequences. Eight drugs (vincristine [VCR], hydroxyurea, procarbazine, CCNU, cisplatin, cytosine arabinoside [Ara-C] high-dose methylprednisolone, and either cyclophosphamide or dacarbazine) were administered within 12 hours in an attempt to minimize myelosuppression. Courses were repeated at 2- to 4-week intervals. The regimen was devised to include lipid and water soluble drugs, polar and nonpolar agents, phase-specific and cell-cycle independent agents, and antineoplastics with different mechanisms of action. More than 330 courses of the regimen were administered to 107 children with brain tumors whose tumor had recurred or had been incompletely resected at diagnosis. Tumor response according to protocol-specified criteria and independent review was evaluable in 78% of the patients. After just two cycles of chemotherapy and within a 4- to 6-week interval, 50% had an objective tumor response including 15.5% who had a complete response (CR). Nephrotoxicity and high-frequency hearing losses were noted after three to five courses of therapy in approximately half of the patients. Transfusions with red cells or platelets and use of antibiotics for fever and neutropenia were required in 10% to 25% of patients. The regimen appears satisfactory for preradiation chemotherapy in newly diagnosed patients with residual tumor after surgery, but it must be compared with standard therapeutic approaches in prospective controlled trials before its relative value can be established.
An empirical broad spectrum antibiotic therapy in health‐care–associated infections improves survival in patients with cirrhosis: A randomized trial
Authors: Manuela Merli, Cristina Lucidi, Vincenza Di Gregorio, Barbara Lattanzi, Valerio Giannelli, Michela Giusto, Alessio Farcomeni, Giancarlo Ceccarelli, Marco Falcone, Oliviero Riggio, Mario Venditti
Journal: Hepatology (2015)

Early diagnosis and appropriate treatment of infections in cirrhosis are crucial because of their high morbidity and mortality. Multidrug‐resistant (MDR) infections are on the increase in health care settings. Health‐care–associated (HCA) infections are still frequently treated as community‐acquired with a detrimental effect on survival. We aimed to prospectively evaluate in a randomized trial the effectiveness of a broad spectrum antibiotic treatment in patients with cirrhosis with HCA infections. Consecutive patients with cirrhosis hospitalized with HCA infections were enrolled. After culture sampling, patients were promptly randomized to receive a standard or a broad spectrum antibiotic treatment (NCT01820026). The primary endpoint was in‐hospital mortality. Efficacy, side effects, and the length of hospitalization were considered. Treatment failure was followed by a change in antibiotic therapy. Ninety‐six patients were randomized and 94 were included. The two groups were similar for demographic, clinical, and microbiological characteristics. The prevalence of MDR pathogens was 40% in the standard versus 46% in the broad spectrum group. In‐hospital mortality showed a substantial reduction in the broad spectrum versus standard group (6% vs. 25%; P = 0.01). In a post‐hoc analysis, reduction of mortality was more evident in patients with sepsis. The broad spectrum showed a lower rate of treatment failure than the standard therapy (18% vs. 51%; P = 0.001). Length of hospitalization was shorter in the broad spectrum (12.3 ± 7 days) versus standard group (18 ± 15 days; P = 0.03). Five patients in each group developed a second infection during hospitalization with a similar prevalence of MDR (50% broad spectrum vs. 60% standard). Conclusions : A broad spectrum antibiotic therapy as empirical treatment in HCA infections improves survival in cirrhosis. This treatment was significantly effective, safe, and cost saving. (H epatology 2016;63:1632‐1639)
The mechanism of action and resistance of sunitinib in RCC.
Authors: B. T. Teh, D. Huang, Y. Ding, M. Zhou, B. I. Rini, D. Petillo, C. Qian, R. J. Kahnoski, P. Futreal, K. A. Furge
Journal: Journal of Clinical Oncology (2010)

e13606 Background: Sunitinib is considered the first-line therapy for advanced clear cell renal cell carcinoma (ccRCC). However, a complete understanding of its targets and mechanism of action and resistance in ccRCC remains incomplete. The aim of this study was to evaluate the mechanism action of sunitinib and its resistance in RCC and to identify potential targets to overcome sunitinib resistance. Methods: Western blotting of ccRCC and endothelial cell lines confirmed that PDGFR and VEGFR, but not other sunitinib targets, were expressed in these cells. In vitro studies found that sunitinib was unable to inhibit survival or proliferation of ccRCC cells at pharmacologically relevant concentrations (∼0.1 μM) which inhibit RTK targets. In contrast, sunitinib inhibited endothelial cell proliferation and invasion at these concentrations through suppression of VEGFR-2 signaling. Sunitinib inhibited growth of ccRCC xenografts and decreased tumor microvessel density as soon as 12 hours post-treatment; however, sunitinib showed no significant effects on tumor cell proliferation or apoptosis after up to 72 hours post-treatment. Results: Our studies indicate that sunitinib inhibits ccRCC growth primarily through an anti-angiogenic mechanism and not through direct targeting of ccRCC tumor cells. Higher microvessel density was found in sunitinib-resistant tumors, which indicated that an escape from anti-angiogenesis occurred in these tumors. This escape coincided with increased tumor secretion of interleukin-8 (IL-8) into the plasma. Co-administration of an IL-8 neutralizing antibody resensitized these tumors to sunitinib treatment, demonstrating the functional contribution of IL-8 to sunitinib resistance. Immunohistochemical staining showed that IL-8 expression was elevated in ccRCC tumors from patients who were refractory to sunitinib treatment, indicating IL-8 levels may predict clinical response to sunitinib. Conclusions: In conclusion, our results demonstrate that IL-8 is an important contributor, among others, to sunitinib resistance in ccRCC. IL-8 may serve as a therapeutic target for treatment of sunitinib resistant ccRCC, as well as a biomarker for both acquired and intrinsic sunitinib resistance. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Global Pharmaceuticals