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  1. Article ; Online: Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial.

    Simpson, Eric L / Parnes, Jane R / She, Dewei / Crouch, Sarah / Rees, William / Mo, May / van der Merwe, René

    Journal of the American Academy of Dermatology

    2018  Volume 80, Issue 4, Page(s) 1013–1021

    Abstract: Background: Tezepelumab (AMG 157/MEDI9929), a first-in-class monoclonal antibody, targets thymic stromal lymphopoietin, a cytokine that is implicated in the pathogenesis of atopic dermatitis (AD).: Objective: We sought to evaluate the efficacy and ... ...

    Abstract Background: Tezepelumab (AMG 157/MEDI9929), a first-in-class monoclonal antibody, targets thymic stromal lymphopoietin, a cytokine that is implicated in the pathogenesis of atopic dermatitis (AD).
    Objective: We sought to evaluate the efficacy and safety of tezepelumab in adults with moderate to severe AD.
    Methods: In this phase 2a study (NCT02525094), 113 patients were randomized 1:1 to subcutaneous tezepelumab 280 mg or placebo every 2 weeks, plus class 3 topical corticosteroids (TCS). The primary endpoint was the week 12 response rate for a ≥50% reduction in the Eczema Area and Severity Index (EASI50). Secondary endpoints including EASI75, Investigator's Global Assessment, SCORAD 50, SCORAD 75, pruritus numeric rating and 5-D itch scales, and exploratory endpoints (including EASI90) were assessed at weeks 12, and 16 (post hoc).
    Results: A numerically greater percentage of tezepelumab plus TCS-treated patients achieved EASI50 (64.7%) versus placebo plus TCS (48.2%; P = .091). Numerical improvements over placebo were demonstrated for week 12 secondary and exploratory endpoints, with further improvements at week 16. Treatment-emergent adverse events were similar between treatment groups.
    Limitations: Greater than expected response rates in placebo-treated patients were possibly attributable to TCS.
    Conclusion: Although not statistically significant, numerical improvements over placebo for all week 12 endpoints were demonstrated, with greater week 16 responses.
    MeSH term(s) Administration, Cutaneous ; Adrenal Cortex Hormones/administration & dosage ; Adult ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/therapeutic use ; Biomarkers/blood ; Cell Adhesion Molecules/blood ; Chemokine CCL17/blood ; Cytokines/antagonists & inhibitors ; Dermatitis, Atopic/blood ; Dermatitis, Atopic/complications ; Dermatitis, Atopic/drug therapy ; Dermatologic Agents/adverse effects ; Dermatologic Agents/therapeutic use ; Dipeptidyl Peptidase 4/blood ; Double-Blind Method ; Female ; Humans ; Injections, Subcutaneous ; Male ; Middle Aged ; Pruritus/drug therapy ; Pruritus/etiology ; Severity of Illness Index ; Young Adult
    Chemical Substances Adrenal Cortex Hormones ; Antibodies, Monoclonal ; Biomarkers ; CCL17 protein, human ; Cell Adhesion Molecules ; Chemokine CCL17 ; Cytokines ; Dermatologic Agents ; POSTN protein, human ; tezepelumab ; Dipeptidyl Peptidase 4 (EC 3.4.14.5) ; thymic stromal lymphopoietin (GT0IL38SP4)
    Language English
    Publishing date 2018-12-12
    Publishing country United States
    Document type Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
    ZDB-ID 603641-7
    ISSN 1097-6787 ; 0190-9622
    ISSN (online) 1097-6787
    ISSN 0190-9622
    DOI 10.1016/j.jaad.2018.11.059
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1540: Show issues Location:
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  2. Article ; Online: Preoperative CT predictors of survival in patients with pancreatic ductal adenocarcinoma undergoing curative intent surgery.

    Dickinson, Shannan M / McIntyre, Caitlin A / Schilsky, Juliana B / Harrington, Kate A / Gerst, Scott R / Flynn, Jessica R / Gonen, Mithat / Capanu, Marinela / Wong, Winston / Lawrence, Sharon / Allen, Peter J / O'Reilly, Eileen M / Jarnagin, William R / D'Angelica, Michael I / Balachandran, Vinod P / Drebin, Jeffrey A / Kingham, T Peter / Simpson, Amber L / Do, Richard K

    Abdominal radiology (New York)

    2020  Volume 46, Issue 4, Page(s) 1607–1617

    Abstract: Purpose: To evaluate the associations between computed tomography (CT) imaging features extracted from the structured American Pancreatic Association (APA)/Society of Abdominal Radiology (SAR) template and overall survival in patients with resected ... ...

    Abstract Purpose: To evaluate the associations between computed tomography (CT) imaging features extracted from the structured American Pancreatic Association (APA)/Society of Abdominal Radiology (SAR) template and overall survival in patients with resected pancreatic ductal adenocarcinoma (PDAC).
    Methods: This retrospective analysis included consecutive patients with PDAC who consented to genomic tumor testing and underwent preoperative imaging and curative intent surgical resection from December 2006 to July 2017. Two radiologists assessed preoperative CT imaging using the APA/SAR PDAC-reporting template. Univariable associations between overall survival and imaging variables were evaluated using Cox proportional hazards regression.
    Results: The study included 168 patients (66 years ± 11; 91 women). 126/168 patients (75%) received upfront surgical resection whereas 42/168 (25%) received neoadjuvant therapy prior to surgical resection. In the entire cohort, features associated with decreased overall survival were tumor arterial contact of any kind (hazard ratio (HR) 1.89, 95% CI 1.13-3.14, p = 0.020), tumor contact with the common hepatic artery (HR 2.33, 95% CI 1.35-4.04, p = 0.009), and portal vein deformity (HR 3.22, 95% CI 1.63-6.37, p = 0.003). In the upfront surgical group, larger tumor size was associated with decreased overall survival (HR 2.30, 95% CI 1.19-4.42, p = 0.013). In the neoadjuvant therapy group, the presence of venous collaterals was the only feature associated with decreased overall survival (HR 2.28, 95% CI 1.04-4.99, p = 0.042).
    Conclusion: The application of the APA/SAR pancreatic adenocarcinoma reporting template may identify predictors of survival that can aid in preoperative stratification of patients.
    MeSH term(s) Adenocarcinoma/diagnostic imaging ; Adenocarcinoma/surgery ; Carcinoma, Pancreatic Ductal/diagnostic imaging ; Carcinoma, Pancreatic Ductal/surgery ; Female ; Humans ; Pancreatic Neoplasms/diagnostic imaging ; Pancreatic Neoplasms/surgery ; Prognosis ; Retrospective Studies ; Tomography, X-Ray Computed
    Language English
    Publishing date 2020-09-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2839786-1
    ISSN 2366-0058 ; 2366-004X
    ISSN (online) 2366-0058
    ISSN 2366-004X
    DOI 10.1007/s00261-020-02726-w
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  3. Article ; Online: Prenatal vs postnatal diagnosis of 22q11.2 deletion syndrome: cardiac and noncardiac outcomes through 1 year of age.

    Freud, Lindsay R / Galloway, Stephanie / Crowley, T Blaine / Moldenhauer, Julie / Swillen, Ann / Breckpot, Jeroen / Borrell, Antoni / Vora, Neeta L / Cuneo, Bettina / Hoffman, Hilary / Gilbert, Lisa / Nowakowska, Beata / Geremek, Maciej / Kutkowska-Kaźmierczak, Anna / Vermeesch, Joris R / Devriendt, Koen / Busa, Tiffany / Sigaudy, Sabine / Vigneswaran, Trisha /
    Simpson, John M / Dungan, Jeffrey / Gotteiner, Nina / Gloning, Karl-Philipp / Digilio, Maria Cristina / Unolt, Marta / Putotto, Carolina / Marino, Bruno / Repetto, Gabriela / Fadic, Magdalena / Garcia-Minaur, Sixto / Achón Buil, Ana / Thomas, Mary Ann / Fruitman, Deborah / Beecroft, Taylor / Hui, Pui Wah / Oskarsdottir, Solveig / Bradshaw, Rachael / Criebaum, Amanda / Norton, Mary E / Lee, Tiffany / Geiger, Miwa / Dunnington, Leslie / Isaac, Jacqueline / Wilkins-Haug, Louise / Hunter, Lindsey / Izzi, Claudia / Toscano, Marika / Ghi, Tullio / McGlynn, Julie / Romana Grati, Francesca / Emanuel, Beverly S / Gaiser, Kimberly / Gaynor, J William / Goldmuntz, Elizabeth / McGinn, Daniel E / Schindewolf, Erica / Tran, Oanh / Zackai, Elaine H / Yan, Qi / Bassett, Anne S / Wapner, Ronald / McDonald-McGinn, Donna M

    American journal of obstetrics and gynecology

    2023  Volume 230, Issue 3, Page(s) 368.e1–368.e12

    Abstract: Background: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a ... ...

    Abstract Background: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis.
    Objective: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome.
    Study design: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site.
    Results: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019).
    Conclusion: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection.
    MeSH term(s) Infant ; Infant, Newborn ; Pregnancy ; Female ; Humans ; Male ; DiGeorge Syndrome/diagnosis ; DiGeorge Syndrome/genetics ; Retrospective Studies ; Prenatal Diagnosis ; Heart Defects, Congenital/diagnosis ; Heart Defects, Congenital/epidemiology ; Heart Defects, Congenital/genetics ; Prenatal Care
    Language English
    Publishing date 2023-09-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80016-8
    ISSN 1097-6868 ; 0002-9378
    ISSN (online) 1097-6868
    ISSN 0002-9378
    DOI 10.1016/j.ajog.2023.09.005
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  4. Article ; Online: Overview of the Alaskan Layered Pollution and Chemical Analysis (ALPACA) Field Experiment.

    Simpson, William R / Mao, Jingqiu / Fochesatto, Gilberto J / Law, Kathy S / DeCarlo, Peter F / Schmale, Julia / Pratt, Kerri A / Arnold, Steve R / Stutz, Jochen / Dibb, Jack E / Creamean, Jessie M / Weber, Rodney J / Williams, Brent J / Alexander, Becky / Hu, Lu / Yokelson, Robert J / Shiraiwa, Manabu / Decesari, Stefano / Anastasio, Cort /
    D'Anna, Barbara / Gilliam, Robert C / Nenes, Athanasios / St Clair, Jason M / Trost, Barbara / Flynn, James H / Savarino, Joel / Conner, Laura D / Kettle, Nathan / Heeringa, Krista M / Albertin, Sarah / Baccarini, Andrea / Barret, Brice / Battaglia, Michael A / Bekki, Slimane / Brado, T J / Brett, Natalie / Brus, David / Campbell, James R / Cesler-Maloney, Meeta / Cooperdock, Sol / Cysneiros de Carvalho, Karolina / Delbarre, Hervé / DeMott, Paul J / Dennehy, Conor J S / Dieudonné, Elsa / Dingilian, Kayane K / Donateo, Antonio / Doulgeris, Konstantinos M / Edwards, Kasey C / Fahey, Kathleen / Fang, Ting / Guo, Fangzhou / Heinlein, Laura M D / Holen, Andrew L / Huff, Deanna / Ijaz, Amna / Johnson, Sarah / Kapur, Sukriti / Ketcherside, Damien T / Levin, Ezra / Lill, Emily / Moon, Allison R / Onishi, Tatsuo / Pappaccogli, Gianluca / Perkins, Russell / Pohorsky, Roman / Raut, Jean-Christophe / Ravetta, Francois / Roberts, Tjarda / Robinson, Ellis S / Scoto, Federico / Selimovic, Vanessa / Sunday, Michael O / Temime-Roussel, Brice / Tian, Xinxiu / Wu, Judy / Yang, Yuhan

    ACS ES&T air

    2024  Volume 1, Issue 3, Page(s) 200–222

    Abstract: The Alaskan Layered Pollution And Chemical Analysis (ALPACA) field experiment was a collaborative study designed to improve understanding of pollution sources and chemical processes during winter (cold climate and low-photochemical activity), to ... ...

    Abstract The Alaskan Layered Pollution And Chemical Analysis (ALPACA) field experiment was a collaborative study designed to improve understanding of pollution sources and chemical processes during winter (cold climate and low-photochemical activity), to investigate indoor pollution, and to study dispersion of pollution as affected by frequent temperature inversions. A number of the research goals were motivated by questions raised by residents of Fairbanks, Alaska, where the study was held. This paper describes the measurement strategies and the conditions encountered during the January and February 2022 field experiment, and reports early examples of how the measurements addressed research goals, particularly those of interest to the residents. Outdoor air measurements showed high concentrations of particulate matter and pollutant gases including volatile organic carbon species. During pollution events, low winds and extremely stable atmospheric conditions trapped pollution below 73 m, an extremely shallow vertical scale. Tethered-balloon-based measurements intercepted plumes aloft, which were associated with power plant point sources through transport modeling. Because cold climate residents spend much of their time indoors, the study included an indoor air quality component, where measurements were made inside and outside a house to study infiltration and indoor sources. In the absence of indoor activities such as cooking and/or heating with a pellet stove, indoor particulate matter concentrations were lower than outdoors; however, cooking and pellet stove burns often caused higher indoor particulate matter concentrations than outdoors. The mass-normalized particulate matter oxidative potential, a health-relevant property measured here by the reactivity with dithiothreiol, of indoor particles varied by source, with cooking particles having less oxidative potential per mass than pellet stove particles.
    Language English
    Publishing date 2024-02-21
    Publishing country United States
    Document type Journal Article
    ISSN 2837-1402
    ISSN (online) 2837-1402
    DOI 10.1021/acsestair.3c00076
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  5. Article ; Online: Phase I/II Trial of Labetuzumab Govitecan (Anti-CEACAM5/SN-38 Antibody-Drug Conjugate) in Patients With Refractory or Relapsing Metastatic Colorectal Cancer.

    Dotan, Efrat / Cohen, Steven J / Starodub, Alexander N / Lieu, Christopher H / Messersmith, Wells A / Simpson, Pamela S / Guarino, Michael J / Marshall, John L / Goldberg, Richard M / Hecht, J Randolph / Wegener, William A / Sharkey, Robert M / Govindan, Serengulam V / Goldenberg, David M / Berlin, Jordan D

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology

    2017  Volume 35, Issue 29, Page(s) 3338–3346

    Abstract: Purpose The objectives were to evaluate dosing schedules of labetuzumab govitecan, an antibody-drug conjugate targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) for tumor delivery of 7-ethyl-10-hydroxycamptothecin (SN-38), in ... ...

    Abstract Purpose The objectives were to evaluate dosing schedules of labetuzumab govitecan, an antibody-drug conjugate targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) for tumor delivery of 7-ethyl-10-hydroxycamptothecin (SN-38), in an expanded phase II trial of patients with relapsed or refractory metastatic colorectal cancer. Patients and Methods Eligible patients with at least one prior irinotecan-containing therapy received labetuzumab govitecan once weekly at 8 and 10 mg/kg, or two times per week at 4 and 6 mg/km on weeks 1 and 2 of 3-week repeated cycles. End points were safety, response, pharmacokinetics, and immunogenicity. Results Eighty-six patients who had undergone a median of five prior therapies (range, one to 13) were each enrolled into one of the four cohorts. On the basis of Response Evaluation Criteria in Solid Tumors 1.1, 38% of these patients had a tumor as well as plasma carcinoembryonic antigen reduction from baseline after labetuzumab govitecan treatment; one patient achieved a partial response with a sustained response spanning > 2 years, whereas 42 patients had stable disease as the best overall response. Median progression-free survival and overall survival were 3.6 and 6.9 months, respectively. The major toxicities (grade ≥ 3) among all cohorts were neutropenia (16%), leukopenia (11%), anemia (9%), and diarrhea (7%). The antibody-drug conjugate's mean half-life was 16.5 hours for the four cohorts. Anti-drug/anti-antibody antibodies were not detected. The two once-weekly dose schedules, showing comparable toxicity and efficacy, were chosen for further study. Conclusion Monotherapy with labetuzumab govitecan demonstrated a manageable safety profile and therapeutic activity in heavily pretreated patients with metastatic colorectal cancer, all with prior irinotecan therapy. Further studies of labetuzumab govitecan treatment alone or in combination with other therapies in earlier settings are indicated.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/pharmacokinetics ; Camptothecin/administration & dosage ; Camptothecin/adverse effects ; Camptothecin/analogs & derivatives ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/mortality ; Colorectal Neoplasms/pathology ; Disease Progression ; Disease-Free Survival ; Drug Administration Schedule ; Drug Resistance, Neoplasm ; Female ; Half-Life ; Humans ; Infusions, Intravenous ; Irinotecan ; Male ; Middle Aged ; Neoplasm Metastasis ; Survival Analysis ; Treatment Outcome
    Chemical Substances Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Irinotecan (7673326042) ; labetuzumab govitecan (8E3HI6QQ9J) ; Camptothecin (XT3Z54Z28A)
    Language English
    Publishing date 2017-08-17
    Publishing country United States
    Document type Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Multicenter Study
    ZDB-ID 604914-x
    ISSN 1527-7755 ; 0732-183X
    ISSN (online) 1527-7755
    ISSN 0732-183X
    DOI 10.1200/JCO.2017.73.9011
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    Zs.MO 650: Show issues

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  6. Article ; Online: SWI/SNF complexes are required for full activation of the DNA-damage response.

    Smith-Roe, Stephanie L / Nakamura, Jun / Holley, Darcy / Chastain, Paul D / Rosson, Gary B / Simpson, Dennis A / Ridpath, John R / Kaufman, David G / Kaufmann, William K / Bultman, Scott J

    Oncotarget

    2015  Volume 6, Issue 2, Page(s) 732–745

    Abstract: SWI/SNF complexes utilize BRG1 (also known as SMARCA4) or BRM (also known as SMARCA2) as alternative catalytic subunits with ATPase activity to remodel chromatin. These chromatin-remodeling complexes are required for mammalian development and are mutated ...

    Abstract SWI/SNF complexes utilize BRG1 (also known as SMARCA4) or BRM (also known as SMARCA2) as alternative catalytic subunits with ATPase activity to remodel chromatin. These chromatin-remodeling complexes are required for mammalian development and are mutated in ~20% of all human primary tumors. Yet our knowledge of their tumor-suppressor mechanism is limited. To investigate the role of SWI/SNF complexes in the DNA-damage response (DDR), we used shRNAs to deplete BRG1 and BRM and then exposed these cells to a panel of 6 genotoxic agents. Compared to controls, the shRNA knockdown cells were hypersensitive to certain genotoxic agents that cause double-strand breaks (DSBs) associated with stalled/collapsed replication forks but not to ionizing radiation-induced DSBs that arise independently of DNA replication. These findings were supported by our analysis of DDR kinases, which demonstrated a more prominent role for SWI/SNF in the activation of the ATR-Chk1 pathway than the ATM-Chk2 pathway. Surprisingly, γH2AX induction was attenuated in shRNA knockdown cells exposed to a topoisomerase II inhibitor (etoposide) but not to other genotoxic agents including IR. However, this finding is compatible with recent studies linking SWI/SNF with TOP2A and TOP2BP1. Depletion of BRG1 and BRM did not result in genomic instability in a tumor-derived cell line but did result in nucleoplasmic bridges in normal human fibroblasts. Taken together, these results suggest that SWI/SNF tumor-suppressor activity involves a role in the DDR to attenuate replicative stress and genomic instability. These results may also help to inform the selection of chemotherapeutics for tumors deficient for SWI/SNF function.
    MeSH term(s) Cell Line, Tumor ; Cell Survival/genetics ; DNA Damage ; DNA Helicases/deficiency ; DNA Helicases/genetics ; Female ; Gene Knockdown Techniques ; HeLa Cells ; Humans ; Nuclear Proteins/deficiency ; Nuclear Proteins/genetics ; RNA, Small Interfering/genetics ; Transcription Factors/deficiency ; Transcription Factors/genetics ; Uterine Cervical Neoplasms/genetics
    Chemical Substances Nuclear Proteins ; RNA, Small Interfering ; SMARCA2 protein, human ; Transcription Factors ; SMARCA4 protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-)
    Language English
    Publishing date 2015-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.2715
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  7. Article ; Online: Ultrasound-triggered therapeutic microbubbles enhance the efficacy of cytotoxic drugs by increasing circulation and tumor drug accumulation and limiting bioavailability and toxicity in normal tissues.

    Ingram, Nicola / McVeigh, Laura E / Abou-Saleh, Radwa H / Maynard, Juliana / Peyman, Sally A / McLaughlan, James R / Fairclough, Michael / Marston, Gemma / Valleley, Elizabeth M A / Jimenez-Macias, Jorge L / Charalambous, Antonia / Townley, William / Haddrick, Malcolm / Wierzbicki, Antonia / Wright, Alexander / Volpato, Milène / Simpson, Peter B / Treanor, Darren E / Thomson, Neil H /
    Loadman, Paul M / Bushby, Richard J / Johnson, Benjamin R G / Jones, Pamela F / Evans, J Anthony / Freear, Steven / Markham, Alexander F / Evans, Stephen D / Coletta, P Louise

    Theranostics

    2020  Volume 10, Issue 24, Page(s) 10973–10992

    Abstract: Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to ... ...

    Abstract Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs.
    MeSH term(s) Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Biological Availability ; Cell Line, Tumor ; Colorectal Neoplasms/diagnostic imaging ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/pathology ; Combined Modality Therapy/methods ; Drug Delivery Systems/methods ; Female ; Humans ; Irinotecan ; Microbubbles/therapeutic use ; Microfluidic Analytical Techniques ; Positron-Emission Tomography ; Tissue Distribution/radiation effects ; Ultrasonic Waves ; Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors ; Vascular Endothelial Growth Factor Receptor-2/metabolism ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; Irinotecan (7673326042) ; KDR protein, human (EC 2.7.10.1) ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1)
    Language English
    Publishing date 2020-09-01
    Publishing country Australia
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2592097-2
    ISSN 1838-7640 ; 1838-7640
    ISSN (online) 1838-7640
    ISSN 1838-7640
    DOI 10.7150/thno.49670
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  8. Article ; Online: A retrospective analysis of survival and prognostic factors after stereotactic radiosurgery for aggressive meningiomas.

    Ferraro, Daniel J / Funk, Ryan K / Blackett, John William / Ju, Michelle R / DeWees, Todd A / Chicoine, Michael R / Dowling, Joshua L / Rich, Keith M / Drzymala, Robert E / Zoberi, Imran / Simpson, Joseph R / Jaboin, Jerry J

    Radiation oncology (London, England)

    2014  Volume 9, Page(s) 38

    Abstract: Background: While most meningiomas are benign, aggressive meningiomas are associated with high levels of recurrence and mortality. A single institution's Gamma Knife radiosurgical experience with atypical and malignant meningiomas is presented, ... ...

    Abstract Background: While most meningiomas are benign, aggressive meningiomas are associated with high levels of recurrence and mortality. A single institution's Gamma Knife radiosurgical experience with atypical and malignant meningiomas is presented, stratified by the most recent WHO classification.
    Methods: Thirty-one patients with atypical and 4 patients with malignant meningiomas treated with Gamma Knife radiosurgery between July 2000 and July 2011 were retrospectively reviewed. All patients underwent prior surgical resection. Overall survival was the primary endpoint and rate of disease recurrence in the brain was a secondary endpoint. Patients who had previous radiotherapy or prior surgical resection were included. Kaplan-Meier and Cox proportional hazards models were used to estimate survival and identify factors predictive of recurrence and survival.
    Results: Post-Gamma Knife recurrence was identified in 11 patients (31.4%) with a median overall survival of 36 months and progression-free survival of 25.8 months. Nine patients (25.7%) had died. Three-year overall survival (OS) and progression-free survival (PFS) rates were 78.0% and 65.0%, respectively. WHO grade II 3-year OS and PFS were 83.4% and 70.1%, while WHO grade III 3-year OS and PFS were 33.3% and 0%. Recurrence rate was significantly higher in patients with a prior history of benign meningioma, nuclear atypia, high mitotic rate, spontaneous necrosis, and WHO grade III diagnosis on univariate analysis; only WHO grade III diagnosis was significant on multivariate analysis. Overall survival was adversely affected in patients with WHO grade III diagnosis, prior history of benign meningioma, prior fractionated radiotherapy, larger tumor volume, and higher isocenter number on univariate analysis; WHO grade III diagnosis and larger treated tumor volume were significant on multivariate analysis.
    Conclusion: Atypical and anaplastic meningiomas remain difficult tumors to treat. WHO grade III diagnosis and treated tumor volume were significantly predictive of recurrence and survival on multivariate analysis in aggressive meningioma patients treated with radiosurgery. Larger tumor size predicts poor survival, while nuclear atypia, necrosis, and increased mitotic rate are risk factors for recurrence. Clinical and pathologic predictors may help identify patients that are at higher risk for recurrence.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Meningeal Neoplasms/diagnosis ; Meningeal Neoplasms/mortality ; Meningeal Neoplasms/pathology ; Meningeal Neoplasms/surgery ; Meningioma/diagnosis ; Meningioma/mortality ; Meningioma/pathology ; Meningioma/surgery ; Middle Aged ; Prognosis ; Radiosurgery ; Retrospective Studies ; Survival Analysis ; Treatment Outcome
    Language English
    Publishing date 2014-01-27
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1748-717X
    ISSN (online) 1748-717X
    DOI 10.1186/1748-717X-9-38
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Survival following gamma knife radiosurgery for brain metastasis from breast cancer.

    Jaboin, Jerry J / Ferraro, Daniel J / DeWees, Todd A / Rich, Keith M / Chicoine, Michael R / Dowling, Joshua L / Mansur, David B / Drzymala, Robert E / Simpson, Joseph R / Magnuson, William J / Patel, Anushka H / Zoberi, Imran

    Radiation oncology (London, England)

    2013  Volume 8, Page(s) 131

    Abstract: Background: Breast cancer is the second most common cause of brain metastases in the United States. Although breast cancer induced brain metastases represent an incurable condition, some patients experience prolonged survival. In this retrospective ... ...

    Abstract Background: Breast cancer is the second most common cause of brain metastases in the United States. Although breast cancer induced brain metastases represent an incurable condition, some patients experience prolonged survival. In this retrospective study, we examine a cohort of patients with brain metastases from breast cancer treated with Gamma Knife stereotactic radiosurgery to identify factors that predict better outcomes.
    Methods: A retrospective database of 100 patients treated for brain metastases due to breast cancer via Gamma Knife radiosurgery (GKS) from July 1998 through March 2009 was reviewed. Patients who received radiosurgery as sole treatment, as a planned boost after whole brain radiotherapy or surgical resection, or as salvage after prior whole brain radiation therapy (WBRT) or surgical resection were included. Prognostic factors identified to be significant for survival in previous brain metastasis studies were analyzed for significance by univariate and multivariate Cox analysis.
    Results: Overall, the median brain progression-free survival time was 7.1 months and the median survival time was 12.3 months. No prognostic variables were significant for brain progression-free survival. For patients treated with a planned GKS after WBRT, GKS as sole treatment, GKS salvage after WBRT, GKS boost after surgery, or GKS for surgical salvage the median survival times (MSTs) were as follows: 12.2 months, 12.4 months, 9.5 months, 27.6 months and 33.4 months respectively. Differences between the groups were not significant (p = 0.06); however, GKS boost after surgery and GKS for salvage after surgery did have a trend toward better overall survival.
    Conclusion: Stereotactic radiosurgery offers good local control and prolonged survival in selected patients. Age and number of lesions are strong predictors of overall survival.
    MeSH term(s) Adult ; Aged ; Brain Neoplasms/mortality ; Brain Neoplasms/secondary ; Brain Neoplasms/surgery ; Breast Neoplasms/mortality ; Breast Neoplasms/pathology ; Breast Neoplasms/surgery ; Disease-Free Survival ; Female ; Humans ; Kaplan-Meier Estimate ; Proportional Hazards Models ; Radiosurgery ; Retrospective Studies
    Language English
    Publishing date 2013-05-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1748-717X
    ISSN (online) 1748-717X
    DOI 10.1186/1748-717X-8-131
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Integrin β1 signals through Arg to regulate postnatal dendritic arborization, synapse density, and behavior.

    Warren, M Sloan / Bradley, William D / Gourley, Shannon L / Lin, Yu-Chih / Simpson, Mark A / Reichardt, Louis F / Greer, Charles A / Taylor, Jane R / Koleske, Anthony J

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2012  Volume 32, Issue 8, Page(s) 2824–2834

    Abstract: Integrins are heterodimeric extracellular matrix receptors that are essential for the proper development of the vertebrate nervous system. We report here that selective loss of integrin β1 in excitatory neurons leads to reductions in the size and ... ...

    Abstract Integrins are heterodimeric extracellular matrix receptors that are essential for the proper development of the vertebrate nervous system. We report here that selective loss of integrin β1 in excitatory neurons leads to reductions in the size and complexity of hippocampal dendritic arbors, hippocampal synapse loss, impaired hippocampus-dependent learning, and exaggerated psychomotor sensitivity to cocaine in mice. Our biochemical and genetic experiments demonstrate that the intracellular tail of integrin β1 binds directly to Arg kinase and that this interaction stimulates activity of the Arg substrate p190RhoGAP, an inactivator of the RhoA GTPase. Moreover, genetic manipulations that reduce integrin β1 signaling through Arg recapitulate the integrin β1 knock-out phenotype in a gene dose-sensitive manner. Together, these results describe a novel integrin β1-Arg-p190RhoGAP pathway that regulates dendritic arbor size, promotes synapse maintenance, supports proper hippocampal function, and mitigates the behavioral consequences of cocaine exposure.
    MeSH term(s) Analysis of Variance ; Animals ; Animals, Newborn ; Avoidance Learning/drug effects ; Avoidance Learning/physiology ; Basic Helix-Loop-Helix Transcription Factors/deficiency ; Cells, Cultured ; Cocaine/administration & dosage ; Dendrites/metabolism ; Dendrites/ultrastructure ; Enzyme-Linked Immunosorbent Assay ; Exploratory Behavior/drug effects ; Exploratory Behavior/physiology ; GTPase-Activating Proteins/genetics ; GTPase-Activating Proteins/metabolism ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Hippocampus/cytology ; Hippocampus/ultrastructure ; Immunoprecipitation ; Integrin beta1/genetics ; Integrin beta1/metabolism ; Male ; Mice ; Mice, Knockout ; Mutation/physiology ; Nerve Tissue Proteins/deficiency ; Neurons/cytology ; Neurons/physiology ; Neurons/ultrastructure ; Organ Culture Techniques ; Post-Synaptic Density/genetics ; Post-Synaptic Density/pathology ; Post-Synaptic Density/ultrastructure ; Protein Binding/drug effects ; Protein Binding/genetics ; Recognition, Psychology/drug effects ; Recognition, Psychology/physiology ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Synapses/physiology ; Synapses/ultrastructure ; alpha-Fetoproteins/genetics ; alpha-Fetoproteins/metabolism ; src Homology Domains/drug effects ; src Homology Domains/physiology
    Chemical Substances Arhgap35 protein, mouse ; Basic Helix-Loop-Helix Transcription Factors ; GTPase-Activating Proteins ; Integrin beta1 ; Nerve Tissue Proteins ; Neurod6 protein, mouse ; Repressor Proteins ; alpha-Fetoproteins ; alpha-fetoprotein related protein, mouse ; Green Fluorescent Proteins (147336-22-9) ; Cocaine (I5Y540LHVR)
    Language English
    Publishing date 2012-02-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.3942-11.2012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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