bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pemetrexed Combined with Oxaliplatin or Carboplatin as First-Line Treatment in Advanced Non–Small Cell Lung Cancer: A Multicenter, Randomized, Phase II Trial
Authors: Scagliotti Giorgio V. , Kortsik Cornelius , Dark Graham G. , Price Allan , Manegold Christian , Rosell Rafael , O'Brien Mary , Peterson Patrick M. , Castellano Daniel , Selvaggi Giovanni , Novello Silvia , Blatter Johannes , Kayitalire Louis , Crino Lucio , Paz-Ares Luis 
Published: June 2022

Abstract
Purpose: To determine efficacy and toxicity of two pemetrexed-based regimens in chemonaive patients with locally advanced or metastatic non–small cell lung cancer.
Experimental Design: Patients were randomly assigned to receive pemetrexed 500 mg/m2 plus oxaliplatin 120 mg/m2 (PemOx) or pemetrexed plus carboplatin AUC6 (PemCb). All drugs were given on day 1 of a 21-day cycle for up to six cycles. Folic acid and vitamin B12 were given to all patients to minimize pemetrexed-related toxicities.
Results: Forty-one patients received PemOx and 39 received PemCb. Objective tumor response rates were 26.8% for PemOx patients (95% confidence interval, 14.2-42.9) and 31.6% for PemCb patients (95% confidence interval, 17.5-48.7). Median time to progression was 5.5 and 5.7 months, respectively, for PemOx and PemCb. Median overall survival times were 10.5 months for both treatment groups (range, &lt;1 to &gt;20 months). The 1-year survival rate was 49.9% for PemOx patients and 43.9% for PemCb patients. Common toxicity criteria grade 3 or 4 hematologic toxicities among PemOx patients were grade 3 or 4 neutropenia (7.3%), grade 3 thrombocytopenia (2.4%), and grade 3 anemia (2.4%). PemCb patients experienced grade 3 or 4 neutropenia (25.6%), grade 3 or 4 thrombocytopenia (17.9%), and grade 3 anemia (7.7%). Grade 3 vomiting occurred in three PemOx patients and grade 3 fatigue occurred in three PemCb patients. One grade 3 neurosensory toxicity occurred in the PemOx group. Three patients (PemOx 1 and PemCb 2) experienced febrile neutropenia.
Conclusions: Efficacy measures for both regimens seem similar to the most effective chemotherapies for advanced non–small cell lung cancer (platinum combinations) with less hematologic and nonhematologic toxicity. Comparing either of these two regimens to platinum-based therapies in a large randomized trial is warranted.
Sequential Immunogene Therapy with Interleukin-12– and Interleukin-15–Engineered Neuroblastoma Cells Cures Metastatic Disease in Syngeneic Mice
Authors: Croce Michela , Meazza Raffaella , Orengo Anna Maria , Radic' Luana , De Giovanni Barbara , Gambini Claudio , Carlini Barbara , Pistoia Vito , Mortara Lorenzo , Accolla Roberto S. , Corrias Maria Valeria , Ferrini Silvano 
Published: June 2022

AbstractPurpose: To investigate the potential synergistic effects of Neuro2a neuroblastoma cells engineered with IL-12 and/or IL-15 genes in improving survival of syngeneic mice bearing neuroblastoma metastatic disease.Experimental Design: Neuro2a cells engineered with interleukin (IL)-12 (Neuro2a/IL-12), IL-15 (Neuro2a/IL-15), or both cytokines (Neuro2a/IL-12/IL-15) were injected s.c. in syngeneic A/J mice challenged i.v. with Neuro2a parental cells (Neuro2apc) using different schedules of administration in either preventive or therapeutic settings.Results: A single injection of Neuro2a/IL-12 or Neuro2a/IL-15 cells induced resistance to a subsequent i.v. Neuro2apc challenge in 45% and 28% of mice, respectively. Neuro2a/IL-12/IL-15 cells protected 28% of mice, showing no synergistic effect. However, sequential vaccination with Neuro2a/IL-12 (day −30) followed by Neuro2a/IL-15 (day −15) protected 71% of mice from subsequent challenge with Neuro2apc. A single dose of Neuro2a/IL-12 prolonged the mean survival time of mice bearing established metastatic neuroblastoma from 21 ± 3 to 46 ± 27 days but failed to cure mice, whereas Neuro2a/IL-15 or Neuro2a/IL-12/IL-15 were ineffective. However, sequential vaccination with Neuro2a/IL-12 (day +3) followed by Neuro2a/IL-15 (day +13) cured 43% of mice as assessed by histologic analysis of different organs from long-term surviving mice. CTL activity against Neuro2apc cells was observed in splenocytes from treated mice, and CD8+ T-cell depletion abrogated the therapeutic effect of vaccination.Conclusions: Sequential vaccination with IL-12- and IL-15-engineered neuroblastoma cells induced optimal preventive and therapeutic effects, which may be related to the Th1 priming effect of IL-12 followed by the enhancement of CD8+ T-cell responses and their maintenance mediated by IL-15.
Thalidomide Radiosensitizes Tumors through Early Changes in the Tumor Microenvironment
Authors: Ansiaux Réginald , Baudelet Christine , Jordan Bénédicte F. , Beghein Nelson , Sonveaux Pierre , De Wever Julie , Martinive Philippe , Grégoire Vincent , Feron Olivier , Gallez Bernard 
Published: June 2022

Abstract
Purpose: The aim of this work was to study changes in the tumor microenvironment early after an antiangiogenic treatment using thalidomide (a promising angiogenesis inhibitor in a variety of cancers), with special focus on a possible “normalization” of the tumor vasculature that could be exploited to improve radiotherapy.
Experimental Design: Tumor oxygenation, perfusion, permeability, interstitial fluid pressure (IFP), and radiation sensitivity were studied in an FSAII tumor model. Mice were treated by daily i.p. injection of thalidomide at a dose of 200 mg/kg. Measurements of the partial pressure of oxygen (pO2) were carried out using electron paramagnetic resonance oximetry. Three complementary techniques were used to assess the blood flow inside the tumor: dynamic contrast-enhanced magnetic resonance imaging, Patent Blue staining, and laser Doppler imaging. IFP was measured by a “wick-in-needle” technique.
Results: Our results show that thalidomide induces tumor reoxygenation within 2 days. This reoxygenation is correlated with a reduction in IFP and an increase in perfusion. These changes can be attributed to extensive vascular remodeling that we observed using CD31 labeling.
Conclusions: In summary, the microenvironmental changes induced by thalidomide were sufficient to radiosensitize tumors. The fact that thalidomide radiosensitization was not observed in vitro, and that in vivo radiosensitization occurred in a narrow time window, lead us to believe that initial vascular normalization by thalidomide accounts for tumor radiosensitization.
Clinical Evaluation of BR96 sFv-PE40 Immunotoxin Therapy in Canine Models of Spontaneously Occurring Invasive Carcinoma
Authors: Henry Carolyn J. , Buss Michael S. , Hellström Ingegerd , Hellström Karl Erik , Brewer William G. , Bryan Jeffrey N. , Siegall Clay B. 
Published: June 2022

AbstractPurpose: The immunotoxin BR96 sFv-PE40 is an effective antitumor agent against human breast and lung carcinoma xenografts in rodents. This study was designed to (a) determine the frequency with which canine carcinoma cells express Lewisy (Ley) antigen, thereby identifying canine carcinoma types suitable for the clinical evaluation of BR96 sFv-PE40, and (b) determine the safety and efficacy of BR96 sFv-PE40 in a canine model of spontaneously occurring cancers for investigation of targeted therapy.Experimental Design: Carcinoma tissue samples were obtained from client-owned dogs presented for medical care. The tissues were assessed for Ley antigen expression using immunohistochemical methods. Dogs with tumors expressing Ley antigen were offered enrollment in a clinical trial to receive twice-weekly infusions of 4 to 12 mg/m2 BR96 sFv-PE40. Clinical toxicity and response data were assessed at each treatment.Results: Twenty-two of 61 carcinomas evaluated were positive for Ley expression, including mammary, prostate, lung, and rectal carcinomas, and 12 dogs were enrolled in the clinical trial. The primary side effect was transient emesis. Partial responses or disease stabilization were noted in dogs with inflammatory mammary, bronchogenic, rectal, and tonsillar carcinoma. At least nine of the dogs developed antibodies to the immunotoxin after two to five infusions.Conclusions: Although development of anti-BR96 sFv-PE40 antibodies limited the long-term effectiveness of this immunotoxin in dogs, rapid clinical responses in several aggressive canine carcinomas suggest the immunotoxin has utility for treatment of certain naturally occurring tumors and that its clinical evaluation for treatment of similar human carcinomas is warranted.
Intracellular Localization and Trafficking of Fluorescein-Labeled Cisplatin in Human Ovarian Carcinoma Cells
Authors: Safaei Roohangiz , Katano Kuniyuki , Larson Barrett J. , Samimi Goli , Holzer Alison K. , Naerdemann Wiltrud , Tomioka Mika , Goodman Murray , Howell Stephen B. 
Published: June 2022

Abstract
Purpose: We sought to identify the subcellular compartments in which cisplatin [cis-diamminedichloroplatinum (DDP)] accumulates in human ovarian carcinoma cells and define its export pathways.
Experimental Design: Deconvoluting digital microscopy was used to identify the subcellular location of fluorescein-labeled DDP (F-DDP) in 2008 ovarian carcinoma cells stained with organelle-specific markers. Drugs that block vesicle movement were used to map the traffic pattern.
Results: F-DDP accumulated in vesicles and were not detectable in the cytoplasm. F-DDP accumulated in the Golgi, in vesicles belonging to the secretory export pathway, and in lysosomes but not in early endosomes. F-DDP extensively colocalized with vesicles expressing the copper efflux protein, ATP7A, whose expression modulates the cellular pharmacology of DDP. Inhibition of vesicle trafficking with brefeldin A, wortmannin, or H89 increased the F-DDP content of vesicles associated with the pre-Golgi compartments and blocked the loading of F-DDP into vesicles of the secretory pathway. The importance of the secretory pathway was confirmed by showing that wortmannin and H89 increased whole cell accumulation of native DDP.
Conclusions: F-DDP is extensively sequestered into vesicular structures of the lysosomal, Golgi, and secretory compartments. Much of the distribution to other compartments occurs via vesicle trafficking. F-DDP detection in the vesicles of the secretory pathway is consistent with a major role for this pathway in the efflux of F-DDP and DDP from the cell.
Continuous Delivery of Endogenous Inhibitors from Poly(Lactic-Co-Glycolic Acid) Polymeric Microspheres Inhibits Glioma Tumor Growth
Authors: Benny Ofra , Duvshani-Eshet Maayan , Cargioli Theresa , Bello Lorenzo , Bikfalvi Andreas , Carroll Rona S. , Machluf Marcelle 
Published: June 2022

Abstract
Purpose: There is an urgent need for modalities that can localize and prolong the administration of the antitumor agents, particularly antiangiogenic, to achieve long-term tumor inhibition. However, one of the major obstacles is designing a device in which the biological activity of sensitive endogenous inhibitors is retained. We have designed a biodegradable polymeric device, which provides a unique and practical means of localizing and continuously delivering hemopexin (PEX) or platelet factor 4 fragment (PF-4/CTF) at the tumor site while maintaining their biological activity. The potential and efficacy of this system is shown in vitro and in vivo in a human glioma mouse model.
Experimental Design: Polymeric microspheres made of poly(lactic-co-glycolic acid) (PLGA) were loaded with very low amounts of PEX and PF-4/CTF. The release profiles of these factors from PLGA and their biological activity were confirmed in vitro using proliferation assays done on endothelial and tumor cells. Tumor inhibition using this system was studied in nude mice bearing a human s.c. glioma.
Results: PEX and PF-4/CTF released in vitro from PLGA microspheres were biologically active and significantly inhibited the proliferation of human umbilical vein endothelial cells, bovine capillary endothelial cells, and U87-MG cells. A single local s.c. injection of PLGA microspheres loaded with low amounts of PEX or PF-4/CTF resulted in an 88% and 95% reduction in glioma tumor volume 30 days post-treatment. Immunohistochemical analysis of the treated tumors showed a marked decrease in tumor vessel density compared with untreated tumors.
Conclusion: Our findings show that polymeric microspheres are a very promising approach to locally and efficiently deliver endogenous inhibitors to the tumor site leading to a significant inhibition of the tumor.
Biodistribution of Yttrium-90–Labeled Anti-CD45 Antibody in a Nonhuman Primate Model
Authors: Nemecek Eneida R. , Hamlin Donald K. , Fisher Darrell R. , Krohn Kenneth A. , Pagel John M. , Appelbaum Frederick R. , Press Oliver W. , Matthews Dana C. 
Published: June 2022

Abstract
Purpose: Radioimmunotherapy may improve the outcome of hematopoietic cell transplantation for hematologic malignancies by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the organ localization of yttrium-90-labeled anti-CD45 (90Y-anti-CD45) antibody in macaques, a model that had previously predicted iodine-131-labeled anti-CD45 (131I-anti-CD45) antibody biodistribution in humans.
Experimental Design: Twelve Macaca nemestrina primates received anti-CD45 antibody labeled with 1 to 2 mCi of 90Y followed by serial blood sampling and marrow and lymph node biopsies, and necropsy. The content of 90Y per gram of tissue was determined by liquid scintillation spectrometry. Time-activity curves were constructed using average isotope concentrations in each tissue at measured time points to yield the fractional residence time and estimate radiation absorbed doses for each organ per unit of administered activity. The biodistribution of 90Y-anti-CD45 antibody was then compared with that previously obtained with 131I-anti-CD45 antibody in macaques.
Results: The spleen received 2,120, marrow 1,060, and lymph nodes 315 cGy/mCi of 90Y injected. The liver and lungs were the nontarget organs receiving the highest radiation absorbed doses (440 and 285 cGy/mCi, respectively). Ytrrium-90-labeled anti-CD45 antibody delivered 2.5- and 3.7-fold more radiation to marrow than to liver and lungs, respectively. The ratios previously observed with 131I-anti-CD45 antibody were 2.5-and 2.2-fold more radiation to marrow than to liver and lungs, respectively.
Conclusions: This study shows that 90Y-anti-CD45 antibody can deliver relatively selective radiation to hematopoietic tissues, with similar ratios of radiation delivered to target versus nontarget organs, as compared with the 131I immunoconjugate in the same animal model.
Adenoviral Transduction of TESTIN Gene into Breast and Uterine Cancer Cell Lines Promotes Apoptosis and Tumor Reduction In vivo
Authors: Sarti Manuela , Sevignani Cinzia , Calin George A. , Aqeilan Rami , Shimizu Masayoshi , Pentimalli Francesca , Picchio Maria Cristina , Godwin Andrew , Rosenberg Anne , Drusco Alessandra , Negrini Massimo , Croce Carlo M. 
Published: June 2022

Abstract
Purpose: The human TESTIN (TES) gene is a putative tumor suppressor gene in the fragile chromosomal region FRA7G at 7q31.1/2 that was reported to be altered in leukemia and lymphoma cell lines. In this report, we investigated the effect of TES gene expression in vivo to evaluate a possible role of TES gene in human cancer.
Experimental Design: We have analyzed the expression of TES gene in a panel of 25 breast tumors and 17 cell lines of breast, colon, and uterine cancers. Furthermore, to evaluate the potential of TES gene therapy, we studied the effects of adenoviral TES transduction (Ad-TES) in cell lines with undetectable TES expression (T47D and MES-SA) as well as in MCF-7 cell line where TES expression is normal.
Results: Twenty-five percent of primary breast tumor samples as well as the breast cancer cell line T47D and the uterine sarcoma cell line MES-SA were negative or displayed low levels of TES. After TES restoration by Ad-TES transduction, T47D and MES-SA cell lines underwent apoptosis. Furthermore, TES expression significantly reduced the tumorigenic potential of both T47D and MES-SA in nude mice, whereas the untreated cells and Ad-GFP-infected cells showed tumor growth in vivo. The TES-positive cell line control (MCF-7) was not affected by TES expression and did not show a reduction of tumorigenicity in nude mice after infection with Ad-TES.
Conclusions: Ad-TES expression inhibit the growth of breast and uterine cancer cells lacking of TES expression through caspase-dependent and caspase-independent apoptosis, respectively, suggesting that Ad-TES infection should be explored as a therapeutic strategy.
Mathematical Modeling and Optimization of Drug Delivery from Intratumorally Injected Microspheres
Authors: Tzafriri Abraham Rami , Lerner Elyakum Itzhak , Flashner-Barak Moshe , Hinchcliffe Michael , Ratner Eli , Parnas Hanna 
Published: June 2022

Abstract
Purpose: Paclitaxel is a highly promising phase-sensitive antitumor drug that could conceivably be improved by extended lower dosing as opposed to intermittent higher dosing. Although intratumoral delivery of paclitaxel to the whole tumor at different loads and rates has already been achieved, determining an optimal release mode of paclitaxel for tumor eradication remains difficult. This study set out to rationally design such an optimal microsphere release mode based on mathematical modeling.
Experimental Design: A computational reaction-diffusion framework was used to model drug release from intratumorally injected microspheres, drug transport and binding in tumor interstitum, and drug clearance by microvasculature and intracellular uptake and binding.
Results: Numerical simulations suggest that interstitial drug concentration is characterized by a fast spatially inhomogeneous rise phase, during which interstitial and intracellular binding sites are saturated, followed by a slow spatially homogeneous phase that is governed by the rate of drug release from microspheres. For zero-order drug release, the slow phase corresponds to a plateau drug concentration that is proportional to the ratio of the rate of blood clearance of drug to the rate of drug release from microspheres. Consequently, increasing the duration of intratumoral drug release extends the duration of cell exposure to the drug but lowers the plateau drug concentration. This tradeoff implies that intratumoral drug release can be designed to optimize tumor cell kill. Synthesizing our modeling predictions with published dose-response data, we propose an optimal protocol for the delivery of paclitaxel-loaded microspheres to small solid tumors.
In vivoDrug-Linker Stability of an Anti-CD30 Dipeptide-Linked Auristatin Immunoconjugate
Authors: Sanderson Russell J. , Hering Michelle A. , James Stephanie F. , Sun Michael M.C. , Doronina Svetlana O. , Siadak Anthony W. , Senter Peter D. , Wahl Alan F. 
Published: June 2022

AbstractEffective antibody-drug conjugates (ADC) combine high drug-linker stability in circulation and efficient intratumoral release of drug. Conjugation of monomethyl auristatin E (MMAE) to the anti-CD30 monoclonal antibody (mAb), cAC10, produced a selective and potent ADC against CD30+ anaplastic large cell lymphoma and Hodgkin's disease models. This ADC, cAC10-valine-citrulline-MMAE, uses a protease-sensitive dipeptide linker designed to release MMAE by lysosomal cathepsin B in target cells but maintain a stable linkage and attenuate drug potency in circulation. To evaluate ADC stability in vivo, we developed methods for measuring drug/mAb ratios at progressive times in plasma from ADC-treated mice and nonhuman primates. Anti-idiotype mAb permitted the capture and quantitation of mAb cAC10, whereas antidrug mAb and MMAE-conjugated horseradish peroxidase reporter provided quantitative detection of conjugated drug following its in vitro release by cathepsin B. These data were validated by an alternative ELISA using anti-idiotype and anti-MMAE mAbs for capture and detection, respectively. Both methods differentiated ADC with variable levels of drug loading and were subsequently applied to stability studies in severe combined immunodeficient mice and cynomolgus monkeys. Evaluation of ADC from mouse circulation showed the linker half-life to be ∼144 hours (6.0 days), significantly greater than that reported for disulfide- or hydrazone-linked ADCs in mice or human trials. In cynomolgus monkey, the apparent linker half-life was ∼230 hours (9.6 days), suggesting that the drug-linker will be highly stable in humans. These data represent the longest reported drug-linker half-life to date and provide the basis for the pronounced specificity and antitumor activity of cAC10-valine-citrulline-MMAE.
Immunoglobulin Superfamily Receptor Translocation Associated 2 Protein on Lymphoma Cell Lines and Hairy Cell Leukemia Cells Detected by Novel Monoclonal Antibodies
Authors: Ise Tomoko , Maeda Hiroshi , Santora Kenneth , Xiang Laiman , Kreitman Robert J. , Pastan Ira , Nagata Satoshi 
Published: June 2022

Abstract
Purpose: The immunoglobulin superfamily receptor translocation associated 2 (IRTA2) gene encodes a cell surface receptor homologous to the family of Fc receptors. Because of the restricted expression of mRNA in B cell–lineage cells, IRTA2 is a new potential target for the immunotherapy of B cell malignancies. To study the expression of the IRTA2 gene product, we produced monoclonal antibodies (MAbs) specific to IRTA2.
Experimental Design: A mouse used for cell fusion was DNA-immunized with an expression plasmid encoding the IRTA2 cDNA. The reactivity of MAbs secreted from the hybridomas were characterized with recombinant proteins of IRTA family members in an enzyme immunoassay and a fluorescence-activated cell sorter (FACS). Nineteen human lymphoma cell lines and blood cells from five patients with hairy cell leukemia (HCL) were analyzed with IRTA2 expression using FACS.
Results: Three MAbs (F25, F56, and F119) were selected based on their specific reactivity with recombinant IRTA2 and lack of cross-reactivity with other IRTA family members. In a FACS analysis, MAbs F56 and F119 detected IRTA2 expression in six of seven B cell non–Hodgkin's lymphoma and one of six Burkitt's lymphoma cell lines. Reverse transcriptase-PCR experiments and Western blotting using MAb F25 confirmed the expression profile. We also found that HCL cells from five patients expressed IRTA2.
Conclusions: Our results provide the first evidence that IRTA2 is expressed on the surface of human lymphoma cell lines and HCL cells. IRTA2 could be useful as a new target for immunotherapy.
The Molecular Pharmacology of Estrogen Receptor Modulators: Implications for the Treatment of Breast Cancer
Authors: McDonnell Donald P. 
Published: June 2022

Abstract
In addition to physiologic activities in the reproductive, skeletal, and central nervous systems, estrogens have been shown to play important roles in the aberrant cell proliferation observed in breast and reproductive tract cancers. Not surprisingly, pharmaceuticals that target different steps in the estrogen signal transduction pathway have found widespread use in the treatment of a wide variety of estrogen-linked disorders. The goal of this review is to outline what is known about the molecular pharmacology of the estrogen receptor and discuss how this information can be used to guide selection of drugs for a particular therapeutic application, and identify new targets where pharmaceutical exploitation could yield novel therapeutics.