bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Purpose: 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

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

Purpose: 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

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

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

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

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

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

Effective 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

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

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.
Endocrine Therapy Trials of Aromatase Inhibitors for Breast Cancer in the Adjuvant and Prevention Settings
Authors: Ingle James N.
Published: June 2022

The recent past has witnessed the appearance of substantial data relating to endocrine therapy of breast cancer. In the adjuvant therapy setting in early breast cancer, several large, well-conducted, randomized, double-blind clinical trials have provided evidence for the value of the third-generation aromatase inhibitors (AI) anastrozole, exemestane, and letrozole. The three major studies to date [i.e., Arimidex, tamoxifen alone, or in combination (ATAC), International Exemestane Study (IES), and letrozole after 5 years of tamoxifen (MA.17)] evaluated three different populations of women from the standpoints of duration of prior tamoxifen and thus time since the treatment of the primary breast cancer. A consistent pattern of improvement in disease-free survival was seen whether the control arm was tamoxifen (ATAC and IES) or placebo following tamoxifen (MA.17). From a toxicity standpoint, the major findings with the AIs were a decreased incidence of thromboembolic events and endometrial cancers but an increase in musculoskeletal complaints and potential for decreasing bone density. The last issue should be clarified with ongoing studies addressing the impact of the three AIs on bone density and fractures. In summary, based on ATAC, IES, and MA.17, respectively, the following conclusions can be drawn relating to postmenopausal women with hormone receptor positive early breast cancer: anastrozole is a reasonable choice for initial endocrine adjuvant therapy, exemestane should be considered for women who have received 2 to 3 years of tamoxifen, and letrozole should be considered for those who have completed about 5 years of tamoxifen.

In the prevention setting, tamoxifen has been evaluated in multiple trials involving >28,000 women and, despite clear evidence of benefit, the level of acceptance of this agent by women seems to be low. Two recently developed prevention trials, IBIS 2 and MAP.3, involve the study of aromatase inhibitors against a placebo control rather than tamoxifen. Whereas the recent adjuvant trials have established the value of the third-generation aromatase inhibitors in early-stage breast cancer, the marked reductions in contralateral breast cancers seen in these trials suggest they will be of value in the prevention setting in women at increased risk of developing the disease.
TAS-108: A Novel Steroidal Antiestrogen
Authors: Buzdar Aman U.
Published: June 2022

TAS-108 is a novel steroidal antiestrogen compound that has a strong binding affinity to the estrogen receptor and, in preclinical studies, has antitumor activity against tamoxifen-resistant breast cancer cell lines. Its molecular mechanisms of actions are different from those of tamoxifen and fulvestrant. TAS-108 showed tissue-selective agonist activity in the bone and cardiovascular systems and, in preclinical and phase I studies, did not show any effect on the endometrium. In a phase I study, TAS-108 was well tolerated at doses ranging from 40 to 160 mg/d with no maximum tolerated dose. Toxicities included hot flashes, headache, and nausea and vomiting. The drug has linear pharmacokinetics. In the phase I study, there was evidence of biological antitumor activity, with stable disease noted in several patients. A phase II study is ongoing, and phase III studies are being planned with the drug.
Tamoxifen versus Aromatase Inhibitors for Breast Cancer Prevention
Authors: Yue Wei , Wang Ji-Ping , Li Yuebai , Bocchinfuso Wayne P. , Korach Kenneth S. , Devanesan Prabu D. , Rogan Eleanor , Cavalieri Ercole , Santen Richard J.
Published: June 2022

Long-term exposure to estradiol is associated with an increased risk of breast cancer, but the mechanisms responsible are not firmly established. The prevailing theory postulates that estrogens increase the rate of cell proliferation by stimulating estrogen receptor (ER)–mediated transcription, thereby increasing the number of errors occurring during DNA replication. An alternative theory suggests that estradiol is metabolized to quinone derivatives, which directly remove base pairs from DNA through a process called depurination. Error-prone DNA repair then results in point mutations. We postulate that both processes act in an additive or synergistic fashion. If correct, aromatase inhibitors would block both processes, whereas antiestrogens would only inhibit receptor-mediated effects. Accordingly, aromatase inhibitors would be more effective in preventing breast cancer than antiestrogens. Our initial studies showed that catechol-estrogen metabolites are formed in MCF-7 human breast cancer cells in culture. We then used an animal model that allows dissociation of ER-mediated function from the effects of estradiol metabolites and showed formation of genotoxic estradiol metabolites. We also examined the incidence of tumors formed in these ERα knockout mice bearing the Wnt-1 transgene. The absence of estradiol markedly reduced the incidence of tumors and delayed their onset. In aggregate, our results support the concept that metabolites of estradiol may act in concert with ER-mediated mechanisms to induce breast cancer. These findings support the possibility that aromatase inhibitors might be more effective than antiestrogens in preventing breast cancer.
Dual Role of Transforming Growth Factor β in Mammary Tumorigenesis and Metastatic Progression
Authors: Muraoka-Cook Rebecca S. , Dumont Nancy , Arteaga Carlos L.
Published: June 2022

It is generally accepted that transforming growth factor β (TGFβ) is both a tumor suppressor and tumor promoter. Whereas loss or attenuation of TGFβ signal transduction is permissive for transformation, introduction of dominant-negative TGFβ receptors into metastatic breast cancer cells has been shown to inhibit epithelial-to-mesenchymal transition, motility, invasiveness, survival, and metastases. In addition, there is evidence that excess production and/or activation of TGFβ by cancer cells can contribute to tumor progression by paracrine mechanisms involving neoangiogenesis, production of stroma and proteases, and subversion of immune surveillance mechanisms in tumor hosts. These data provide a rationale in favor of blockade of autocrine/paracrine TGFβ signaling in human mammary tumors with therapeutic intent. Several treatment approaches are currently in early clinical development and have been the focus of our laboratory. These include (1) ligand antibodies or receptor-containing fusion proteins aimed at blocking ligand binding to cognate receptors and (2) small-molecule inhibitors of the type I TGFβ receptor serine/threonine kinase. Many questions remain about the viability of anti-TGFβ treatment strategies, the best molecular approach (or combinations) for inhibition of TGFβ function in vivo, the biochemical surrogate markers of tumor response, the molecular profiles in tumors for selection into clinical trials, and potential toxicities, among others.
Insulin-Like Growth Factor-I and Breast Cancer Therapy
Authors: Ibrahim Yasir H. , Yee Douglas
Published: June 2022

Targeting hormonal and growth factor signaling pathways has proven to be useful in the treatment of breast cancer. In vitro, animal, and epidemiologic evidence provide a rationale for the relevance of the insulin-like growth factor (IGF) system to breast cancer biology. The IGF system has been implicated in promoting mitogenic, metastatic, and antiapoptotic phenotypes in breast cancer. As a consequence of the ability of IGF to promote tumorigenesis, pharmacologic interventions targeting the IGF system are being devised. Such strategies include decreasing ligand production, ligand binding, or receptor activation. In this article, directed anti-IGF strategies and the possible clinical impact of using such therapies for treating breast cancer are discussed.
Expression of Erythropoietin and Erythropoietin Receptor in Non–Small Cell Lung Carcinomas
Authors: Dagnon Koami , Pacary Emilie , Commo Frédéric , Antoine Martine , Bernaudin Myriam , Bernaudin Jean-Francois , Callard Patrice
Published: June 2022

Purpose: Expression of erythropoietin (Epo) and its receptor (Epo-R) has been shown in various normal and neoplastic nonhematopoietic tissues. This study, in non–small cell lung carcinoma, was designed to investigate the previously unreported expression of Epo and Epo-R as well as hypoxia-inducible factor-1α (HIF-1α), which is known to control Epo expression.

Experimental Design: Samples from lung squamous cell carcinomas (n = 17) and adenocarcinomas (n = 12) were obtained from patients undergoing curative surgery. mRNA transcripts of Epo, Epo-R, soluble Epo-R (sEpo-R), HIF-1α, and factor inhibiting HIF-1 (FIH-1) were evaluated by reverse transcription-PCR, whereas localization of Epo, Epo-R, and HIF-1α was assessed by immunohistochemistry.

Results: Epo, Epo-R, sEpo-R, HIF-1α, and FIH-1 transcripts were detected by reverse transcription-PCR in all samples tested, but with heterogeneous levels of expression for Epo, Epo-R, and sEpo-R. Coordinated levels of mRNA were observed for HIF-1α and FIH-1.

Epo was detected in carcinomatous cells by immunohistochemistry in 50% of samples and Epo-R was detected in 96% of samples. Co-expression of Epo and Epo-R was observed on contiguous sections from 50% of tumors. HIF-1α was immunolocalized in 80% of non–small cell lung carcinomas.

Conclusion: Epo-R was expressed in almost all samples and Epo was expressed in one half of samples on immunohistochemistry and in 100% of samples by mRNA detection, suggesting a potential paracrine and/or autocrine role of endogenous Epo in non–small cell lung carcinoma. The detection of stabilized HIF-1α suggests a possible role in Epo expression. Moreover, in the light of these results, the potential interactions between therapeutic recombinant Epo and the putative neoplastic Epo/Epo-R signaling pathways must be considered.
The Genotoxic Effect of Nasal Steroids on Human Nasal Septal Mucosa and Cartilage Cells In Vitro
Authors: Türkoğlu Babakurban Seda , Vural Ömer , Korkmaz Kasap Yeşim , Hızal Evren , Yurtcu Erkan , Büyüklü Adnan Fuat
Published: June 2022

Objective:

To determine whether budesonide (Bud) and triamcinolone acetate (TA) cause DNA fractures in the nasal mucosa and septal cartilage cells through examinations using the comet assay technique.

Study design:

Prospective, controlled experimental study.

Setting:

University hospital.

Methods:

Septal mucosal epithelial and cartilage tissue samples were taken from 9 patients. Cell cultures were prepared from these samples. Then, budesonide and triamcinolone acetate active ingredients at 2 different doses of 0.2 and 10 µM were separately applied to the cell cultures formed from both tissues of each patient, except the control cell culture, for 7 days in one group and 14 days in one group. After the applications, genotoxic damage was scored with the comet assay technique and the groups were compared.

Results:

In both the budesonide and triamcinolone acetate groups, the comet scores at low and high doses, on the 7th and 14th days were found to be significantly higher in both cartilage and epithelial tissue than in the control group.

Conclusion:

The study results showed that budesonide and triamcinolone acetate lead to a significantly high rate of genotoxic damage in both epithelial tissue and cartilage tissue.
ALPK1 Aggravates TMJOA Cartilage Degradation via NF-κB and ERK1/2 Signaling
Authors: Liu X. , Zhao J. , Jiang H. , Li H. , Feng Y. , Ke J. , Long X.
Published: June 2022

Temporomandibular joint osteoarthritis (TMJOA) is a common degenerative joint disease without effective intervention strategies. Previous research implied that alpha-kinase 1 (ALPK1) is involved in the inflammatory responses of gout, a chronic arthritis. Herein, we found the main distribution of ALPK1 in a proliferative layer of condylar cartilage and marrow cavity of subchondral bone, as well as a lining layer of synovial tissues in human temporomandibular joint. Moreover, the expression of ALPK1 was augmented in degraded condylar cartilage of monosodium iodoacetate (MIA)–induced TMJOA mice. After MIA induction, ALPK1 knockout mice exhibited attenuated damage of cartilage and subchondral bone, as well as synovitis, as compared with wide type mice. In contrast, intra-articular administration of recombinant human ALPK1 aggravated the pathology of MIA-induced TMJOA. Furthermore, ex vivo study demonstrated that ALPK1 exacerbated chondrocyte catabolism by upregulating matrix metalloproteinase 13 and cyclooxygenase 2 by activating NF-κB (nuclear factor–kappaB) signaling and suppressed anabolism by downregulating aggrecan by inhibiting ERK1/2 (extracellular signal–regulated kinase 1/2) in articular chondrocytes. Taken together, ALPK1 exacerbates the degradation of condylar cartilage during TMJOA through the NF-κB and ERK1/2 signaling pathway. This study provides a new insight regarding the role of ALPK1 during TMJOA pathology.
Strain Measurement within an Intact Swine Periodontal Ligament
Authors: Houg K.P. , Camarillo A.M. , Doschak M.R. , Major P.W. , Popowics T. , Dennison C.R. , Romanyk D.L.
Published: June 2022

The periodontal ligament (PDL) provides support, proprioception, nutrition, and protection within the tooth–PDL–bone complex (TPBC). While understanding the mechanical behavior of the PDL is critical, current research has inferred PDL mechanics from finite element models, from experimental measures on complete TPBCs, or through direct measurement of isolated PDL sections. Here, transducers are used in an attempt to quantify ex vivo PDL strain. In-fiber Bragg grating (FBG) sensors are small flexible sensors that can be placed within an intact TPBC and yield repeatable strain measurements from within the PDL space. The objective of this study was to determine: 1) if the FBG strain measured from the PDL space of intact swine premolars ex vivo was equivalent to physical PDL strains estimated through finite element analysis and 2) if a change in FBG strain could be linearly related to a change in finite element strain under variable tooth displacement, applied to an intact swine TPBC. Experimentally, individual TPBCs were subjected to 2 displacements ( n = 14). The location of the FBG was determined from representative micro–computed tomography images. From a linear elastic finite element model of a TPBC, the strain magnitudes at the sensor locations were recorded. An experimental ratio (i.e., FBG strain at the first displacement divided by the FBG strain at the second displacement) and a finite element ratio (i.e., finite element strain at the first displacement divided by the finite element strain at the second displacement) were calculated. A linear regression model indicated a statistically significant relationship between the experimental and finite element ratio ( P = 0.017) with a correlation coefficient ( R2) of 0.448. It was concluded that the FBG sensor could be used as a measure for a change in strain and thus could be implemented in applications where the mechanical properties of an intact PDL are monitored over time.
Municipal Pathways in Response to COVID-19: A Strategic Management Perspective on Local Public Administration Resilience
Authors: Clement Jessica , Esposito Giovanni , Crutzen Nathalie
Published: June 2022

This paper aims to understand the different resilience pathways local governments may take during moments of crisis, specifically focusing on the COVID-19 pandemic. Through survey responses from local administrations in Wallonia, Belgium, we consider how varied contexts led to different strategic resilience pathways. These pathways range from static (i.e., no strategy) to innovative change. Our findings highlight that digital technology solutions may play a role in supporting resilience across the different pathways. Therefore, we adapt strategic public management literature to suggest propositions for future research to test the specific role that digital technologies play in supporting resilience within local administrations.
Extending Green Innovations Across Clusters: HOW can Firms Benefit Most?
Authors: Díez-Vial Isabel , Belso-Martínez Jose A. , Gregorio Martín-de-Castro
Published: June 2022

This paper analyses how green product and process innovations affect firms’ sustainable performance. It seems evident that green innovations should benefit not only society but also the firms, although it is not clearly stated how this relationship works, especially inside clusters. We theorise that green process and product innovations have a curvilinear relationship with firm sustainable performance and that the geographical concentration of clusters has a positive reinforcing role for green product innovations. To test these theoretical expectations, moderated regression and quantile regression were applied to a sample of 175 firms from the Spanish footwear industry. Results confirm that although green innovations do improve performance, they have an inverted “U” shape that makes investments in green innovation less profitable above a certain threshold. In addition, we observe that geographical concentration is stronger for green product innovations since green process innovations need more tacit-based knowledge and internal capabilities, making the cluster effect less significant.
Social Participation Through the Retirement Transition: Differences by Gender and Employment Status
Authors: Lim-Soh Jeremy W. , Lee Yeonjin
Published: June 2022

This study examines how retirees’ formal and informal social participation change over time and investigates gendered differences. Seven waves of the Korean Longitudinal Study of Ageing track the frequency of social participation. A comparison group of employed individuals, weighted with coarsened exact matching, controls for age and time trends, and mixed model regressions estimate changes over time. Retirees show a gradual decline in the frequency of meeting friends and an abrupt decrease in the frequency of attending a social gathering, compared to their working peers. These trends are much stronger for men than women, and compound pre-existing gender differences in social participation. The more severe decline in the social participation of men is of great concern and points to the persistence of gendered employment structures into the retirement transition, putting Korean retirees at risk of social isolation and related health deterioration.
When should palliative care be introduced for people with progressive fibrotic interstitial lung disease? A meta-ethnography of the experiences of people with end-stage interstitial lung disease and their family carers
Authors: Palmer Evelyn , Kavanagh Emily , Visram Shelina , Bourke Anne-Marie , Forrest Ian , Exley Catherine
Published: June 2022

Background:

Little is currently known about the perspectives of people with interstitial lung disease and their carers in relation to the timing of palliative care conversations.

Aim:

To establish patients’ and carers’ views on palliative care in interstitial lung disease and identify an optimum time to introduce the concept of palliative care.

Design:

Meta-ethnography of qualitative evidence. The review protocol was prospectively registered with PROSPERO (CRD42021243179).

Data sources:

Five electronic healthcare databases were searched (Medline, Embase, CINAHL, Scopus and Web of Science) from 1st January 1996 to 31st March 2022. Studies were included that used qualitative methodology and included patients’ or carers’ perspectives on living with end-stage disease or palliative care. Quality was assessed using the Critical Appraisal Skills Programme checklist.

Results:

About 1779 articles were identified by initial searches. Twelve met the inclusion criteria, providing evidence from 266 individuals across five countries. Three stages were identified in the illness journey of a person with interstitial lung disease: (1) Information seeking, (2) Grief and adjustment, (3) Fear of the future. Palliative care involvement was believed to be most appropriate in the latter two stages and should be prompted by changes in patients’ health such as respiratory infections, onset of new symptoms, hospital admission, decline in physical function and initiation of oxygen.

Conclusions:

Patients and carers prefer referral to palliative care services to be prompted by changes in health status. Future research should focus on supporting timely recognition of changes in patients’ health status and how to respond in a community setting.
Racial Discrimination and Private Regard Among Black Early Adolescents: Testing Between- and Within-Person Associations Over Time
Authors: Lavner Justin A. , Carter Sierra E. , Hart Ariel R. , Adesogan Olutosin , Beach Steven R. H.
Published: June 2022

The current study examined concurrent and longitudinal associations between experiences of racial discrimination and private regard (i.e., feelings about being Black and other Black people) among 346 Black early adolescents who completed four assessments over two years. Between-person (interpersonal) and within-person (intrapersonal) effects were tested to provide a rigorous and comprehensive examination of these associations. There was minimal evidence of significant between-person effects in which youth experiencing varying levels of racial discrimination differed in their private regard. However, at the within-person level, there were significant negative concurrent associations between racial discrimination and private regard, indicating that youths’ positive racial identity was undermined at times when they were encountering higher levels of racial discrimination than they typically did. Results highlight significant intrapersonal links between racial discrimination and private regard and underscore the continued need for interventions to eliminate racial discrimination and to support Black youth experiencing it.
Association of bladder trabeculation and neurogenic bladder with spinal cord injury
Authors: Won Yu Hui , Kim Da-Sol , Kim Gi-Wook , Park Sung-Hee , Ko Myoung-Hwan , Seo Jeong-Hwan
Published: June 2022

Objective

To compare clinical findings and urodynamic parameters according to trabeculation grade and analyze their correlations with trabeculation severity in neurogenic bladder caused by suprasacral spinal cord injury (SCI).

Methods

A retrospective chart review was performed of neurogenic bladder caused by SCI. Bladder trabeculation grade was compared with SCI-related clinical parameters and bladder-related urodynamic parameters.

Results

In SCI patients, factors such as disease duration, bladder capacity, detrusor pressure, peak detrusor pressure values, and compliance were significantly different between different grades of bladder trabeculation, while neurological level of injury, completeness, and detrusor sphincter dyssynergia had no clear relationship with bladder trabeculation grade. In the correlation analysis, vesicoureteral reflux was moderately correlated with trabeculation grade (correlation coefficient 0.433), while the correlation coefficients of disease duration, involuntary detrusor contraction, and bladder filling volume were between 0.3 and 0.4.

Conclusion

Bladder trabeculation with suprasacral-type neurogenic bladder was graded. Although disease duration was positively correlated with bladder trabeculation grade, differences in the neurological level of injury or American Spinal Injury Association Impairment Scale score were not observed. Bladder volume, peak detrusor pressure, compliance, reflex volume, and vesicoureteral reflux also showed significant differences according to trabeculation grade. Vesicoureteral reflux was moderately correlated with trabeculation grade.
Macro Analysis to Estimate Electric Vehicles Fast-Charging Infrastructure Requirements in Small Urban Areas
Authors: Singh Harprinderjot , Kavianipour Mohammadreza , Soltanpour Amirali , Fakhrmoosavi Fatemeh , Ghamami Mehrnaz , Zockaie Ali , Jackson Robert
Published: June 2022

Electric vehicles (EVs) are known to reduce emissions and fossil fuel dependency. However, the limited range, long charging time, and inadequate charging infrastructure have hampered the adoption of EVs. The current EV charging infrastructure planning studies and tools require detailed information, extensive resources, and skills that can be a significant barrier to urban areas for finding the required charging infrastructure to support a targeted EV market share. This study generates regression models to estimate the number of direct current fast charging stations and the chargers to support the EV charging demand for urban areas. These models provide macro-level estimates of the required infrastructure investment in urban areas, which can be easily implemented by policy-makers and city planners. This study incorporates data obtained from applying a disaggregate optimization-based charger placement model, developed recently by the same authors, for multiple case studies to generate the required data to calibrate the macro-level models, in the state of Michigan. This simulated data set includes the number of charging stations and chargers for each market share, technology advancement scenario, and the transportation network topology. The results show that the number of charging stations reduces with battery size and charging power and increases with EV market share and the road network lane length. The number of chargers reduces with charging power, whereas it increases with battery size, EV market share, and vehicle miles traveled in the system. The model developed here can be applied to any state having urban characteristics and weather conditions similar to Michigan.
Social Suffering: A New Reference Framework for Economic Analysis
Authors: ballet Jerome , Mahieu François-Regis
Published: June 2022

Social suffering has become a recurrent theme in various disciplines (sociology, social psychology, anthropology), but remains absent from economic analysis. The aim of our article is hence to reinstate the role of social suffering in economics. We first define the scope of the concept, which should be interpreted as a form of suffering generated by economic systems, particularly the current capitalist system. We then dismiss the objections to this conception of social suffering. In particular, we dismiss the attempt to reduce social suffering to a set of categorical phenomena that can be interpreted independently of the functioning of an economic system. Finally, we point out that lowering social suffering should take precedence over the pursuit of happiness.

JEL Classification: B40, P46, A13
Rethinking Rigor in Multiple Baseline and Multiple Probe Designs
Authors: Ledford Jennifer R. , Zimmerman Kathleen N.
Published: June 2022

A number of resources are available for evaluating the rigor of single-case designs, including the commonly used multiple baseline design. In this article, we discuss two characteristics commonly cited as necessary for the highest rigor in multiple baseline designs—concurrence and response-guided baseline condition duration. We suggest that both nonconcurrence and response-independent baseline condition duration may be appropriate in some situations. Suggestions for researchers include improved reporting and graphing. Future research is needed to determine experimental differences when these design variations are used.