Online degree programmes in nurse education-Students' perceptions and academic performance: An integrative review.

OBJECTIVES: The aim of this integrative review is to identify, describe, and synthesise evidence regarding students' perceptions of online degree programmes in nurse education, their academic performance, and the factors associated with their academic performance. DESIGN: Integrative review. DATA SOURCES: Four databases, CINAHL, ERIC (Ebsco), PubMed/MEDLINE, and Web of Science were searched. The reference lists of included studies were reviewed to identify other relevant studies. REVIEW METHODS: Whittemore and Knafl's method was used as a guideline for the integrative review. Peer-reviewed studies describing students' perceptions of-or academic performance in-online degree programmes in nurse education were included in the review without time limitations. The quality of the selected article was assessed using the Mixed Method Appraisal Tool. RESULTS: Nursing students' perceptions of online degree programmes were categorised into enabling career development, content delivered online, and community belonging. Factors related to student's academic performance were associated with individual students and the characteristics of online learning environments. Factors associated with students' academic performance were individual self-direction, formal communication skills, and working and educational backgrounds. Factors associated with academic performance in an online learning environment were categorised into regular feedback and methods for learning. CONCLUSIONS: Online degree programmes in nurse education contribute to developing pedagogy through a satisfactory work-life balance, students' experiences of community and support, pleasant digital content, and various teaching methods by faculties. The study findings of this review have implications for educators to develop and adopt strategies for advancing digital environments with the pedagogy that supports community building to meet the needs of individual students.

Impact of multiple sclerosis phenotypes on burden of disease in Finland.

Aims: The aim of this study was to quantify how multiple sclerosis (MS) phenotypes differ from each other in respect of costs and quality-of-life.Materials and methods: The study is based on survey data from Finnish patients with MS (n = 553). The information contained disease type, disease severity according to self-reported Expanded Disease Severity Scale (EDSS), healthcare resource use, and medication use. In addition, information related to employment and early retirement was collected. EQ-5D-VAS and Multiple Sclerosis Impact Scale-29 (MSIS-29) instruments were used to collect quality-of-life data, and Fatigue Severity Scale (FSS) instrument for evaluating fatigue. Patients were stratified based on their disease type (relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS)) and disease severity. The data were primarily analyzed using summary statistics.Results: SPMS had the highest annual total cost (71,177€) followed by PPMS (51,082€) and RRMS (36,492€). Early retirement covered the greatest share of costs in RRMS (39%) and SPMS (43%). In PPMS, early retirement and professional care were the two most equally important cost drivers, contributing together 56% of the total costs. Direct healthcare costs were responsible for 33%, 19%, and 18% of total costs in RRMS, SPMS, and PPMS. The mean EDSS in RRMS, SPMS, and PPMS were 2.5, 5.5, and 5.9, respectively. Differences in the quality-of-life were observed with both disease specific (MSIS-29) and generic (EQ-5D-VAS) instruments. The mean utility value from EQ-5D among patients with RRMS, SPMS, and PPMS was 0.76, 0.52, and 0.49, respectively. In addition, patients with SPMS and PPMS were more likely to report fatigue than patients with RRMS.Conclusions: MS phenotype has an impact on costs and quality-of-life of the patients. Early retirement seems to be one of the most important contributors to MS-related costs.

Validity and reliability of the Finnish version of the Multiple Sclerosis Impact Scale-29.

BACKGROUND: The Multiple Sclerosis Impact Scale-29 (MSIS-29) has been increasingly used to evaluate the self-perceived impact of multiple sclerosis (MS) on a patient. OBJECTIVES: The aim of this study was to evaluate the psychometric properties of the Finnish version of MSIS-29 in patients with MS. METHODS: A total of 553 patients with MS completed the MSIS-29 and self-administered questionnaires capturing information on demographics, disease characteristics and severity, perceived quality of life (EuroQol 5D-3L instrument), and fatigue (Fatigue Severity Scale). RESULTS: The data quality for MSIS-29 was excellent, with 99.5% computable scores for the MSIS-29 physical scale and 99.3% for the MSIS-29 psychological scale. Floor and ceiling effects were minimal. Excellent Cronbach's alpha values of 0.97 and 0.90 were seen for MSIS-29 physical and psychological subscales, respectively. The physical subscale showed highest correlations with measures of physical functioning, such as disease severity and the mobility domain of the quality of life. Similarly, the psychological subscale showed highest correlations with self-reported fatigue and the anxiety/depression domains of the quality of life. MSIS-29 physical scores related strongly to disease severity, whereas the MSIS-29 psychological scores increased in mild disease but declined in more severe disease forms. CONCLUSION: The Finnish version of MSIS-29 has satisfactory psychometric properties. Consistent with the previous recommendations, the use of two MSIS-29 subscale scores instead of a total score was supported.

Validity and reliability of the Fatigue Severity Scale in Finnish multiple sclerosis patients.

BACKGROUND: Fatigue is one of the most debilitating symptoms in multiple sclerosis (MS) considerably interfering with patients' daily functioning. Both researchers and clinicians need psychometrically robust methods to evaluate fatigue in MS. OBJECTIVES: The objective of this study was (i) to evaluate the psychometric properties of the Finnish version of the Fatigue Severity Scale (FSS) and (ii) to describe the results among patients with MS. METHODS: In total, 553 patients with MS (mean age, 53.8 years; standard deviation [SD], 11.4; 79% women: mean patient-defined disease severity, Expanded Disability Status Scale [EDSS] 4.0, SD, 2.5) completed the self-administered questionnaires including the FSS. A standard procedure was used for the translation of the FSS. RESULTS: The mean (SD) score for the FSS was 4.5 (1.7); in 65% of the patients, the score was ≥4.0. The data quality of the FSS was excellent, with 99.6% of computable scale scores. Floor and ceiling effects were minimal. The FSS showed high internal consistency (Cronbach's alpha, 0.95). Unidimensionality was supported based on confirmatory factor analysis with the comparative fit index being 0.94. The FSS showed moderate/high correlations with the perceived burden of the disease, quality of life and disease severity, whereas, age or gender did not have a significant effect on the FSS score. CONCLUSIONS: The Finnish version of the FSS showed satisfactory reliability and validity and thus can be regarded as a feasible measure of self-reported fatigue.

Mesenchymal stromal cells from female donors enhance breast cancer cell proliferation in vitro.

The interplay between tumor stroma and breast cancer cells (BCCs) is thought to play a significant role in breast cancer. The current knowledge of human mesenchymal stromal cell (MSC) and BCC interaction is contradictory, and the donor sex issue is not addressed at all. We hypothesized that donor sex could have an effect on proliferation of MSCs or BCCs in co-culture in vitro. Three estrogen receptor-negative BCC lines, 19 primary human MSCs and breast tissue-derived fibroblasts from 4 donors were used. MSCs from female donors enhanced BCC proliferation (p = 0.005). The change in BCC proliferation was only partly due to soluble factors excreted by MSCs. The highly aggressive BCC line MDA-MB- 231 induced the proliferation of MSCs (p < 0.001) and fibroblasts (p = 0.037) in co-culture experiments. The magnitude in proliferation change was cell line dependent and partly sex dependent.

Transient proteolytic modification of mesenchymal stromal cells increases lung clearance rate and targeting to injured tissue.

Systemic infusion of therapeutic cells would be the most practical and least invasive method of administration in many cellular therapies. One of the main obstacles especially in intravenous delivery of cells is a massive cell retention in the lungs, which impairs homing to the target tissue and may decrease the therapeutic outcome. In this study we showed that an alternative cell detachment of mesenchymal stromal/stem cells (MSCs) with pronase instead of trypsin significantly accelerated the lung clearance of the cells and, importantly, increased their targeting to an area of injury. Cell detachment with pronase transiently altered the MSC surface protein profile without compromising cell viability, multipotent cell characteristics, or immunomodulative and angiogenic potential. The transient modification of the cell surface protein profile was sufficient to produce effective changes in cell rolling behavior in vitro and, importantly, in the in vivo biodistribution of the cells in mouse, rat, and porcine models. In conclusion, pronase detachment could be used as a method to improve the MSC lung clearance and targeting in vivo. This may have a major impact on the bioavailability of MSCs in future therapeutic regimes.

Cell surface structures influence lung clearance rate of systemically infused mesenchymal stromal cells.

The promising clinical effects of mesenchymal stromal/stem cells (MSCs) rely especially on paracrine and nonimmunogenic mechanisms. Delivery routes are essential for the efficacy of cell therapy and systemic delivery by infusion is the obvious goal for many forms of MSC therapy. Lung adhesion of MSCs might, however, be a major obstacle yet to overcome. Current knowledge does not allow us to make sound conclusions whether MSC lung entrapment is harmful or beneficial, and thus we wanted to explore MSC lung adhesion in greater detail. We found a striking difference in the lung clearance rate of systemically infused MSCs derived from two different clinical sources, namely bone marrow (BM-MSCs) and umbilical cord blood (UCB-MSCs). The BM-MSCs and UCB-MSCs used in this study differed in cell size, but our results also indicated other mechanisms behind the lung adherence. A detailed analysis of the cell surface profiles revealed differences in the expression of relevant adhesion molecules. The UCB-MSCs had higher expression levels of α4 integrin (CD49d, VLA-4), α6 integrin (CD49f, VLA-6), and the hepatocyte growth factor receptor (c-Met) and a higher general fucosylation level. Strikingly, the level of CD49d and CD49f expression could be functionally linked with the lung clearance rate. Additionally, we saw a possible link between MSC lung adherence and higher fibronectin expression and we show that the expression of fibronectin increases with MSC culture confluence. Future studies should aim at developing methods of transiently modifying the cell surface structures in order to improve the delivery of therapeutic cells.

SPECT/CT imaging of hNIS-expression after intravenous delivery of an oncolytic adenovirus and 131I.

Oncolytic adenoviruses can be engineered for better tumor selectivity, gene delivery and be armed for imaging and concentrating radionuclides into tumors for synergistic oncolysis. We constructed Ad5/3-hTERT-hNIS where replication is controlled by hTERT-promoter. Ad5/3-hTERT-hNIS expresses hNIS for imaging of transgene expression and for treatment of infected tumors by radioiodine. Ad5/3-hTERT-hNIS efficiently killed prostate cancer cells and induced iodine uptake in vitro and in vivo after intratumoral virus administration. Survival of mice treated with intravenous Ad5/3-hTERT-hNIS significantly prolonged survival over mock or radioiodine only but the combination of virus with radioiodine was not more effective than virus alone. Temporal and spatial changes in hNIS-expression during therapy were detected with SPECT, demonstrating feasibility of evaluation of the combination therapy with hNIS-expressing adenoviruses and radioiodide.

Induction of interferon pathways mediates in vivo resistance to oncolytic adenovirus.

Oncolytic adenoviruses are an emerging experimental approach for treatment of tumors refractory to available modalities. Although preclinical results have been promising, and clinical safety has been excellent, it is also apparent that tumors can become virus resistant. The resistance mechanisms acquired by advanced tumors against conventional therapies are increasingly well understood, which has allowed development of countermeasures. To study this in the context of oncolytic adenovirus, we developed two in vivo models of acquired resistance, where initially sensitive tumors eventually gain resistance and relapse. These models were used to investigate the phenomenon on RNA and protein levels using two types of analysis of microarray data, quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. Interferon (IFN) signaling pathways were found upregulated and Myxovirus resistance protein A (MxA) expression was identified as a marker correlating with resistance, while transplantation experiments suggested a role for tumor stroma in maintaining resistance. Furthermore, pathway analysis suggested potential therapeutic targets in oncolytic adenovirus-resistant cells. Improved understanding of the antiviral phenotype causing tumor recurrence is of key importance in order to improve treatment of advanced tumors with oncolytic adenoviruses. Given the similarities between mechanisms of action, this finding might be relevant for other oncolytic viruses as well.

Targeted chemotherapy for head and neck cancer with a chimeric oncolytic adenovirus coding for bifunctional suicide protein FCU1.

PURPOSE: Transfer of prodrug activation systems into tumors by using replication-deficient viruses has been suggested to be an effective method for achieving high local and low systemic anticancer drug concentrations. However, most current suicide gene therapy strategies are still hindered by poor efficiency of in vivo gene transfer, inefficient tumor penetration, limited bystander cell killing effect, and need of large prodrug doses. We hypothesized that local amplification provided by a replication competent platform would help overcome these limitations. EXPERIMENTAL DESIGN: We generated a transductionally and transcriptionally targeted oncolytic adenovirus Ad5/3-Delta24FCU1 expressing the fusion suicide gene FCU1. FCU1 encodes a bifunctional fusion protein that efficiently catalyzes the direct conversion of 5-FC, a relatively nontoxic antifungal agent, into the toxic metabolites 5-fluorouracil and 5-fluorouridine monophosphate, bypassing the natural resistance of certain human tumor cells to 5-fluorouracil. RESULTS: We examined the efficacy of Ad5/3-Delta24FCU1 and the replication-defective control Ad5/3-FCU1 with and without 5-FC. FCU1 expression was confirmed by Western blot, whereas enzymatic conversion levels in vitro and in vivo were determined by high-performance liquid chromatography separation. Significant antitumor effect was observed in vitro and in vivo in a murine model of head and neck squamous cell carcinoma. Although we observed a decrease in viral DNA copy number in vitro and in tumors treated with Ad5/3-Delta24FCU1 and 5-FC, suggesting an effect on virus replication, the highest antitumor effect was observed for this combination. CONCLUSIONS: It seems feasible and efficacious to combine adenovirus replication to the FCU1 prodrug activation system.

Mre11 inhibition by oncolytic adenovirus associates with autophagy and underlies synergy with ionizing radiation.

New treatment approaches are needed for hormone refractory prostate cancer. Oncolytic adenoviruses are promising anti-cancer agents, and their efficacy can be improved by combining with conventional therapies such as ionizing radiation. The aim of this study was to determine the timing of oncolytic adenovirus treatment with regard to radiation and study the mechanisms of synergy in combination treatment. Prostate cancer cells were infected with oncolytic adenoviruses, irradiated and synergy mechanisms were assessed. In vivo models of combination treatment were tested. Radiation and oncolytic viruses were synergistic when viral infection was scheduled 24 hr after irradiation. Combination of oncolytic adenovirus with radiotherapy significantly increased antitumor efficacy in vivo compared to either agent alone. Microarray analysis showed dysregulated pathways including cell cycle, mTOR and antigen processing pathways. Functional analysis showed that adenoviral infection was accompanied with degradation of proteins involved in DNA break repair. Mre11 was degraded for subsequent inactivation of Chk2-Thr68 in combination treated cells, while gammaH2AX-Ser139 was elevated implicating the persistence of DNA double strand breaks. Increased autophagocytosis was seen in combination treated cells. Combination treatment did not increase apoptosis or virus replication. The results provide evidence of the antitumor efficacy of combining oncolytic adenoviruses with irradiation as a therapeutic strategy for the treatment of prostate cancer. Further, these findings propose a molecular mechanism that may be important in radiation induced cell death, autophagy and viral cytopathic effect.

Targeted radiotherapy for prostate cancer with an oncolytic adenovirus coding for human sodium iodide symporter.

PURPOSE: Oncolytic adenoviruses are promising tools for cancer therapy. Although several clinical reports have indicated both safety and promising antitumor capabilities for these viruses, there are only a few examples of complete tumor eradication. Thus, the antitumor efficacy of oncolytic adenoviruses needs to be improved. One potentially useful approach is combination with radiotherapy. EXPERIMENTAL DESIGN: To target systemically administered radioiodide to tumors, we created Ad5/3-Delta24-human sodium iodide symporter (hNIS), a Rb-p16 pathway selective infectivity enhanced oncolytic adenovirus encoding hNIS. RESULTS: Ad5/3-Delta24-hNIS replication effectively killed prostate cancer cells in vitro and in vivo. Also, the virus-mediated radioiodide uptake into prostate cancer cells in vitro and into tumors in vivo. Furthermore, Ad5/3-Delta24-hNIS with radioiodide was significantly more effective than virus alone in mice with prostate cancer xenografts. CONCLUSIONS: These results suggest that oncolytic adenovirus-mediated targeted radiotherapy might be a potentially useful option for enhancing the efficacy or adenoviral virotherapy.

Oncolytic Semliki forest virus vector as a novel candidate against unresectable osteosarcoma.

Oncolytic viruses are a promising tool for treatment of cancer. We studied an oncolytic Semliki Forest virus (SFV) vector, VA7, carrying the enhanced green fluorescent protein gene (EGFP), as a novel virotherapy candidate against unresectable osteosarcoma. The efficiency and characteristics of the VA7-EGFP treatment were compared with a widely studied oncolytic adenovirus, Ad5Delta24, both in vitro and in vivo. VA7-EGFP resulted in more rapid oncolysis and was more efficient at low multiplicities of infection (MOI) when compared with Ad5Delta24 in vitro. Yet, in MG-63 cells, a subpopulation resistant to the VA7-EGFP vector emerged. In subcutaneous human osteosarcoma xenografts in nude mice treatment with either vector reduced tumor size, whereas tumors in control mice expanded quickly. The VA7-EGFP-treated tumors were either completely abolished or regressed to pinpoint size. The efficacy of VA7-EGFP vector was studied also in an orthotopic osteosarcoma nude mouse model characterized by highly aggressive tumor growth. Treatment with oncolytic SFV extended survival of the animals significantly (P < 0.01), yet none of the animals were finally cured. Sera from SFV-treated mice contained neutralizing antibodies, and as nude mice are not able to establish IgG response, the result points out the role of IgM class antibodies in clearance of virus from peripheral tumors. Furthermore, biodistribution analysis at the survival end point verified the presence of virus in some of the brain samples, which is in line with previous studies demonstrating that IgG is required for clearance of SFV from central nervous system.

Generation of a conditionally replicating adenovirus based on targeted destruction of E1A mRNA by a cell type-specific MicroRNA.

MicroRNAs have emerged as important players in tissue-specific mammalian gene regulation and have also been exploited in experimental targeting of gene expression. We have constructed a recombinant adenovirus that contains sequences complementary to the liver-specific microRNA 122 (miR122) in the 3' untranslated region of the E1A gene. In Huh7 cells, which resemble normal hepatocytes in expressing high levels of miR122, this feature resulted in strongly reduced levels of E1A mRNA and protein. This property allowed us to generate a novel recombinant adenovirus that was severely attenuated in cells of hepatic origin but replicated normally in other cells. This strategy may be useful in circumventing liver toxicity associated with the systemic delivery of oncolytic adenoviruses. These data provide the first example of exploiting differential microRNA expression patterns to alter the natural tropism of a DNA virus. In addition, these results suggest that other microRNAs expressed in a tissue- or transformation-specific manner may also be used for the targeting of adenoviral replication and that the same principle may be applied to other viruses that have shown promise as oncolytic or gene delivery platforms.

Tissue-specific promoters active in CD44+CD24-/low breast cancer cells.

It has been proposed that human tumors contain stem cells that have a central role in tumor initiation and posttreatment relapse. Putative breast cancer stem cells may reside in the CD44(+)CD24(-/low) population. Oncolytic adenoviruses are attractive for killing of these cells because they enter through infection and are therefore not susceptible to active and passive mechanisms that render stem cells resistant to many drugs. Although adenoviruses have been quite safe in cancer trials, preclinical work suggests that toxicity may eventually be possible with more active agents. Therefore, restriction of virus replication to target tissues with tissues-specific promoters is appealing for improving safety and can be achieved without loss of efficacy. We extracted CD44(+)CD24(-/low) cells from pleural effusions of breast cancer patients and found that modification of adenovirus type 5 tropism with the serotype 3 knob increased gene delivery to CD44(+)CD24(-/low) cells. alpha-Lactalbumin, cyclo-oxygenase 2, telomerase, and multidrug resistance protein promoters were studied for activity in CD44(+)CD24(-/low) cells, and a panel of oncolytic viruses was subsequently constructed. Each virus featured 5/3 chimerism of the fiber and a promoter controlling expression of E1A, which was also deleted in the Rb binding domain for additional tumor selectivity. Cell killing assays identified Ad5/3-cox2L-d24 and Ad5/3-mdr-d24 as the most active agents, and these viruses were able to completely eradicate CD44(+)CD24(-/low) cells in vitro. In vivo, these viruses had significant antitumor activity in CD44(+)CD24(-/low)-derived tumors. These findings may have relevance for elimination of cancer stem cells in humans.

The cyclo-oxygenase 2 promoter is induced in nontarget cells following adenovirus infection, but an AU-rich 3'-untranslated region destabilization element can increase specificity.

BACKGROUND: Cyclo-oxygenase 2 (Cox-2) is expressed in many types of tumors, but typically undetectable in normal tissues. However, Cox-2 is known to be induced following infection by many microbial agents, which might threaten the tumor selectivity of the Cox-2 promoter in the context of virotherapy or viral gene delivery. Cox-2 expression is regulated in part post-transcriptionally by stimulation or inhibition of mRNA degradation by 3'-untranslated region (3'-UTR) AU-rich elements. In the present study, we investigated the induction of the Cox-2 promoter both in normal and tumor cells after adenovirus infection and explored the utility of AU-rich elements for regaining promoter selectivity. METHODS: Nontumor and tumor cells were transfected in vitro and in vivo with plasmids containing the Cox-2 or cytomegalovirus immediate early promoter driving luciferase (with or without 3'-UTR elements) followed by adenoviral infection. Selectivity and activity of the promoters and 3'-UTR elements were analysed by luciferase assay and in-vivo imaging. RESULTS: The Cox-2 promoter was induced in both normal and tumor cells following infection with E1 containing replicative adenoviruses but not in the absence of E1. Utilization of AU-rich elements counteracted promoter induction in vitro and in vivo in nonmalignant cells but not in cancer cells, thus increasing the selectivity of the approach ten-fold without loss of potency. CONCLUSIONS: Adenoviral infection induces the Cox-2 promoter in normal and tumor cells, which might compromise specificity of the promoter. Utilization of AU-rich destabilization elements can rescue the tumor selectivity of the promoter.

Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses.

Renal cancer is a common and deadly disease that lacks curative treatments when metastatic. Here, we have used oncolytic adenoviruses, a promising developmental approach whose safety has recently been validated in clinical trials. Although preliminary clinical efficacy data exist for selected tumor types, potency has generally been less than impressive. One important reason may be that expression of the primary receptor, coxsackie-adenovirus receptor, is often low on many or most advanced tumors, although not evaluated in detail with renal cancer. Here, we tested if fluorescence-assisted cell sorting could be used to predict efficacy of a panel of infectivity-enhanced capsid-modified marker gene expressing adenoviruses in renal cancer cell lines, clinical specimens, and subcutaneous and orthotopic murine models of peritoneally metastatic renal cell cancer. The respective selectively oncolytic adenoviruses were tested for killing of tumor cells in these models, and biodistribution after locoregional delivery was evaluated. In vivo replication was analyzed with noninvasive imaging. Ad5/3-Delta24, Ad5-Delta24RGD, and Ad5.pK7-Delta24 significantly increased survival of mice compared with mock or wild-type virus and 50% of Ad5/3-Delta24 treated mice were alive at 320 days. Because renal tumors are often highly vascularized, we investigated if results could be further improved by adding bevacizumab, a humanized antivascular endothelial growth factor antibody. The combination was well tolerated but did not improve survival, suggesting that the agents may be best used in sequence instead of together. These results set the stage for clinical testing of oncolytic adenoviruses for treatment of metastatic renal cancer currently lacking other treatment options.

Oncolytic adenoviruses kill breast cancer initiating CD44+CD24-/low cells.

Cancer stem cells have been indicated in the initiation of tumors and are even found to be responsible for relapses after apparently curative therapies have been undertaken. In breast cancer, they may reside in the CD44(+)CD24(-/low) population. The use of oncolytic adenoviruses presents an attractive anti-tumor approach for eradication of these cells because their entry occurs through infection and they are, therefore, not susceptible to those mechanisms that commonly render stem cells resistant to many drugs. We isolated CD44(+)CD24(-/low) cells from patient pleural effusions and confirmed stem cell-like features including oct4 and sox2 expression and Hoechst 33342 exclusion. CD44(+)CD24(-/low) cells, including the Hoechst excluding subpopulation, could be effectively killed by oncolytic adenoviruses Ad5/3-Delta24 and Ad5.pk7-Delta24. In mice, CD44(+)CD24(-/low) cells formed orthotopic breast tumors but virus infection prevented tumor formation. Ad5/3-Delta24 and Ad5.pk7-Delta24 were effective against advanced orthotopic CD44(+)CD24(-/low)-derived tumors. In summary, Ad5/3-Delta24 and Ad5.pk7-Delta24 can kill CD44(+)CD24(-/low), and also committed breast cancer cells, making them promising agents for treatment of breast cancer.

Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors.

Systemic adenoviral delivery into tumors is inefficient because of liver sequestration of intravenously administered virus. One potential solution for improving bioavailability is the use of carrier cells such as human mesenchymal stem cells (MSCs), which have been suggested to have inherent tumor tropism. Here we investigated the capacity of capsid-modified adenoviruses to infect and replicate in MSCs. Further, biodistribution and tumor-killing efficacy of MSCs loaded with oncolytic adenoviruses were evaluated in orthotopic murine models of lung and breast cancer. In vitro, heparan sulfate proteoglycan- and alpha(v)beta integrin-targeted viruses enhanced gene delivery to bone marrow- and adipose tissue-derived MSCs up to 11,000-fold over adenovirus serotype 5 (Ad5). Infectivity-enhanced oncolytic adenoviruses showed notably higher rates of cytolysis of in vitro-passaged MSCs in comparison with wild-type virus. In vivo, intravenously injected MSCs homed primarily to the lungs, and virus was released into advanced orthotopic breast and lung tumors for therapeutic efficacy and increased survival. When the same dose of virus was injected intravenously without MSCs, only transduction of the liver was seen. These results suggest that MSCs loaded with oncolytic adenoviruses might be a useful approach for improving the bioavailability of systemically administered oncolytic adenoviruses.