Associations of School Diversity with Students' Race-based Victimization and School Connectedness: A Combined Influence of Student and Teacher Racial/Ethnic Diversity and Socioeconomic Diversity.

School diversity has been shown to be associated with students' school experiences. However, most studies have focused solely on student racial/ethnic diversity, in spite of the multifaceted nature of diversity. This study assessed how the combined influence of student and teacher racial/ethnic diversity and socioeconomic diversity were related to race-based victimization, school connectedness, and racial/ethnic disparities of these outcomes. The participants were Asian, Black, Latinx, and White students (n = 100,408; 46.2-53.5% female) in Grade 7 to Grade 12 attending 278 public schools in California. The participating schools' diversity contexts were categorized into four latent profiles differentiated by varying levels of student and teacher racial/ethnic diversity and socioeconomic diversity. Race-based victimization was the least prevalent in schools with low student racial/ethnic diversity, low socioeconomic diversity, and moderate teacher racial/ethnic diversity. The magnitude of racial/ethnic disparities in race-based victimization differed across the four latent profiles; racial/ethnic disparities were minimal when there were similar numbers of students in each racial/ethnic group. School diversity's relation with school connectedness was minimal. White students perceived higher school connectedness than other racial/ethnic groups across profiles, but the White-Latinx gap was smaller in profiles with schools having a homogeneous Latinx student population. The findings underline the importance of understanding school diversity's interaction with students' characteristics, particularly racial/ethnic identity, on students' school experiences.

Teacher victimization and teachers' subjective well-being: Does school climate matter?

Guided by the job demands-resources model, we examined the multilevel associations between victimization experience with student violence directed against teachers, school climate, and teachers' subjective well-being (i.e., school connectedness and teaching efficacy) among 1711 teachers (7th-12th grade) from 58 middle and high schools in China. Hierarchical linear modeling analyses revealed that teachers who reported more frequent teacher victimization perceived a lower level of teaching efficacy; however, teachers in schools with a higher level of teacher victimization scores at the school level perceived a higher level of teaching efficacy. Although school climate was positively related to teacher well-being at both teacher and school levels, the negative association between teacher victimization and teachers' subjective well-being at the teacher level was exacerbated in schools with a more positive school climate at the school level. The significant cross-level moderating effect of school-level school climate in the association between teacher-level victimization and subjective well-being was consistent with the "healthy context paradox" but contradicted with the "emotion contagion hypothesis." Our findings support the risk influence of teacher victimization and the promotive role of positive school climate on teachers' subjective well-being. Our results also indicate that teachers in schools with a more positive and collective perception of school climate tend to be more attuned to the negative influences of teacher victimization on their subjective well-being than teachers in schools with a less positive and collective perception of school climate.

Peer Victimization and Problem Behaviors: The Roles of Self-Esteem and Parental Attachment Among Chinese Adolescents.

Guided by the social-ecological diathesis-stress model, this longitudinal study examined the roles of self-esteem, parental attachment, and gender on the association between peer victimization and problem behaviors among Chinese early adolescents. A total of 466 Chinese middle school students (Mage  = 12.8 years) completed measures of peer victimization, self-esteem, and paternal and maternal attachment twice (T1 and T2; 6-month interval). Their guardians also completed ratings on adolescents' problem behaviors at both T1 and T2. Results indicated that self-esteem mediated the association between peer victimization and problem behaviors. Paternal attachment, but not maternal attachment, moderated the mediating effect of self-esteem. Moreover, the moderating effect of maternal attachment on the association between peer victimization and self-esteem varied depending on adolescents' gender.

Exploration of Textile-Silicone Composites and Materials for Personal Impact-Resistant Protection.

Conventional cushioning materials such as silicone sheets which have been recommended for resisting impact generally cause discomfort to the wearer from heat and perspiration. With the increasing need for personal protective equipment, textile-silicone composite structures are proposed in this study to reduce acute impact and moisture while enhancing thermal comfort. The influence of the composite structure and thickness on the mechanical and thermal properties of textile-silicone materials are systematically investigated. The results show that an additional knitted powernet fabric as a composite material can significantly improve the tensile properties of silicone rubber by up to 315%. However, only a slight improvement is found in the thermal conductivity (up to 16%), compression elasticity (up to 18%) and force reduction performance (up to 3.6%). As compared to inlaid spacer fabric, which has also been used for cushioning and preserving thermal comfort, the textile-silicone composites have higher tensile and compression elasticity, exhibit force reduction with the largest difference of 43% and are more thermally conductive, with increases more than 38%. The findings of this study introduced a cost-effective new silicone-textile composite for optimal impact protection and wear comfort for protective applications.

A Scientometric Analysis and Visualization of Prosthetic Foot Research Work: 2000 to 2022.

This study aims to highlight recent research work on topics around prosthetic feet through a scientometric analysis and historical review. The most cited publications from the Clarivate Analytics Web of Science Core Collection database were identified and analyzed from 1 January 2000 to 31 October 2022. Original articles, reviews with full manuscripts, conference proceedings, early access documents, and meeting abstracts were included. A scientometric visualization analysis of the bibliometric information related to the publications, including the countries, institutions, journals, references, and keywords, was conducted. A total of 1827 publications met the search criteria in this study. The related publications grouped by year show an overall trend of increase during the two decades from 2000 to 2022. The United States is ranked first in terms of overall influence in this field (n = 774). The Northwestern University has published the most papers on prosthetic feet (n = 84). Prosthetics and Orthotics International has published the largest number of studies on prosthetic feet (n = 151). During recent years, a number of studies with citation bursts and burst keywords (e.g., diabetes, gait, pain, and sensor) have provided clues on the hotspots of prosthetic feet and prosthetic foot trends. The findings of this study are based on a comprehensive analysis of the literature and highlight the research topics on prosthetic feet that have been primarily explored. The data provide guidance to clinicians and researchers to further studies in this field.

Ten frequently asked questions about latent transition analysis.

Latent transition analysis (LTA), also referred to as latent Markov modeling, is an extension of latent class/profile analysis (LCA/LPA) used to model the interrelations of multiple latent class variables. LTA methods have become increasingly accessible and in-turn are being utilized in applied research. The current article provides an introduction to LTA by answering 10 questions commonly asked by applied researchers. Topics discussed include: (1) an overview of LTA; (2) a comparison of LTA to other longitudinal models; (3) software used to run LTA; (4) sample size suggestions; (5) modeling steps in LTA; (6) measurement invariance; (7) the inclusion of auxiliary variables; (8) interpreting results of an LTA; (9) the nature of data (e.g., longitudinal, cross-sectional); and (10) extensions of LTA. An applied example of LTA is included to help understand how to build an LTA and interpret results. Finally, the article suggests future areas of research for LTA. This article provides an overview of LTA, highlighting key decisions researchers need to make to navigate and implement an LTA analysis from start to finish. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Heterogeneity Among Moderate Mental Health Students on the Mental Health Continuum-Short Form (MHC-SF).

Measures of positive well-being are needed to support the shift away from a deficit-based approach to mental health. This study examined one measure, the Mental Health Continuum-Short Form (MHC-SF), as a measure of positive well-being used in school-based mental health monitoring efforts. This study used latent profile analysis (LPA) to explore the mental health classifications of 10,880 California high school students' responses to MHC-SF emotional, psychological, and social well-being items. Five latent mental wellness profiles emerged, including two ordered profiles (i.e., High Well-Being and Low Well-Being) and three profiles spanning the two ordered profiles. The High Well-Being profile had the most favorable psychological adjustment, and the three moderate well-being range profiles had differentiated functioning. Informing the utility of the MHC-SF, this study also compared the MHC-SF categorical diagnostic criteria with the LPA's empirical classification approach and found the two classification approaches to be congruent. The findings provide an impetus for educators to attend to students in moderate well-being ranges and emphasize promoting positive mental well-being as an essential component of school-based mental health services.

Social support profiles associations with adolescents' psychological and academic functioning.

Social support is empirically linked to improved adolescent psychological and academic functioning. This study explored typologies characterized by family, peer, and school support among students in early (Grade 7; n = 27,399) and late (Grade 11; n = 27,984) adolescence. We assessed how each latent profile related to key aspects of psychological and academic functioning and the moderation of gender in these associations. Three convergent profiles (i.e., High, Moderate, and Low Support) and two divergent profiles (i.e., Minimum Peer Support and Minimum Family Support) were found in both grade levels, with psychological and academic functioning differentiated by the profiles. The Minimum Peer Support and Minimum Family Support profiles showed the lowest functioning in all domains across grade levels. The High Support profile showed the highest psychological health and academic performance. Gender moderation was observed in the associations between social support profiles and psychological functioning and was more prominent among 7th graders than 11th graders. Findings suggest that social support's impact is determined by combinations of various support sources, age, and gender. The social support profiles and their associations with students' characteristics and outcomes may inform practitioners in supporting vulnerable groups and planning interventions.

Parental perceptions of school climate in the United States and China: Advancing cross-country understanding.

To advance cross-country understanding of parental perceptions of school climate, this study examined the psychometric properties of the Delaware School Climate Survey-Home version (DSCS-H) and also compared the parental perception of school climate among Chinese (n = 999) and American (n = 1,251) parents. Confirmatory factor analyses revealed that the DSCS-H was best supported by a second-order factor model in both samples and full measurement invariance across countries was evident. Comparison of overall school climate latent means revealed that American parents from elementary schools perceived a more positive overall school climate than did Chinese parents. Conversely, Chinese parents of students in high school perceived a more positive overall school climate than the American parents. The latent-mean difference of parental perception of the overall school climate in middle schools across the United States and China was not significantly different. Finally, the latent mean differences in school climate subfactors varied across grade levels. Implications for using the DSCS-H for assessing and understanding the perception of school climate among parents from diverse cultural and linguistic backgrounds are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Training Experience in the US School Psychology Program: Understanding Asian International Students' Assets, Challenges, and Coping.

To address the rapidly increasing demand for culturally and linguistically diverse school psychologists and training needs for international school psychology students in the USA, this study was grounded in the risk and resilience framework and used semi-structured interviews to explore the nuanced experiences of Asian international trainees in school psychology programs in the USA. Participants included 11 Asian international students who were enrolled in or recently graduated from school psychology programs in the USA. Thematic analysis revealed that Asian international school psychology students identified some assets they have brought to the program, including their diverse perspectives and experiences, awareness and commitment to social justice, and the potential to diversify the school psychology workforce. Participants also identified several challenges they were facing, such as acculturative stress, microaggression and discrimination, training program-related issues, and working restrictions related to their visa status. Moreover, they identified some effective strategies (i.e., seeking resources and increasing internal strengths) they have used to cope with these challenges. The findings provide important implications for school psychology graduate programs in the USA to improve the training experiences and training outcomes for international students from Asia and other countries.

Elementary school teacher well-being and supportive measures amid COVID-19: An exploratory study.

As frontline education providers, teachers have encountered many challenges since the outbreak of the COVID-19 pandemic. To better understand teacher well-being during this crisis and inform practices to support them, this study employed an online survey with a mixed-methods approach to assess teacher well-being and the support they need to work effectively. A sample of 151 elementary school teachers in the United States was recruited in summer 2020 to complete an online survey through emails and social media outlets. Participants were asked to provide retrospective reports of their experiences teaching in spring 2020 after schools closed due to COVID-19. The majority of participants reported feeling emotionally exhausted and high levels of task stress and job ambiguity. Consistent with hypotheses, path analysis testing a model informed by the job demand-resources framework indicated that task stress and job ambiguity were robustly related to teacher well-being. Moreover, three job resources (i.e., teaching efficacy, school connectedness, and teaching autonomy) were related to job satisfaction. A moderation finding revealed that teachers who reported high teaching efficacy felt emotionally exhausted when they were unclear of their job duties. Thematic analysis of responses to an open-ended question found that teachers would feel supported if provided resources to develop competence in distance learning, workplace emotional support, and flexibility during COVID-19. The findings identified a critical need to allocate more attention and resources to support teacher psychological health by strengthening emotional support, autonomy, and teaching efficacy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

School-wide social emotional learning (SEL) and bullying victimization: Moderating role of school climate in elementary, middle, and high schools.

Guided by the school-wide social-emotional learning framework and social-ecological model, in this study we examined the associations between students' perceptions of four core social emotional learning (SEL) competencies (i.e., responsible decision-making, social awareness, self-management, and relationship skills) and school climate and their experience with bullying victimization through a multilevel framework. We also examined the multilevel moderating effects of students' perceptions of school climate, gender, and school levels (elementary, middle, and high schools) on the association between SEL competencies and bullying victimization. Participants were 23,532 students (4th to 12th grade) from 90 schools in Delaware. Using hierarchical linear modeling and controlling for demographic factors and school climate at both student and school levels, we found that three of the four core SEL competencies (i.e., social awareness, relationship skills, and self-management) and student-level school climate perceptions had significant associations with students' bullying victimization experiences. Moreover, the positive association between social awareness and bullying victimization and the negative association between self-management and bullying victimization were both mitigated in schools with more positive school climate at the student level. The association between some of the SEL competencies and bullying victimization varied depending on students' gender and grade levels. The findings highlight the unique and differentiated relations among the four core SEL competencies and students' bullying victimization experiences; they also suggest the importance of including school climate assessment and applying gender- and grade-level-specific efforts in bullying prevention programs with an SEL focus.

Association between school climate and bullying victimization: Advancing integrated perspectives from parents and cross-country comparisons.

To advance our scientific understanding about school climate and bullying victimization from the perspectives of both parents and cross-country comparisons, the present study examined the cross-country similarities and differences of the associations between overall school climate and 3 forms of bullying victimization between United States (U.S.; N = 1,251) and Chinese (N = 999) parents across elementary, middle, and high schools. Confirmatory factor analyses and measurement invariance tests were first conducted to examine the cross-country validity of the Delaware Bullying Victimization Survey-Home (DBVS-H) between U.S. and Chinese parents. Comparison of latent means of bullying victimization revealed that U.S. parents reported higher frequencies of social/relational and verbal bullying victimization compared with Chinese parents. Structural equation modeling (SEM) was then used to examine the cross-country differences of the relationship between school climate and bullying victimization. For parents in both China and the U.S., school climate was found to be significantly associated with 3 types of bullying victimization (i.e., physical, verbal, and social/relational). The negative associations between school climate and all 3 types of bullying victimization reported by U.S. parents were significantly stronger than those found in Chinese parents. Implications for bullying prevention efforts involving parents from diverse cultural and linguistic backgrounds were discussed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Real-time diagnostic imaging of tumors and metastases by use of a replication-competent herpes vector to facilitate minimally invasive oncological surgery.

Current efforts on expanding minimally invasive techniques into the realm of oncological surgery are hindered by lack of accurate visualization of tumor margins and failure to detect micro metastases in real time. We used a systemic delivery of a herpes viral vector with cancer-selective infection and replication to precisely differentiate between normal and malignant tissue. NV1066 is a genetically modified, replication-competent herpes simplex virus carrying a transgene for enhanced green fluorescent protein (GFP). We tested the potential of NV1066 in delineating tumor tissue in vitro and in vivo in a wide range of cancers and whether NV1066-induced GFP expression can detect small foci of tumors and metastases in in vivo models using an operating endoscope with fluorescent filters. Our findings indicate that NV1066 can be used for real-time intraoperative imaging and enhanced detection of early cancers and metastases. We demonstrate that a single dose of NV1066, administered either locally (intratumoral or intracavitary) or systemically, will detect loco-regional and distant disease throughout the body. Such cancer selectivity is confirmed in 110 types of cancer cells from 16 different primary organs. Fluorescence-aided minimally invasive endoscopy revealed microscopic tumor deposits unrecognized by conventional laparoscopy/thoracoscopy. Furthermore, NV1066 ability to transit and infect tumor and metastases is proven in syngenic and transplanted tumors in different animal models, both immunocompetent and immunodeficient. Cancer-selective GFP expression is confirmed by histology, immunohistochemistry, and qRT-PCR. These studies form the basis for real-time, intraoperative diagnostic imaging of tumor and metastases by minimally invasive endoscopic technology.

Cisplatin-induced GADD34 upregulation potentiates oncolytic viral therapy in the treatment of malignant pleural mesothelioma.

BACKGROUND: NV1066, a replication-competent oncolytic herpes simplex virus type 1 (HSV-1) attenuated by a deletion in the gene gamma(1)34.5, preferentially replicates in and kills malignant cells. gamma(1)34.5 encodes ICP34.5, a viral protein essential for productive replication, which has homology with mammalian stress response induced GADD34 (growth arrest and DNA damage-inducible protein). We hypothesized that cisplatin upregulates GADD34 expression, which enhances NV1066 replication and oncolysis. METHODS: Ten human malignant pleural mesothelioma (MPM) cell lines were infected with NV1066 at multiplicities of infection (MOI; ratio of viral particles per tumor cell) 0.005 to 0.8 in vitro, with and without cisplatin (1 to 4 microM). In the MPM cell line VAMT, viral replication was determined by plaque assay, cell kill by lactate dehydrogenase assay, and GADD34 induction by quantitative RT-PCR and Western blot. Synergistic efficacy was confirmed by the isobologram and combination index methods of Chou-Talalay. GADD34 upregulation by cisplatin was inhibited with GADD34 siRNA to further confirm the synergistic efficacy dependence with GADD34. RESULTS: Combination therapy with NV1066 and cisplatin showed strong synergism in epithelioid (H-2452, H-Meso), sarcomatoid (H-2373, H-28), and biphasic (JMN, Meso-9, MSTO-211H) MPM cell lines, and an additive effect in others. In VAMT cells combination therapy enhanced viral replication 4 to 11-fold (p < 0.01) and cell kill 2 to 3-fold (p < 0.01). Significant dose reductions for both agents (2 to 600-fold) were achieved over a wide range of therapeutic-effect levels (LD50-LD99) without compromising cell kill. Synergistic cytotoxicity correlated with GADD34 upregulation (2 to 4-fold, p < 0.01) and was eliminated following transfection with GADD34 siRNA. CONCLUSION: Cisplatin-induced GADD34 expression selectively enhanced the cytotoxicity of the gamma(1)34.5-deficient oncolytic virus, NV1066. This provides a cellular basis for combination therapy with cisplatin and NV1066 to treat MPM and achieve synergistic efficacy, while minimizing dosage and toxicity.

Estrogen enhances the efficacy of an oncolytic HSV-1 mutant in the treatment of estrogen receptor-positive breast cancer.

Oncolytic herpes simplex virus-1 (HSV-1) mutants selectively replicate in and lyse tumor cells. Viral replication is dependent on the cellular proliferative mechanism. Estrogen increases cellular proliferation and decreases apoptosis in estrogen receptor-positive (ER+) human breast cancer cells. We hypothesize that the cellular changes produced by estrogen may enhance oncolytic viral replication and improve the treatment of ER+ breast cancer cells. Estrogen increased proliferation and replication of the HSV-1 mutant, NV1066, in ER+ breast cancer cells. Additionally, cells grown with estrogen had lower rates of apoptosis and higher bcl-2 levels at baseline and after infection. Estrogen enhanced the oncolytic effect of NV1066, with cell kills of 95% and 97% at MOIs of 0.1 and 0.5, compared to 53 and 87% respectively without estrogen (p<0.001). Therapy of ER+ human breast cancer cells with a replication-competent HSV-1 mutant is improved in the presence of estrogen, in contrast to more standard therapies, such as chemotherapy and radiation, which demonstrate decreased efficacy in similar conditions. These data provide the mechanistic basis for the use of oncolytic HSV-1 in patients with hormone receptor-positive breast cancer, particularly if the disease progresses with conventional therapies.

Enhanced nectin-1 expression and herpes oncolytic sensitivity in highly migratory and invasive carcinoma.

PURPOSE: Although a variety of malignant tumors are susceptible to therapy with oncolytic herpes simplex viruses, the determinants of tumor sensitivity to these viruses are poorly understood. Nectin-1 is a cell surface adhesion molecule that is a component of intercellular adherens junctions and also functions as a herpes viral receptor. Because highly invasive cells may have decreased intercellular adhesion, we sought to determine if such cells might also have altered availability of cell surface nectin-1 to act as a herpes receptor. EXPERIMENTAL DESIGN AND RESULTS: A series of squamous cell carcinoma lines of increasing migratory and invasive potential, termed MG1-MG14, were selected by serial passages of murine SCC7 through Matrigel invasion chambers. Available cell surface nectin-1 was enhanced on the MG11 and MG14 cell lines in comparison to SCC7 as measured by cellular ELISA and immunofluorescence microscopy. A replication-competent, oncolytic herpes virus (NV1023) showed an increased ability to enter MG11 and MG14 cells as compared with SCC7 cells. Furthermore, MG11 and MG14 supported increased herpes viral replication and cytotoxicity over SCC7. For all three of the cell lines, viral entry assays revealed that the actively migrating cells were significantly more susceptible to herpes infection than the nonmigrating cells. CONCLUSIONS: These results show that malignant cells with highly migratory and invasive properties may exhibit increased cell surface nectin-1 availability, which may serve as a herpes viral receptor to enhance the efficacy of herpes oncolytic therapy. This finding has implications regarding patient selection for future clinical trials using these promising therapeutic vectors.

5-fluorouracil and gemcitabine potentiate the efficacy of oncolytic herpes viral gene therapy in the treatment of pancreatic cancer.

Oncolytic herpes viruses are attenuated, replication-competent viruses that selectively infect, replicate within, and lyse cancer cells and are highly efficacious in the treatment of a wide variety of experimental cancers. The current study seeks to define the pharmacologic interactions between chemotherapeutic drugs and the oncolytic herpes viral strain NV1066 in the treatment of pancreatic cancer cell lines. The human pancreatic cancer cell lines Hs 700T, PANC-1, and MIA PaCa-2 were treated in vitro with NV1066 at multiplicities of infection (MOI; ratio of the number of viral particles per tumor cell) ranging from 0.01 to 1.0 with or without 5-fluorouracil (5-FU) or gemcitabine. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Viral replication was measured using a standard plaque assay. Six days after combination therapy, 76% of Hs 700T cells were killed compared with 43% with NV1066 infection alone (MOI = 0.1) or 0% with 5-FU alone (2 micromol/L) (P < .01). Isobologram and combination-index analyses confirmed a strongly synergistic pharmacologic interaction between the agents at all viral and drug combinations tested (LD5 to LD95) in the three cell lines. Dose reductions up to 6- and 78-fold may be achieved with combination therapy for NV1066 and 5-FU, respectively, without compromising cell kill. 5-FU increased viral replication up to 19-fold compared with cells treated with virus alone. Similar results were observed by combining gemcitabine and NV1066. We have demonstrated that 5-FU and gemcitabine potentiate oncolytic herpes viral replication and cytotoxicity across a range of clinically achievable doses in the treatment of human pancreatic cancer cell lines. The potential clinical implications of this synergistic interaction include improvements in efficacy, treatment-associated toxicity, tolerability of therapeutic regimens, and quality of life. These data provide the cellular basis for the clinical investigation of combined oncolytic herpes virus therapy and chemotherapy in the treatment of pancreatic cancer.

Virally directed fluorescent imaging improves diagnostic sensitivity in the detection of minimal residual disease after potentially curative cytoreductive surgery.

Completeness of cytoreduction is an independent prognostic factor after cure-intended surgery for peritoneal carcinomatosis. NV1066, a genetically engineered herpes simplex virus carrying the transgene for green fluorescent protein, selectively infects cancer cells. We sought to determine the feasibility of virally directed fluorescent imaging in the intraoperative detection of minimal residual disease after cytoreductive surgery. NV1066 infected human gastric cancer cells, OCUM-2MD3, and mesothelioma JMN cells at all doses. The infected cells expressed green fluorescent protein and were killed. OCUM-2MD3, and mesothelioma JMN cells at all doses. Peritoneal carcinomatosis was established in mice by injection of OCUM cells into the peritoneal cavity. Forty-eight hours after intraperitoneal injection of NV1066, two experienced surgeons resected all visible disease and identified mice free of disease. Eight of 13 mice thought to be free of disease were found to have residual disease as identified by green fluorescence (mean number of observations: 5; range: 1-9). Residual disease was most frequently observed in the retroperitoneum, pelvis, peritoneal surface, and liver. Specificity of NV1066 infection to tumor nodules was confirmed by immunohistochemistry and by polymerase chain reaction for viral gene. Virally directed fluorescent imaging, a novel molecular imaging technology, can be used for real-time visualization of minimal residual disease after cytoreductive surgery and can improve the completeness of cure-intended resection.

Angiogenesis inhibition by an oncolytic herpes virus expressing interleukin 12.

PURPOSE: Oncolytic herpes simplex viruses (HSVs) may have significant antitumor effects resulting from the direct lysis of cancer cells. HSVs may also be used to express inserted transgenes to exploit additional therapeutic strategies. The ability of an interleukin (IL)-12-expressing HSV to treat squamous cell carcinoma (SCC) by inhibition of tumor angiogenesis is investigated in this study. EXPERIMENTAL DESIGN: A replication-competent, attenuated, oncolytic HSV carrying the murine IL-12 gene (NV1042), its non-cytokine-carrying analog (NV1023), or saline was used to treat established murine SCC flank tumors by intratumoral injection. The expression of secondary antiangiogenic mediators was measured. Angiogenesis inhibition was assessed by in vivo Matrigel plug assays, flank tumor subdermal vascularity, and in vitro endothelial cell tubule formation assay. RESULTS: Intratumoral injections of NV1042 (2 x 10(7) plaque-forming units) into murine SCC VII flank tumors resulted in smaller tumor volumes as compared with NV1023 or saline. IL-12 and IFN-gamma expression in tumors was 440 and 2.2 pg/mg, respectively, at 24 h after NV1042 injection, but both IL-12 and IFN-gamma were undetectable (<0.2 pg/mg) after NV1023 or saline injections. Expression of two antiangiogenesis mediators, monokine induced by IFN-gamma and IFN-inducible protein 10, was elevated after NV1042 treatment. Matrigel plug assays of NV1042-transfected SCC VII tumor cells demonstrated significantly decreased hemoglobin content and microvessel density as compared with NV1023 and PBS. Excised murine flank tumors treated with NV1042 had decreased subdermal vascularity as compared with NV1023 and PBS. Both splenocytes and IL-12 expression by NV1042 were required for in vitro inhibition of endothelial tubule formation. CONCLUSIONS: IL-12 expression by an oncolytic herpes virus enhances therapy of SCC through antiangiogenic mechanisms. Strategies combining HSV oncolysis with angiogenesis inhibition merit further investigation for potential clinical application.