Tobacco industry marketing and selleck chemicals Gemcitabine adver
According to 2005 data from the U.S. Bureau of the Census, Latinos now comprise over 14% of the nation’s population and are the largest and fastest growing minority group in the United States (Bernstein, 2006). Although the prevalence of smoking is lower among Latinos than the general population (15.2% vs. 20.8%), the adverse consequences of tobacco use on Latino health are severe (Centers for Disease Control and Prevention [CDC], 2007). For example, three of the four leading causes of death among Latinos are related to smoking (cancer, heart disease, and stroke), and lung cancer is the leading cause of cancer death among Latino men and the second leading cause among Latino women (National Cancer Institute [NCI], 2005).

Moreover, Latinos experience tobacco-related disparities associated with access to treatment, tobacco marketing, cultural and language barriers (Bolen, Rhodes, Powell-Griner, Bland, & Holtzman, 1997), and receipt of physician advice to quit smoking (CDC, 2000). Thus, research addressing tobacco use and dependence among minority groups such as Latinos has been identified as a major public health priority (Fiore et al., 2000; U.S. Department of Health and Human Services, 2001). Latino smokers may be relatively unique among racial/ethnic groups with respect to nondaily, low-level daily (i.e., 1�C5 cigarettes/day), or light daily smoking (i.e., 6�C10 cigarettes/day; Fagan, Moolchan, Lawrence, Fernander, & Ponder, 2007; Okuyemi et al., 2002; S. H. Zhu, Pulvers, Zhuang, & Baezconde-Garbanati, 2007).

Data from the National Household Survey on Drug Abuse (1991�C1993) indicated that 27.4% of Latinos were low-level daily smokers, as compared with 18.4% of Black and 9.3% of White smokers (Kandel & Chen, 2000). Unfortunately, low-level smokers have typically been excluded from randomized clinical trials of smoking cessation interventions, perhaps due to perceptions of increased need for research among those with higher levels of tobacco consumption (S. H. Zhu et al., 2007). However, because low-level smokers are at elevated risk of negative health outcomes when compared with former or never-smokers (NCI, 1998), understanding the associations of low-level smoking with tobacco dependence, withdrawal, and cessation is an important public health aim and could lead to specific treatment approaches targeted at these smokers.

Research suggests that cigarette consumption may be a proxy for physical dependence on tobacco, such that low-level smokers demonstrate less dependence than heavier smokers AV-951 (Kandel & Chen, 2000). As a result, low-level smokers are more likely to attempt to quit, to experience less withdrawal (Shiffman, Paty, Gnys, Kassel, & Elash, 1995), and to maintain abstinence than are heavier smokers (cf., S. H. Zhu, Sun, Hawkins, Pierce, & Cummins, 2003).

S. National Institutes of Health (grant number Indian Health Service NARCH III U26IHS300012,); and the National Cancer Institute at the National Institutes of Health (contract number HHSN261200700462P) and grant number CA114609. Declaration of Interests Dorothy K. Hatsukami, inhibitor Ganetespib Ph.D., of the University of Minnesota, was funded for by Nabi Biopharmaceuticals and NIDA to be a site for a multi-site clinical trial for a nicotine vaccine. Dr. Rachel F. Tyndale owns shares and participates in Nicogen Research Inc., a company focused on novel smoking cessation treatment approaches. No Nicogen funds were used in this work and no other Nicogen participants reviewed the data. Dr. Tyndale has also consulted for one day for Novartis and McNeil. Dr. Neal L. Benowitz serves as a consultant to Pfizer Pharmaceuticals, Inc.

and has been a paid expert witness in litigation against tobacco companies. This research was not supported by industry funds. Acknowledgments The scientific team would like to express their gratitude for the leadership and direction from the members of the Board of Directors of the Bristol Bay Area Health Corporation, the members of the Ethics Committee of that organization and the Community Advisory Board for this study, and the BBAHC Director of Community Health Services, Ms. Rose Loera, Ms. Shelly Wallace, all who contributed their time and expertise to making this study possible. We would also like to acknowledge contributions of Ms. Kim Hatt, Ms. Ana Chartier and Ms. Helen Peters who were study assistants to the project. In addition, we would like to acknowledge Drs.

David Ashley and Tom Bernert for advice on study design and Ms. Christie Flanagan for her assistance in manuscript preparation.
Introduction: Studies suggest that initial smoking pleasure influences future smoking behavior. We investigated how initial reactions to cigarettes or Swedish smokeless tobacco (snus) were associated with future use among 10,708 adults from the Swedish Twin Registry. Methods: The Early Smoking Experience questionnaire captured physiologic reactions to initial tobacco use. Binary recursive partitioning (BRP) identified combinations of initial reactions predictive of regular tobacco use. Analyses, stratified by sex, were conducted separately among those who experimented with only cigarettes (EC), only snus (ES), and both products (EC+S). Results: Among EC, 39.

8% of men and 43.7% of women became smokers, while among ES, 78.6% of men and 53.7% of women became snus users. Among EC+S, 31.3% of men and 20.0% of women became dual users. BRP identified different reactions as predictive of future smoking Dacomitinib for men (buzz) and women (dizziness, difficulty inhaling). No initial reaction predicted future snus use among men, but pleasant sensations, later age at first use, and relaxation predicted future snus use for women.

The survey and methodology were approved by the Institutional Review Board at the University of Pennsylvania. Previous work verified that there were no significant differences between panel responders and nonresponders (Weibe, http://www.selleckchem.com/products/ganetespib-sta-9090.html Eyerman, & Loft, 2001). To ensure that participants were current and regular smokers, inclusion criteria were the following: (a) currently smoking cigarettes, (b) had smoked an average of 5 or more cigarettes/day in the past week, and (c) had smoked at least 100 cigarettes in their lifetime. Participants responded to questions related to their own smoking habits and their family history of smoking, as well as their general attitude toward vaccines. Next, participants were randomly assigned to read one of two paragraphs describing the nicotine vaccine.

Supplementary material contains full-text wordings of each paragraph. Both versions explained the vaccine, mentioned safety and efficacy, and the possibility of periodic booster shots for long-term efficacy. One version of the paragraph framed nicotine addiction in terms of genetic susceptibility, while the other version framed nicotine addiction in terms of environmental influences. The ��genetic�� version was 166 words, and the ��environmental�� version was 164 words. Participants were then asked about their intentions to get a nicotine vaccine if one were to become available in the future. Main effects of the experimental manipulation were assessed using analysis of variance, and predictors of intention to vaccinate were determined using multivariate linear regression.

Measures Measures asked prior reading the framing paragraph Number of previous quit attempts. Participants were asked, ��How many times have you previously quit smoking on purpose for more than one complete day?�� Based on distribution of responses, participants were placed into one of four categories: 0, 1�C2, 3�C4, or 5 or more previous quit attempts. Previous quit methods. Participants were asked, ��Have you ever tried any of the following methods to quit smoking.�� Response options were: (a) counseling or calling a quitline; (b) going ��cold turkey�� without using any products; (c) nicotine patch; (d) nicotine gum; (e) nicotine lozenge; (f) nicotine nasal spray; (g) nicotine inhaler; and (h) medications, such as Zyban or Wellbutrin. Participants could choose multiple quit methods if necessary.

Nicotine dependence. Nicotine dependence was measured using the Fagerstr?m Test for Nicotine Dependence (FTND; Heatherton, Kozlowski, AV-951 Frecker, & Fagerstr?m, 1991). Based on distribution, participants�� scores were separated into three categories of nicotine dependence: low (0�C3), medium (4�C5), and high (6�C10). Internal consistency of the FTND has been previously reported as 0.61 (Heatherton et al.). Personal vulnerability to smoking-related illness. Participants were asked, ��To what extent do you feel your overall health has been affected by smoking.

This process has been particularly noted in the BxPC3 pancreatic cancer cell line, which has been reported to exhibit a high level of APP cleavage; however, the accompanying expression and cleavage of APLP2 in this cell line was not examined (24). Proteolysis of APLP2 or APP can be accomplished by the ��-site APP cleaving enzyme 1 (BACE1) or BACE2 (22,23,25). Tofacitinib IC50 In the context of Alzheimer��s disease, BACE1 and BACE2 cleavage of APP has been well characterized, and both conserved and unique cleavage sites on APP have been demonstrated for the two BACE proteins (26�C28). Recently, one BACE1 cleavage site in APLP2 was identified (23); however, BACE2 cut site(s) in APLP2 remain(s) unknown.

Both BACE proteins have been reported in pancreatic tissue, but reports differ on BACE1 and BACE2 expression and activity in pancreatic ductal and acinar cells (22,23,27,29�C32), which are cell types proposed to give rise to pancreatic cancer (33). In our current studies, we have identified increased APLP2 in human pancreatic cancer tissues, as compared to normal pancreatic tissues, and have investigated the forms of APLP2 expressed in pancreatic cancer cell lines. We observed high molecular mass APLP2, at the molecular mass previously shown to be modified by glycosaminoglycans (GAG) (20,34,35), in the majority of pancreatic cancer cell lines, as well as full-length APLP2 without GAG modification and 12�C15 kDa C-terminal fragments generated from secretase cleavage (22,23) in all these cell lines.

C-terminal fragments of APP were only abundantly observed in the BxPC3 cell line in our panel of pancreatic cancer cell lines, suggesting that cleavage of APLP2, rather than APP, is a consistent molecular feature of pancreatic cancer cell lines. Furthermore, we have shown that transformation of pancreatic ductal cells by transfected oncogenes induces an increase in APLP2 expression, with particular enhancement in the expression of the APLP2 C-terminal fragments. Downregulation of APLP2 and/or APP in the pancreatic cancer S2-013 cell line, which displays representatively low expression of APP C-terminal fragments, decreased cell proliferation, suggesting a role for both family members in the growth of pancreatic cancer cell lines. Finally, treatment with inhibitors of ��-secretases, enzymes that cleave APLP2 or APP to release C-terminal fragments, decreased the growth and viability of the pancreatic cancer cell line S2-013 but not of a non-transformed GSK-3 pancreatic ductal cell line. Overall, these studies suggest that APLP2 undergoes extensive modification and cleavage in pancreatic cancer cell lines, APLP2 (and APP) facilitate pancreatic cancer cell growth, and treatments that block APLP2 cleavage can diminish the growth of pancreatic cancer cells.

.. BARF1 protein selleck chemical expressed in SNU601 BARF1 cells was detected as a 23- to 26-kDa band on Western blots with an anti-Flag antibody and the 4A6 anti-BARF1 antibody (Fig. 1C). BARF1 protein was secreted and was observed mainly in culture supernatants and only marginally detectable in cell lysates of SNU601 BARF1. To confirm that BARF1 is secreted via the classical pathway, we first examined BARF1 protein expression in cell culture supernatants treated with brefeldin A, which hinders export from distal Golgi compartments to the cell surface (Fig. 1D and andE).E). BARF1 was detected in cell lysates upon treatment with brefeldin A, and BARF1 secretion was almost completely inhibited (Fig. 1D). These results indicate that BARF1 is a classically secreted protein.

Immunofluorescence analysis showed that brefeldin A blocked secretion and caused retention of the BARF1 protein in the cytoplasm and nucleus (Fig. 1E). BARF1-expressing SNU601 cells show increased proliferation. SNU601 BARF1 cells showed higher proliferation than did SNU601 mock cells (P < 0.05) (Fig. 3B). There were no statistical differences in apoptosis, invasion, or migration between SNU601 BARF1 and SNU601 mock cells (Fig. 3A, ,C,C, and andD).D). The effect of BARF1 knockdown on cell proliferation was investigated in SNU719 cells, which express high endogenous levels of BARF1. SNU719 cells, which are naturally infected with EBV, were transfected with different siRNA oligonucleotides against BARF1 type 1, 2, or 3. Knockdown was verified by RT-PCR. BARF1 mRNA expression was markedly inhibited by the siRNA against BARF1 type 3 (Fig.

4A). Interestingly, we observed a significant reduction in the growth rate of SNU719 cells transfected with siRNA against BARF1 type 3 compared to cells transfected with scrambled siRNA (P < 0.05) (Fig. 4B). Fig 3 Biological properties of BARF1-expressing gastric carcinoma cells. (A) Apoptosis assay. Plots of flow cytometric data indicated no difference in apoptosis between SNU601 BARF1 and SNU601 mock. The percentage of apoptotic cells was determined by calculating ... Fig 4 Analysis of SNU719 (naturally EBV-infected gastric carcinoma cells) transfected with siRNA against BARF1. (A) BARF1 expression was almost completely inhibited upon transfection of 20 ��M siRNA against BARF1 type 3. (B) Cell proliferation was lower ...

BARF1-induced NF-��B RelA increment is associated with cyclin D1 and p21WAF1 expression. In this study, we focused on the IRAK1/I��B��/NF-��B/cyclin D1 Brefeldin_A pathway (31, 33). We observed increased expression of the NF-��B RelA protein in nuclear extracts of SNU601 BARF1 cells compared with SNU601 mock cells (Fig. 5). Increased nuclear expression of NF-��B RelA correlated with increased expression of cyclin D1 and reduced expression of p21WAF1. Interestingly, expression of NF-��B RelA did not correlate with levels of the NF-��B-modulator IRAK1.

First, intermittent exposure to tobacco in the human fetus differs from the continuous nicotine dosing employed in animal models (Slotkin, 2008). Second, there are dramatic differences in brain structure and function http://www.selleckchem.com/products/brefeldin-a.html between rodents and humans (i.e., humans display an enlarged prefrontal cortex, distinct hippocampal structure, and higher density of synaptic connections as compared to rodents). Third, animal studies have primarily focused on perinatal exposure to nicotine alone, whereas human studies necessarily focus on cigarettes and tobacco products, which include nicotine in addition to a numerous other potential neuroteratogens (e.g., arsenic, acetone, and formaldehyde). Finally, the third trimester of human pregnancy corresponds to the postnatal rather than perinatal period in the rodent (Dwyer, McQuown, & Leslie, 2009).

Thus, prior animal studies that have modeled effects of prenatal exposure are not able to provide insight into neural effects of human prenatal exposure in the third trimester. Given these differences, it is critical to investigate effects of MSDP on offspring brain development in humans. Previous comprehensive reviews have summarized studies investigating associations between MSDP and offspring neurobehavioral deficits and disorders from both the human and the animal literatures (Cornelius & Day, 2009; Ernst et al., 2001; Herrmann et al., 2008; Langley et al., 2005; Pauly & Slotkin, 2008).

These reviews have reported relatively consistent links between MSDP and neurobehavioral deficits but highlight the difficulty in establishing causal associations given the number of potentially confounding factors, ethical impossibility of experimental designs in humans, and obstacles in translating findings from animal models to human neurobehavioral outcomes. Previous reviews have also summarized associations between MSDP and offspring neural development with focus on both animal and some human studies (Baler et al., 2008; Blood-Siegfried & Rende, 2010; Dwyer et al., 2009; Shea & Steiner, 2008; Slotkin, 1998). These reviews suggest that dysregulation in the development of receptor, neurotransmitter, and basic synaptic systems by maternal smoking/prenatal nicotine could lead to functional and structural brain changes and neurobehavioral/cognitive impairments in offspring. However, the reviews relied heavily on findings from animal studies and did not provide a comprehensive review of human studies of brain structure and function. Therefore, our aims in the current review are (a) to systematically summarize GSK-3 and critique the small number of human studies of MSDP and brain structure and function and (b) to propose an agenda for future research in this nascent area.

Female 6- to 8-wk-old C57BL/6 mice weighing 15-20 g were purchased from Orient Bio (Sungnam, KyungKiDo, South Korea). All animals were bred and housed in standard shoebox cages in a climate-controlled room with an ambient temperature of 23 �� 2 ��C under a 12-h light-dark cycle for 7 d. The animals were fed standard laboratory chow, allowed water ad libitum, and randomly assigned to control or Enzalutamide supplier experimental groups. The mice were fasted for 18 h before AP was induced. Experimental design AP was induced by intraperitoneal injections of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 ��g/kg) or saline, hourly for 6 h[6]. Prior to injecting the NJ4 treatment group with cerulein, NJ4 (1 ��g/kg, 5 ��g/kg, or 10 ��g/kg, n = 6) or saline (control group, n = 6) were intraperitoneally administered (1 h before the first cerulein injection).

Mice were killed 6 h after the last cerulein injection was administered. Blood samples were taken to determine serum amylase, lipase, and cytokine levels. For histological examination and scoring, the entire pancreas and lungs were rapidly removed from each mouse and fixed in formalin. To measure tissue myeloperoxidase (MPO) activity, an indicator of neutrophil sequestration, and for real-time reverse transcriptase polymerase chain reaction (RT-PCR) studies, the pancreas and lungs were stored at -80 ��C. Histological analysis The pancreases from each treatment group were examined and semi-quantitatively described in terms of necrosis, vacuolization, inflammation, and edema.

A tissue section representing a minimum of 100 fields was examined for each sample and scored on a scale of 0-3 (0 being normal and 3 being severe disease) on the basis of the number of necrotic acinar cells and the presence of interstitial edema and interstitial inflammation. Measurement of serum amylase and lipase Blood samples to determine serum amylase and lipase were obtained 6 h after inducing pancreatitis. Mice were anesthetized with an intraperitoneal injection of ketamine (80 mg/kg) and xylazine (4 mg/kg). After anesthetization, blood was withdrawn from the heart of each mouse into a syringe. Serum amylase and lipase were measured using an assay kit from BioAssay Systems (CA).

Enzyme-linked immunosorbent assay Enzyme-linked immunosorbent assay (ELISA) for IL-1��, IL-6, and TNF-�� were carried out in duplicate in 96-well plates coated with 100 ��L aliquots of anti-mouse IL-1��, IL-6, and TNF-�� monoclonal antibodies in phosphate buffered saline (PBS) at pH 7.4 during an overnight incubation at 4 ��C. The plates were washed in PBS containing 0.05% Tween-20 and blocked with PBS containing 10% FBS GSK-3 for 2 h. After additional washes, standards and samples were added and incubated at room temperature for 2 h.

Children are more likely than adults to become infected, as exemplified by their higher levels of prevalence of infection, and to develop mechanical AEs following treatment, because of the smaller size of their bile ducts and thus higher likelihood of blockage. Consequently, Tofacitinib Citrate mw they are considered both the group at highest risk and the one most sensitive for detection of AEs following treatment. All children attending the primary school and the junior high school of Huacullani were considered eligible for enrolment in the study. Study design A Scientific Committee formed by the Ministerio de Salud y Deportes, the Servicio Departamental de Salud of La Paz, the Universidad Mayor de San Andr��s and the PAHO/WHO was established with the aim of developing a protocol and supervising the implementation of the pilot intervention.

The protocol consisted of five consecutive study phases: baseline data collection; treatment; monitoring of AEs at day 0, day 7 and day 30; first parasitological follow-up 3 months after treatment, with further treatment of any cases still positive; and second parasitological follow-up 2 months after the first follow-up (Figure 1). After a few preparatory meetings, field activities started in April 2008, and were completed in November 2008. Figure 1 Study flow diagram. Baseline data collection Each participating child was given a plastic numbered container on the day of the survey and was asked to return it with a fresh stool sample. A single Kato-Katz thick smear [26], [27] was prepared from each stool sample.

The Kato-Katz test was chosen as �C in spite of its recognized low sensitivity �C it is the standard technique used for assessing burden of helminth infections at community level [1], and also allows a quantitative assessment of the severity (intensity) of the infection, through a measurement of egg density in the faecal sample. Each individual was therefore classified as egg-positive or negative, and intensity of infection (number of eggs per gram of faeces, epg) was assessed in all positive individuals. Prevalence of infection and mean intensity of infection were thus calculated. Treatment All children who tested positive to the Kato-Katz technique were considered eligible for treatment. Triclabendazole (Egaten, Novartis Pharma AG, Basel, Switzerland) was administered at an approximate dose of 10 mg/kg, in a single administration, based on the schema presented in Table 1.

Children with an intensity of infection Drug_discovery ��300 epg were hospitalized at the Ovidio Aliaga Ur��a Children’s Hospital in La Paz before receiving treatment. This precautionary measure was justified by the consideration that individuals infected with a large number of worms are more likely to develop both systemic and mechanical AEs following treatment and might therefore require specialist medical attention and care.

Table 4 Effects baricitinib-ly3009104 of AZ876 and GW3965 on plasma cytokines Figure 6 To investigate the effect of 5 or 20 ��mol?kg?1?day?1 AZ876 or GW3965 (17 ��mol?kg?1?day?1) on vessel wall inflammation, monocytes were stained in the aortic root (A). The number … Discussion In this study, we evaluated the effect of the novel LXR agonist AZ876 on plasma lipid levels and atherosclerosis in hyperlipidaemic APOE*3Leiden transgenic mice. AZ876 and GW3965 both markedly inhibited atherosclerosis development, whereas AZ876 induced a more stable lesion phenotype. Additionally, AZ876 showed no adverse effects when given in low dose, pointing to dose-dependency of the effects induced by AZ876. The results of the present study confirm the findings of previous studies in APOE*3Leiden (Grefhorst et al., 2002;Verschuren et al.

, 2009), LDLr�C/�C (Terasaka et al., 2003) and apoE�C/�C (Dai et al., 2007) mice with another LXR agonist, T0901317, with regard to elevation of plasma triglyceride and HDL levels and reduction of atherosclerosis. In wild-type mice, GW3965 (20�C100 mg?kg?1?day?1) has been reported to be a tissue- and gene-selective modulator of LXR activity with less lipogenic effects than T0901317 after a 3 day treatment (Miao et al., 2004). Also in LDLr�C/�C mice, GW3965 (10 mg?kg?1?day?1) did not affect plasma or liver lipid levels when administered for 8 weeks (Quinet et al., 2009). In contrast to these latter reports, we showed that in a more sensitive model of hyperlipidaemia, the APOE*3Leiden mouse, even a relatively low dose of GW3965 given for 20 weeks (17 ��mol?kg?1?day?1, ~10 mg?kg?1?day?1) increased plasma triglyceride levels.

The low dose of 5 ��mol?kg?1?day?1 AZ876 did not affect plasma triglycerides; however, Entinostat the high dose of 20 ��mol?kg?1?day?1 AZ876 did induce hypertriglyceridaemia indicative of a dose-dependent effect. Next to the undesired induction of hypertriglyceridaemia, GW3965 and 20 ��mol?kg?1?day?1 AZ876 increased HDL levels, thereby resembling findings described for T0901317 and fenofibrate-treated APOE*3Leiden mice (Kooistra et al., 2006;Verschuren et al., 2009), as reflected by the appearance of a large cholesteryl ester-rich HDL-1 particle in the lipoprotein profile, containing mainly the apoE, and to a minor extent apoB and no apoAI (Gruen et al., 2005). The appearance of this large HDL-1 particle upon LXR agonist treatment is specific for species without CETP and may have atheroprotective effects by supporting apoAI-independent cholesterol efflux (Jiang et al., 1992). In species containing CETP, like hamsters and cynomolgus monkeys (Groot et al., 2005; Quinet et al., 2009) and APOE*3Leiden.CETP transgenic mice (PCN Rensen and HMG Princen, unpubl. data), this HDL is absent via the action of CETP.

TABLE 1. In vitro infectivity of SFV-LacZ and ��-galactosidase protein expression in woodchuck and human HCC-derived cell lines In found order to test if SFV vectors can infect in vivo woodchuck hepatic tumor cells, two chronic WHV carrier woodchucks with HCC were selected, each having three tumors with sizes between 1 and 3 cm in diameter. The first woodchuck received intratumorally 1 �� 109 vp of an SFV vector expressing luciferase (SFV-Luc) into one tumor (tumor 1), whereas the other two tumors (tumors 2 and 3) were left untreated (Fig. (Fig.1A).1A). This woodchuck was euthanized 24 h later, and luciferase activity in the treated and untreated tumors and in surrounding liver tissue was measured. Luciferase activity was detected at high levels only in the treated tumor, demonstrating that transgene expression was mainly confined to the area of injection.

FIG. 1. Infectivity of SFV vectors in chronic WHV carrier woodchucks with HCC. (A) One woodchuck received intratumorally 1 �� 109 vp of SFV-Luc into one tumor with a size of approximately 3 cm in diameter (tumor 1). Two other tumors with sizes between … The second woodchuck received intratumorally 3 �� 109 vp of SFV-Luc into one tumor (tumor 1) and 3 �� 109 vp of an SFV vector expressing murine IL-12 (SFV-enhIL-12) into a second tumor (tumor 2), whereas a third tumor was left untreated (Fig. (Fig.1B).1B). Following euthanasia 24 h later, luciferase activity and IL-12 expression in treated and untreated tumors, adjacent liver tissues, and several other organs were measured, as presented in Fig. 1C and D.

Luciferase activity was elevated in all sections of tumor 1 and was five- to sevenfold higher than in the first woodchuck, which had received a threefold-lower dose of SFV-Luc (Fig. 1A and C). Luciferase activity was low in all other tissues analyzed, with the exception of liver tissue surrounding tumor 1 and spleen tissue. In this woodchuck, IL-12 protein was detected at high concentrations in two sections of tumor 2 treated with SFV-enhIL-12 (Fig. (Fig.1D).1D). Lower IL-12 concentrations were also detected in other sections of tumor 2, in proximal liver tissue, and in tumor 1 treated with SFV-Luc. The SFV-Luc-treated tumor 1 from the first woodchuck was used as an additional negative control, and IL-12 protein was detectable only at background level (Fig. 1A and D).

These results and the additional observation Dacomitinib that IL-12 was detected in serum of the second woodchuck at a concentration of 152 ng/ml (Fig. (Fig.1E)1E) suggest that this cytokine was secreted from neoplastic cells of tumor 2 following infection with SFV-enhIL-12. For establishing a correlation between the dose of SFV-enhIL-12 administered into a hepatic tumor and the IL-12 concentration detected thereafter in serum, a third woodchuck received intratumorally 1.2 �� 1010 vp of SFV-enhIL-12 into one tumor with a size of approximately 0.7 cm in diameter (Fig. (Fig.1E).1E).