Unusual Near-Horizon Cosmic-Ray-like Events Observed by ANITA-IV.

ANITA's fourth long-duration balloon flight in 2016 detected 29 cosmic-ray (CR)-like events on a background of 0.37_{-0.17}^{+0.27} anthropogenic events. CRs are mainly seen in reflection off the Antarctic ice sheets, creating a phase-inverted waveform polarity. However, four of the below-horizon CR-like events show anomalous noninverted polarity, a p=5.3×10^{-4} chance if due to background. All anomalous events are from locations near the horizon; ANITA-IV observed no steeply upcoming anomalous events similar to the two such events seen in prior flights.

Observation of an Unusual Upward-Going Cosmic-Ray-like Event in the Third Flight of ANITA.

We report on an upward traveling, radio-detected cosmic-ray-like impulsive event with characteristics closely matching an extensive air shower. This event, observed in the third flight of the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload, is consistent with a similar event reported in a previous flight. These events could be produced by the atmospheric decay of an upward-propagating τ lepton produced by a ν_{τ} interaction, although their relatively steep arrival angles create tension with the standard model neutrino cross section. Each of the two events have a posteriori background estimates of ≲10^{-2} events. If these are generated by τ-lepton decay, then either the charged-current ν_{τ} cross section is suppressed at EeV energies, or the events arise at moments when the peak flux of a transient neutrino source was much larger than the typical expected cosmogenic background neutrinos.

Measles elimination and immunisation: national surveillance trends in Japan, 2008-2015.

Measles elimination relies on vaccination programmes. In Japan, a major outbreak started in 2007. In response, 5-year two-dose catch-up vaccination programme was initiated in April 2008 for children 13-16-years-old. In this study, we analysed the epidemic curves, incidence rates for each age group, virus genotype, vaccination coverage and ratio of measles gelatin particle agglutination (PA) antibody using surveillance data for 2008-2015. Monthly case counts markedly decreased as vaccination coverage increased. D5, which is the endemic virus type, disappeared after 2011, with the following epidemic caused by imported viruses. Most cases were confirmed to have a no-dose or single-dose vaccination status. Although the incidence rate among all age groups ⩾5-years-old decreased during the study period, for children <5-years-old, the incidence rate remained relatively high and increased in 2014. The ratio of PA antibody (⩾1:128 titres) increased for the majority of age groups, but with a decrease for specific age groups: the 0-5 months and the 2-4, 14, 19 and most of the 26-55- and the 60-year-old groups (-1 to -9%). This seems to be the result of higher vaccination coverage, which would result in decreasing natural immunity booster along with decreasing passive immunity in infants whose mothers did not have the natural immunity booster. The 20-29- and 30-39-year-old age groups had higher number of cases, suggesting that vaccination within these age groups might be important for eliminating imported viruses.

Correlation between infectious disease and soil radiation in Japan: an exploratory study using national sentinel surveillance data.

We investigated the relationship between epidemics and soil radiation through an exploratory study using sentinel surveillance data (individuals aged <20 years) during the last three epidemic seasons of influenza and norovirus in Japan. We used a spatial analysis method of a geographical information system (GIS). We mapped the epidemic spreading patterns from sentinel incidence rates. We calculated the average soil radiation [dm (µGy/h)] for each sentinel site using data on uranium, thorium, and potassium oxide in the soil and examined the incidence rate in units of 0·01 µGy/h. The correlations between the incidence rate and the average soil radiation were assessed. Epidemic clusters of influenza and norovirus infections were observed in areas with relatively high radiation exposure. A positive correlation was detected between the average incidence rate and radiation dose, at r = 0·61-0·84 (P < 0·01) for influenza infections and r = 0·61-0·72 (P < 0·01) for norovirus infections. An increase in the incidence rate was found between areas with radiation exposure of 0 < dm < 0·01 and 0·15 ⩽ dm < 0·16, at 1·80 [95% confidence interval (CI) 1·47-2·12] times higher for influenza infection and 2·07 (95% CI 1·53-2·61) times higher for norovirus infection. Our results suggest a potential association between decreased immunity and irradiation because of soil radiation. Further studies on immunity in these epidemic-prone areas are desirable.

Characteristics of Four Upward-Pointing Cosmic-Ray-like Events Observed with ANITA.

We report on four radio-detected cosmic-ray (CR) or CR-like events observed with the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload. Two of the four were previously identified as stratospheric CR air showers during the ANITA-I flight. A third stratospheric CR was detected during the ANITA-II flight. Here, we report on characteristics of these three unusual CR events, which develop nearly horizontally, 20-30 km above the surface of Earth. In addition, we report on a fourth steeply upward-pointing ANITA-I CR-like radio event which has characteristics consistent with a primary that emerged from the surface of the ice. This suggests a possible τ-lepton decay as the origin of this event, but such an interpretation would require significant suppression of the standard model τ-neutrino cross section.

Delayed norovirus epidemic in the 2009-2010 season in Japan: potential relationship with intensive hand sanitizer use for pandemic influenza.

Norovirus (NoV) epidemics normally peak in December in Japan; however, the peak in the 2009-2010 season was delayed until the fourth week of January 2010. We suspected intensive hand hygiene that was conducted for a previous pandemic influenza in 2009 as the cause of this delay. We analysed the NoV epidemic trend, based on national surveillance data, and its associations with monthly output data for hand hygiene products, including alcohol-based skin antiseptics and hand soap. The delayed peak in the NoV incidence in the 2009-2010 season had the lowest number of recorded cases of the five seasons studied (2006-2007 to 2010-2011). GII.4 was the most commonly occurring genotype. The monthly relative risk of NoV and monthly output of both alcohol-based skin antiseptics and hand soap were significantly and negatively correlated. Our findings suggest an association between hand hygiene using these products and prevention of NoV transmission.

The spatial diffusion of norovirus epidemics over three seasons in Tokyo.

We studied the spatial trend of norovirus (NoV) epidemics using sentinel gastroenteritis surveillance data for patients aged <15 years (n = 140) in the Tokyo area for the 2006-2007 to 2008-2009 seasons utilizing the kriging method of geographical information system (GIS). This is the first study of the spreading pattern of NoV epidemics using sentinel surveillance data. Correlations of sentinel cases between the seasons and with demographic data were examined to identify the trend and related factors. A similar pattern of diffusion was observed over the seasons, and its mean correlation between seasons was significantly high. A higher number of cases were found in the peripheral area, which surrounds the most populated central area, and showed a correlation with the ratio of the children population (r = 0·321, P < 0·01) and the ratio of residents in larger families (r = 0·263, P < 0·01). While NoV susceptibility remained, the results suggest a transmission route in the local community as a possible epidemic factor. Prevention with focus on the peripheral area is desirable.

Observation of ultrahigh-energy cosmic rays with the ANITA balloon-borne radio interferometer.

We report the observation of 16 cosmic ray events with a mean energy of 1.5 × 10¹9 eV via radio pulses originating from the interaction of the cosmic ray air shower with the Antarctic geomagnetic field, a process known as geosynchrotron emission. We present measurements in the 300-900 MHz range, which are the first self-triggered, first ultrawide band, first far-field, and the highest energy sample of cosmic ray events collected with the radio technique. Their properties are inconsistent with current ground-based geosynchrotron models. The emission is 100% polarized in the plane perpendicular to the projected geomagnetic field. Fourteen events are seen to have a phase inversion due to reflection of the radio beam off the ice surface, and two additional events are seen directly from above the horizon. Based on a likelihood analysis, we estimate angular pointing precision of order 2° for the event arrival directions.

Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region.

An adenovirus (Adv) retaining normal E1A but lacking the 55 kDa E1B protein replicates preferentially in TP53-deficient cancer cells including pancreatic cancer cell lines, resulting in the oncolysis of the tumor. When tumor cells are exposed to hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha) is stabilized and activated to promote the transcription of several genes such as vascular endothelial growth factor (VEGF), but in the presence of E1A hypoxia-induced VEGF m-RNA synthesis is inhibited by E1A binding to p300. In this study, we demonstrated that the cancer cells infected with a mutant Adv in which the p300 binding site in E1A was partially deleted induced a higher expression level of VEGF as compared to those of Adv with normal E1A. An immunoprecipitation study for E1A confirmed that mutant E1A had a reduced binding capacity for p300. Although the expressions of HIF-1alpha m-RNA were almost the same in both cancer cells infected with the mutant Adv and those with the wild Adv, the amount of HIF-1alpha protein in cancer cells infected with the wild E1A Adv was lower than in those infected with the mutant E1A type Adv. In vivo, in contrast to the angiogenesis treated with mutant E1A, wild-E1A inhibited tumor angiogenesis significantly. These results suggested that E1A suppressed the production of VEGF and inhibited tumor angiogenesis by binding with p300, resulting in the inhibition of the HIF-1alpha-mediated transcription of genes through binding to HRE. This study demonstrates, for the first time, the effect of an oncolytic replication-competent Adv in inhibiting tumor angiogenesis.

Deletion mapping in squamous cell carcinomas of the esophagus defines a region containing a tumor suppressor gene within a 4-centimorgan interval of the distal long arm of chromosome 9.

Recent studies in our laboratory indicated that inactivation of a putative tumor suppressor gene on chromosome 9q is likely to be associated with an early step of esophageal carcinogenesis. To further define a region containing the putative tumor suppressor gene, we have examined loss of heterozygosity in 37 esophageal squamous cell carcinomas using 14 microsatellite markers mapped to 9q31-q34.1. Loss of heterozygosity was observed in 30 (81%) of 37 tumors at one or more of the loci examined, and partial or interstitial deletions at 9q31-q34.1 were detected in 13 of these tumors. On the basis of these results, we constructed a detailed deletion map and defined a commonly deleted region between the D9S262 and D9S154 loci at 9q31-q32. The genetic distance between these two loci is estimated to be approximately 4 cM.

Immunoelectron microscopic localization of transforming growth factor beta 1 and latent transforming growth factor beta 1 binding protein in human gastrointestinal carcinomas: qualitative difference between cancer cells and stromal cells.

Transforming growth factor beta 1 (TGF-beta 1) is secreted as an inactive complex associated with latent TGF-beta 1 binding protein (LTBP). Tissue localization of these proteins has not been fully understood in human pathological conditions. We examined the immunohistochemical localization of TGF-beta 1 precursor (proTGF-beta 1) and LTBP in carcinomas and granulation tissue in the human gastrointestinal tract at the light and electron microscopic levels. In normal tissue, endothelial cells and granulocytes sporadically showed immunoreactivity for proTGF-beta 1, while epithelial cells were all negative. In cancer tissue, both cancer cells and stromal cells (fibroblasts, macrophages, and endothelial cells) were positive for proTGF-beta 1, more frequently in diffuse-type gastric carcinomas than in differentiated-type adenocarcinomas. Immunoelectron microscopy revealed that proTGF-beta 1 was localized in rough endoplasmic reticulum and perinuclear cisternae in fibroblasts, macrophages, and endothelial cells in cancer stroma and in fibrous granulation tissue. In contrast, the intracellular localization of proTGF-beta 1 in carcinoma cells was predominantly observed in the cytosol (cytoplasmic matrix). This finding suggests disarranged or blocked intracellular transportation of proTGF-beta 1 in cancer cells. The immunoreactivity for LTBP was not observed in the normal epithelial cells. It was localized in cancer stroma, not in cancer cells. Ultrastructurally, LTBP was located in the extracellular matrix around fibroblasts and smooth muscle cells. The intracellular immunoreactivity for LTBP was observed in rough endoplasmic reticulum of fibroblasts and smooth muscle cells, the same as in granulation tissue. These results suggest that gastrointestinal carcinoma cells produce no or a small amount of LTBP in vivo. Our investigation suggests that extensive fibrosis in both cancer stroma and granulation tissues may be promoted by TGF-beta 1 mainly secreted from stromal cells.

Controlling tumor angiogenesis and metastasis of C26 murine colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785, in two tumor models.

Experimental evidence has directly implicated matrix metalloproteinases (MMPs) in the remodeling of the stromal tissue surrounding tumors. Thus, MMP inhibitors could limit the expansion of both neoplastic cell compartment and endothelial cell compartment of a tumor. Much of the work on the role of MMP inhibitors has concentrated on their inhibitory effects on tumor cell invasion. We have examined the effects of a new MMP inhibitor, KB-R7785 (acting on MMP-1, MMP-3, and MMP-9), on tumor angiogenesis and metastasis of murine colon adenocarcinoma (C-26) in two tumor models in BALB/c mice (transparent chamber model and lung colonization model). KB-R7785 has not shown inhibitory effects on in vitro growth of either C-26 or KOP2.16 murine endothelial cells. In vivo, KB-R7785 administrated twice daily for 15 days (100 mg/kg, i.p.), starting the day of tumor inoculation (5 x 10(5) C26 cells) in transparent chamber, has resulted in 88.2% suppression of tumor growth, compared with that in vehicle-administered mice (controls). Tumors grown in controls have doubled their area in 3.3 days, whereas those treated by KB-R7785 progressed almost four times slower (tumor area doubling time, 12 days). KB-R7785 rendered centrally avascular tumors with only a rim of peripheral neovasculature, which had significant lower functional vascular density and vascular area than the corresponding parameters in control tumors 10 days after inoculation [79.9+/-6.7 cm/cm2 versus 164.1+/-10.1 cm/cm2 (P < 0.01) and 19.8+/-1.5% versus 42.6+/-2.7% (P < 0.01), respectively]. In the lung colonization model (tail vein inoculation of 5 x 10(5) C-26 cells), administration of KB-R7785 (100 mg/kg, i.p.) twice daily for 20 days has reduced the number of surface metastasis by 85.8% and abolished the tumor burden, as compared with controls. The few metastatic colonies found in the lungs of KB-R7785 treated mice appeared to be dormant (i.e., staining with von Willebrand factor antibody revealed few, if any, positive cells within the metastatic foci from MMP inhibitor-treated lungs, whereas terminal deoxynucleotidyl transferase-mediated nick end labeling showed a 4-fold increase in the rate of tumor cell apoptosis compared with controls. The fact that KB-R7785 interferes with early steps of angiogenesis and cancer spread suggests that MMP inhibitors may control both primary and secondary tumor growths by limiting the expansion of endothelial cells, as well as cancer cells, composing the tumors.

Detailed deletion mapping in squamous cell carcinomas of the esophagus narrows a region containing a putative tumor suppressor gene to about 200 kilobases on distal chromosome 9q.

We previously reported definition of a region containing a putative tumor suppressor gene for esophageal squamous cell carcinoma within an approximately 4-cM genomic segment at 9q31-q32. We have investigated this region further using six new microsatellite markers isolated from yeast artificial chromosome clones covering the deleted region and have narrowly defined the commonly deleted region to a segment between two loci, KM9.1 and D9S177. On the basis of the contig map of cosmid and yeast artificial chromosome clones, we estimate the physical size of the region of interest to be about 200 kb. Because the distal 9q region also has been implicated as the site of a tumor suppressor gene(s) related to squamous cell carcinomas of other tissues, our map provides useful information for attempts to identify a common gene for carcinomas of this cell type.

MUC1-specific targeting immunotherapy with bispecific antibodies: inhibition of xenografted human bile duct carcinoma growth.

For the purpose of establishing a new adoptive immunotherapy for bile duct carcinoma (BDC), we synthesized two bispecific antibodies (BsAbs), MUC1 x CD3 BsAb constructed with MUSE11 (anti-MUC1 tumor antigen) and OKT-3 (anti-CD3), and MUC1 x CD28 BsAb constructed with MUSE11 and 15E8 (anti-CD28) antibodies. These two BsAbs reacted well with both MUC1-positive target tumor cells and effector lymphokine-activated killer (LAK) cells. Investigation of in vitro cytotoxicity [3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide assay] revealed that the MUC1 x CD3 BsAb could antigen-specifically enhance the cytotoxicity of LAK cells. Addition of the two BsAbs (MUC1 x CD3 BsAb plus MUC1 x CD28 BsAb) in vitro resulted in a 60% cytotoxicity, similar to that obtained with BsAb (MUC1 x CD3) alone. Interleukin 12-induced LAK cells demonstrated far greater cytotoxicity (50%) than their interleukin 2-induced counterparts (LAK cells), and this was also enhanced by the BsAbs. When 2 x 10(7) LAK cells sensitized with both kinds of BsAbs were administered four times i.v. to BDC-grafted severe combined immunodeficient mice (tumor size 5 mm in diameter), inhibition of tumor growth was observed. Thus, BsAb-LAK therapy for control of BDC warrants clinical trials.

Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay.

The tumor suppressor gene PTEN is frequently mutated in diverse human cancers and in autosomal dominant cancer predisposition disorders. Recent studies have shown that the lipid phosphatase activity of PTEN is critical for its tumor suppressor function and that PTEN negatively regulates the phosphatidylinositol 3'-kinase-protein kinase B pathway. Although more than half of PTEN mutations result in protein truncation, a significant fraction of PTEN mutations are missense mutations. To examine whether tumor-derived and germ-line-derived missense mutations inactivate PTEN lipid phosphatase function, we constructed 42 distinct types of PTEN missense mutations and expressed them in Escherichia coli. The purified (His)6-tagged PTEN proteins were tested for their ability to dephosphorylate inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-triphosphate. In addition, we examined the effect of mutant PTENs on the ability of PTEN to bind to the phospholipid membrane. The results revealed that the majority of PTEN missense mutations [38 of 42 (90%)] eliminated or reduced phosphatase activity and that all of the mutations examined had no effect on the membrane binding activity of PTEN. Our study indicated that phosphoinositide phosphatase activity is important for the tumor suppressor function of PTEN and that there may be other mechanisms of PTEN inactivation that are not monitored by in vitro phosphatase assay and in vitro membrane binding assay.

Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12.

As an antitumor agent, interleukin-12 (IL-12) has been revealed to be a key regulator of the immune response, particularly that involving CTL and natural killer (NK) cells. We report herein the antiangiogenesis effect of IL-12 on human as well as murine tumors in NK-depleted severe-combined immunodeficient mice using fibroblasts genetically engineered to secrete this cytokine. Although the in vitro growth of tumor cells was not affected by the presence of IL-12, coinoculation of IL-12-secreting fibroblasts strongly inhibited tumor growth in immunodeficient mice. The neovascularization surrounding the tumor was remarkably inhibited in the area in which the IL-12-secreting fibroblasts were implanted, resulting in the suppression of tumor growth. Lectin staining in tumor sample sections also showed a significant reduction in the number of vessels. The RNA expression of IFN-gamma and its inducible antiangiogenic chemokine IFN gamma-inducible protein 10 was stimulated in endothelial cells cultured with IL-12. It was also found that IL-12 down-regulated the expression of the endothelial cell mitogens vascular endothelial growth factor and basic fibroblast growth factor. The antitumor effects of IL-12 were accompanied by interesting histological changes consisting of a high degree of keratinization and apoptosis and a decrease in the proliferation rate of human tumors and extensive necrosis in the murine ones.

Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer.

Using the method of microsatellite analysis, we studied 40 tissues with pancreatic ductal adenocarcinoma and identified two commonly deleted regions on the long arm of chromosome 12. One (region A) was found between D12S81 and D12S1719 at 12q21 at a frequency of 67.5%, and the other (region B) was located between D12S360 and D12S78 at 12q22-q23.1 at a frequency of 60%; the latter was reported previously (M. Kimura, et al. Genes Chromosomes Cancer, 17: 88-93, 1996). The results of microsatellite analyses were verified by fluorescence in situ hybridization. We further analyzed 19 pancreatic cancer cell lines by fluorescence in situ hybridization and found that 10 of them showed allelic loss at D12S81 and 6 showed allelic loss at D12S360. Yeast artificial chromosome contigs were constructed to cover the deleted regions. Region B was completely covered by a 650-kb yeast artificial chromosome clone. The frequently deleted regions in chromosome 12q in pancreatic cancer that were identified here may provide new avenues for isolating novel tumor suppressor genes.

Effective adoptive immunotherapy by T-LAK cells retargeted with bacterial superantigen-conjugated antibody to MUC1 in xenografted severe combined immunodeficient mice.

To reinforce cytotoxic activity and the targeting ability of lymphokine-activated killer cells with a T-cell phenotype (T-LAK) for adoptive immunotherapy against human bile duct carcinoma (BDC), staphylococcal enterotoxin A (SEA) was conjugated chemically with MUSE11 monoclonal antibody (MUSE11 mAb), directed to the MUC1 antigen, using N-succinimidyl 3-(2-pyridyldithio) propionate and 2-iminothiolane HCl. Both SEA-conjugated MUSE11 mAb (SEA-MUSE11) and the F(ab')2 of MUSE11 mAb (SEA-F(ab')2) showed significant enhancement of T-LAK cell tumor neutralization for MUC1 positive-target tumor cells, even with a concentration of 0.01 microg/ml at an E:T ratio of 5:1 in vitro. In this in vitro test, MUC1-positive BDC cells were observed to attach to surrounding T-LAK cells in the presence of SEA-MUSE11 or SEA-F(ab')2. Remarkable tumor growth inhibition was observed in BDC-grafted severe combined immunodeficient mice to which 2 x 10(7) T-LAK cells preincubated with 2 microg of SEA-MUSE11 or SEA-F(ab')2, together with recombinant interleukin 2 (500 IU), were administered i.v. for 4 consecutive days, when tumor size was 5 mm in diameter. These results point to a promising adoptive immunotherapy for patients with BDC.

Invited Article: miniTimeCube.

We present the development of the miniTimeCube (mTC), a novel compact neutrino detector. The mTC is a multipurpose detector, aiming to detect not only neutrinos but also fast/thermal neutrons. Potential applications include the counterproliferation of nuclear materials and the investigation of antineutrino short-baseline effects. The mTC is a plastic 0.2% (10)B-doped scintillator (13 cm)(3) cube surrounded by 24 Micro-Channel Plate (MCP) photon detectors, each with an 8 × 8 anode totaling 1536 individual channels/pixels viewing the scintillator. It uses custom-made electronics modules which mount on top of the MCPs, making our detector compact and able to both distinguish different types of events and reject noise in real time. The detector is currently deployed and being tested at the National Institute of Standards and Technology Center for Neutron Research nuclear reactor (20 MWth) in Gaithersburg MD. A shield for further tests is being constructed, and calibration and upgrades are ongoing. The mTC's improved spatiotemporal resolution will allow for determination of incident particle directions beyond previous capabilities.

Effective gene therapy for pancreatic cancer by cytokines mediated by restricted replication-competent adenovirus.

Pancreatic cancer has a poor prognosis even when surgical treatment can be accomplished. Studies have demonstrated that pancreatic cancer is associated with various genetic abnormalities in oncogenes and tumor suppressor genes including p53. New therapeutic approaches for pancreatic cancer can be developed by targeting these genetic alterations. Adenovirus (Adv) lacking the 55-kDa E1B protein (E1B55K) replicates preferentially in p53-deficient cancer cells. We constructed E1B55K-deleted Adv (AxE1AdB), and studied its replication and cytopathic effect on pancreatic cancer cells. AxE1AdB replicated in and caused cell death of the p53-deficient pancreatic cancer cell lines tested (e.g., PANC-1, MIAPaCa-2, SU.86.86, BxPC-3, and PK-1). To enhance its therapeutic effect, we examined the combination of coinfecting this restricted replication-competent adenovirus (RRCA) with other Adv. Coinfection of E1-deficient Adv expressing the reporter lacZ gene (AxCAlacZ) together with AxE1AdB resulted in the replication of both viruses and a marked increase in reporter gene expression. PANC-1 cells coinfected with AxE1AdB and the Adv for human IL-2 (AxCAhIL2), produced 110 times more IL-2 than those infected with AxCAhIL2 alone. Similarly, coinfection of AxE1AdB and Adv for human IL-12 augmented the IL-12 production by 370-fold. Injecting AxE1AdB into the PANC-1 tumor of severe combined immunodeficient mice (SCID mice) resulted in marked reduction of the volume of the tumor. Moreover, injecting AxE1AdB with AxCAhIL2 into the PANC-1 tumor resulted in complete regression of the established tumors. These data suggest that RRCA, which augments the antitumor effect of a viral transgene (i.e., cytokines), may be a powerful tool for treating p53-deficient pancreatic cancer.