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Poole, inevitably, was also to take in a match – completing his set of grounds at the first three steps of the national Pyramid.
The figures come after the Rotherham scandal, which found more than 1,400 children had been sexually exploited in the South Yorkshire town between 1997 and 2003 – most by Asian men.
What is clear now is that the best chance for us to steal a march with the Powerhouse is to make a case for devolution, and this will not be granted without a so-called �Metro Mayor’ for both the North-East and Tees Valley areas. The championship means Canada's women curlers have finally come out of the shadow of their men's teams, who have won gold at the last two Olympics.
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Despite major improvements in technology, Professor Br unl says creating a seamless, human-like robot is still difficult to achieve.
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I too received a parking fine notice from Smart Parking stating the same reason as did Mr Briggs (overstayed paid time).
That is not to say it is the end of Johnson's career, but it could be that the more defensive role he adopted at Edgbaston could become the norm for him.
I'm suprised you've chosen to quote such a pathetic attempt at propaganda, unless of course you are one of those Nimbys??? We do business with a fruit and vegetable trader in Manchester and one of them has just bought a Lamborghini Aventador, think that’ll do me if push came to shove.
Mr Harker said: “We have had fantastic success in the county championships and we’re lauded for our success in bringing young players into the game. Atkins suggests that to make sure children brush for two minutes, parents should either use an egg timer, or play a song that lasts for that long.
At the starting point of the current escalation, the border to Syria, nothing seems to be happening these days.
Coming off last year, they're on a mission, Detroit coach Ray McCallum said of the Panthers. Mrs Bentley was there when went Champa underwent brain surgery – filmed as part of the BBC Operation Wild series.
Moors had the final say in the last minute, when Nathan Fisher ran through and confidently stuck the ball into the bottom corner. Also known as Othaim Malls, the firm has picked the investment banking arms of Banque Saudi Fransi, Gulf International Bank and National Commercial Bank as lead arrangers for the riyal-denominated bond, or sukuk, the sources said, speaking on condition of anonymity as the information isn't public.
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Her precarious and exquisite installations crafted from found objects unfurl like some strange form of cartography or models for weather systems. BOOTED: Milwaukee Bradley Tech senior Travis Smith (49-3) was ejected from the tournament after making an obscene gesture to the crowd after his D1 145 match against West Bend East sophomore Jordan Gundrum. Of course, the 4x4 system ensures the Cherokee can cover ground that would leave lesser vehicles spinning their wheels in frustration - but it’s a shock to learn that this Jeep has inferior ground clearance to the defiantly on-road Nissan Qashqai.
If your staff can attend the tables with the professionalism and service that they provide in most US restaurants it will do two things! Roche, who was second behind Colombia’s James Rodriguez in the battle for the Puskas Award, has joined the Lady following her release from American side Houston Dash. Genital HSV is the most common sexually transmitted infection (STI) in both men and women, but as many as 90% don’t know they are infected because their symptoms are too mild to notice or mistaken for another condition.
Symptomatic genital herpes is characterized by a burning and itching sensation in the genitals, followed by blistering.
HSV skin lesions usually appears as small blisters or sores around the mouth, nose, genitals, buttocks, and lower back, though infections can develop almost anywhere on the skin. This photo shows HSV-1 lesions on the buttock of a five-year-old girl — also called sacral herpes simplex. Herpetic whitlow is an intensely painful infection of the hand involving 1 or more fingers that typically affects the terminal phalanx. Serologic testing for HSV has limited value in acute clinical diagnosis because of the time delay for seroconversion following initial infection. Acyclovir, valacyclovir and famciclovir are the most commonly used agents for treating HSV infections. A wide disparity exists between the public and medical community regarding the significance of herpes infections. The majority of recurrent oral herpes cases are caused by herpes simplex virus type 1 (HSV-1) and the majority of genital herpes cases are caused by HSV-2. Differentiating between the two types of infection using either type specific swab testing, preferably PCR, or type specific IgG antibody testing, is very important because HSV-1 genitally recurs less, is shed less, and presents far less risk of transmission to others than HSV-2. Fifty seven percent of Americans between 14 and 49 have HSV-1, and 16% of the same group has HSV-2 infection.
An AU in which all the Alpha and Beta kids just hang out in shady alleys for ironic reason. Azithromycin 1 g PO in a single dose (preferred, owing to tetracycline resistance) or doxycycline 100 mg PO bid for 7 days Enter Quantity Like their host cells, many nuclear DNA viruses, including herpesviruses, are subject to the regulatory overlay of chromatin assembled on their genomes. A determination of the relevance of these and other histone modifications for expression of the different classes of viral genes may depend on global mapping under conditions in which specific modification enzymes are depleted or inhibited. Herpes Simplex Type 2 PneumoniaThe nuclei had herpes simplex virus type 2 in many endothelial cells (including vessels with widened walls), macrophages in the alveolar septa and pneumocytes. Herpes Simplex Virus VectorsFebruary 2011 ? UMDNJ ? EOHSS S S T T A A N N D D A A R R D D ? ? O O P P E E R R A A T T I I N N G G ? ? P P R R O O C C E E D D U U R R E E S S . Koi Herpes Virus (KHV)KHV is a serious mover when it infects a fish population and deaths are extensive and swift but the clinical signs are both subtle and easy mistaken for other diseases. STD Testing – Is There A Herpes Blood Test?Type-specific herpes blood tests look for not only whether you have antibodies against a herpes virus but whether they are against HSV-1 or HSV-2. Herpes Brochure- English• The sores of recurrent herpes usually appear on only one side of your genitals. STATE OF IDAHOBOISE, ID – The Idaho State Department of Agriculture (ISDA) is investigating a suspected outbreak of Equine Herpes Virus (EHV-1) within the state. Herpes virus – Wikipedia, The Free EncyclopediaIn colloquial use, herpes virus refers to the herpes simplex virus, particularly when transmitted sexually.
EQUINE HERPESVIRUS INFECTIONSIdeally, all horses should be vaccinated against Equine Herpes viruses 1 and 4 to reduce the incidence of Herpesvirus diseases and to minimize the shedding of virus into the horse environment. Top of pageAbstractIt has been 9 years since the beginning of the first clinical trial in which an oncolytic virus was administered to cancer patients. Top of pageIntroductionClinicians have taken advantage of virus' ability to lyse human cells by using various wild-type viruses to treat cancer over the last century, but the approach was temporarily abandoned due to toxicity (Southam, 1960). Assessment of adenoviral vector safety and toxicity: report of the National Institutes of Health Recombinant DNA Advisory Committee. The big blow was a ball pounded into the dirt by junior Heidi Morrical that scored the go-ahead run and brought home an insurance run after a Germantown throwing error.
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He has been the executive director at the Lower MUA since March 2011, according to his Linkedin page. His unbeaten 39 from the number nine slot, coupled with last man defiance from John Spellman senior (8no), held the Moor machine at bay, Castle just clinging on at 176-9 after 50 overs. Rumours were more persistent three or four years ago when the market was weak, but now the time has come, the move appears to be have been driven by a number of factors.
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He jumped Wednesday for the last time and then rested his legs for the competition Saturday.
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Congress that visited Egypt and held talks with government officials prior to arriving in Tel Aviv on Monday, opposes the deal struck by the members of the UN Security Council, including the United States, and Germany. 22, the Republic school district will host a ribbon cutting ceremony to unveil changes to Sweeny Elementary, according to a news release. This week, it is holding an open day ahead of an additional six apprentices joining the team Mr Duncan concludes: “You have to adapt and take a few knocks. The Tengiz oil field was discovered in 1979 and is one of the deepest and largest oil fields in the world. In women who contract the disease, the cervix is infected 80% to 90% of the time during primary infection.


This photo shows a close-up of lesions on the upper eyelid in a 20-year-old male patient due to HSV-1. Of patients who develop seropositivity, 65% do so within six weeks, while approximately 20% do not make antibodies for six months. While all three drugs decrease the duration and severity of illness and viral shedding, they have no effect on nonreplicating viruses, nor do they eliminate the virus from the ganglia. Although treatment options exist, respondents in one survey considered contracting herpes as worse than breaking up with a significant other, getting fired from a job, or failing a course in school. HSV infection is a persistent and chronic infection of the sensory ganglia with a varying, unpredictable degree of skin expression. Kristie PCR (polymerase chain reaction) is a method to analyze a short sequence DNA or RNA. Tuberculosis (TB) Mycobacterium tuberculosis is the bacterium that causes tuberculosis (TB).
It is worth pointing out once more that all a physician or a medicine can do is treat symptoms of an outbreak of herpes with an antiviral medicine– there is no treatment.
Interestingly, the levels of histone H3 and H3-K9 methylation decrease when viral DNA replication is inhibited, while specific reduction in the levels of H3-K27 methylation appeared to be more highly dependent upon viral genome replication.
An outbreak typically causes small blisters or sores on or around the mouth commonly known as cold sores or fever blisters.
These closely related viruses are two of the nine herpesviruses known to have humans as their primary host. In scientific use, herpesvirus (without the space) refers to a virus of the taxonomic family herpesviridae. Although there has been some scientific discussion regarding the accuracy of this classification (Ronen et al. Since then, oncolytic viruses from five different species have been taken to phase I and II clinical trials in over 300 cancer patients. With the discovery of recombinant technology, however, it became possible to genetically engineer DNA viruses to enhance their safety by increasing their selectivity for tumor cells, an approach first demonstrated in 1991 with herpes simplex virus type one (HSV-1) in an experimental glioma model (Martuza et al., 1991). If Turkey would stop its bombardments and raids against the PKK in Turkish cities and return to peace talks, we could have a cease-fire on the same day.
Consequently, much of the country is without power and there is insufficient fuel to power the pumps. Tensions between Egypt and Iran heightened when the Islamic Republic named a street after Khalid Islambouli, who assassinated Egyptian President Anwar Al-Sadat in October 1981.
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The documents were from a "limited sampling" of her emails and among those 40 reviewed, said the inspector general, Charles McCullough III.
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This is not an easy industry and you must be prepared to react quickly to changing customer needs. Its oil reserves are estimated at between 750 million and 1.1 billion tons (6-9 billion barrels) of recoverable oil. Primary infections can range from subclinical to severe, with fever, headache, malaise, anorexia, pain, lymphadenopathy and edema. Clinical recurrence occurs on average 3 to 4 times a year, but some patients experience monthly outbreaks. Cervical infection alone is rarely symptomatic, but because the cervix is not sensitive to pain, infection may pass unnoticed.
Be sure to provide adequate counseling to help patients put their diagnosis in perspective. This slideshow will highlight variations in presentation and provide more information about diagnosis and treatment. A number of in vitro (test tube) laboratory experiments with calcium elenolate, a salt of elenolic acid, demonstrated a killer effect against many viruses, bacteria and parasitic protozoans. Circumcision had a strong protective effect against the acquisition of HIV by men in Kisumu (aOR = 0. While additional studies will be required to ascertain if the efficacy of any of these agents is high enough to warrant adding them to the existing therapeutic regimen, it has been reassuring that DNA viruses engineered to achieve tumor selectivity and RNA viruses with relative inherent natural tumor selectivity have proven reasonably safe at the wide range of doses that were tested. At 5 years later, the engineered adenovirus Onyx-015 became the first engineered oncolytic virus to undergo a clinical trial in cancer patients (Ganly et al., 2000).
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In that context this literature review produced by the Governance and Social Development Resource Centre (GSDRC) is a useful stock take, citing both humanitarian policy documents as well as real-life examples of LRRD being applied. Unlike the minister, whose every word could affect billions of dollars on the commodity markets, Muhanna can speak more freely. And even though everyone has been bundled up like Nanook of the North lately, no one pointed out the coatroom.
When deciding tosupport UN Security Council Resolution 1970 andmaking no objection toResolution 1973 onLibya, we believed that these decisions would help limit theexcessive use offorce andpave theway fora political settlement. Levofloxacin 500 mg PO daily (qd) for 7 days, OR The results are you will feel energized, have better d (more info) M. Instruct your youngsters that placing something in their mouth that has actually been in somebody else’s mouth is never a good concept.
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The study took place in two cities with a relatively low HIV prevalence (Cotonou, Benin and Yaounde, Cameroon), and two cities with a high HIV prevalence (Kisumu, Kenya and Ndola, Zambia). Specifically put together for emergency preparation for possible exposure to toxic substances, bioterrorism (more info) The second investigated the impacts of viral IE regulatory protein ICP0 on the reduction in absolute levels of heterochromatic histone marks associated with these genes during induction of E gene expression. If I supply the CP Black 6 wire harness I’ll e-mail the new instructions to you (only 1 wire is different). Now, cancer has become the foremost arena in which gene therapy is applied – a recent summary of 1020 open and closed gene therapy clinical trials from 1990 to 2004 found that 675 trials (66%) were in the area of cancer.
Prior to the beginning of each session, the agents were informed that providing false testimony to the body was unlawful. And a few of Ortega’s twelve brothers and sisters live in the area and help out on the farm.
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He assigns her to the island to research immortality, and she suspects the key to realizing it lies in the pre-teen Natalia, another prisoner. Shapcott describes Golf Revolution as the “yoga model”—you join a club and drop in for as much or as little training as you want in a pay-as-you-go way. The CDC recommends the following regimens for presumptive treatment of chlamydial cervicitis[1] : Uniform pellet shape.
In 1962, a scientific paper written by an Italian researcher reported that oleuropein had the ability to lower blood pressure in animals. In contrast, despite the purpose of the first gene therapy clinical trial in 1989 being for gene replacement to treat a monogenetic disorder, only 9% of clinical trials thereafter have been in this category (Edelstein, 2005).Cancer gene therapy involves intratumoral, intracavitary, or intravascular administration of a viral vector whose gene products impede the survival and growth of tumor cells left behind after surgery or other therapies. The BND agents repeatedly insisted that the selectors provided by the US were precisely checked.
It's also Natalia who greets Barry when he arrives on the island six months after Claire and Moira's escape attempt, searching for them. The name riffs on Matson's love of traditional folk textiles and patterns that inspire and become incorporated in her work. Like their cellular hosts, herpesviruses are subject to the regulatory impacts of chromatin assembled on their genomes. For herpes simplex virus (HSV), the initial chromatin state of the viral genome exhibits characteristics of heterochromatin (histone H3 lysine 9 [H3-K9] and H3-27 methylation) (2–4) and appears to be a response of the cell to the infecting nonnucleosomal genome. Currently, these phytochemicals are receiving considerable attention in cardiovascular research for their ability to reduce the harmful oxidation of cholesterol and slow down the accelerated clumping of blood platelets that can lead to dangerous clots.
Oncolytic vectors are viruses with intrinsic or engineered tumor selectivity that lyse tumor cells, while nonlytic vectors express transgenes that generate an anticancer effect.
The insurgents want to carve out a separate state governed by their strict interpretation of Islamic law, and some have links to the Islamic State group. As with conventional therapies, the selectivity of this approach is not perfect, but localized vector delivery to the tumor allows for some selectivity of viral uptake. Additionally, the use of viruses that only propagate in dividing cells or transgenes driven by tumor-specific promoters confers additional selectivity.Of the 675 initiated cancer gene therapy clinical trials, oncolytic viruses have been the focus of slightly over half, with the remainder utilizing nonlytic vectors such as retrovirus, adeno-associated virus (AAV), plasmid DNA, lipofection, RNA transfer, gene gun, and bacteria. The oncolytic viruses with which clinical experience has been reported consist of three DNA viruses engineered in the laboratory to achieve tumor selectivity (adenovirus, HSV, and vaccinia) and two wild-type or spontaneously arising attenuated RNA viruses with intrinsic tumor selectivity (Newcastle disease virus (NDV) and reovirus).
Measles virus will be added to the second group once results of a phase I trial in patients with ovarian cancer are published.
HSV-1 possesses a linear, double-stranded DNA genome of 152 kb encoding more than 80 genes. The genome is composed of unique long (UL) and unique short (US) segments, which are flanked by inverted repeats. The repeats surrounding UL are designated ab and b'a', while the repeats surrounding US are designated a'c' and ca. There are two different origins of replication, oriL in the long segment and oriS in the short segment.
OriS is duplicated, along with ICP4, because they are found in the inverted repeats surrounding the short segment. Similarly, 34.5, ICP0, and LAT are duplicated because they are found in the inverted repeats surrounding the long segment.


Approximately half of the genes are essential for viral replication in cell culture and are labeled above the genome. Genes labeled in red represent nonessential genes that are mutated in several of the replication-conditional viruses studied in brain tumor therapy and described in the text. During lytic infection, HSV-1 genes are expressed in a temporally regulated cascade consisting of three phases, designated , , and . The gene products promote viral DNA synthesis, and include viral DNA polymerase, the large subunit of viral ribonucleotide reductase (RR), and herpes simplex virus type 1 thymidine kinase (HSV-TK). The -gene products create an environment favorable for protein synthesis, contribute to encapsulation of viral DNA, and promote viral envelopment. 34.5 is one of three HSV-1 genes that are duplicated because they are found in inverted repeats. A second potential obstacle when using HSV-1 recombinant vectors is the fact that most humans have pre-existing herpes immunity, which could potentially impair gene delivery. Approximately 90% of the adult population has been exposed to HSV-1 as determined by the detection of viral DNA and antibodies to HSV-1 in serum (Boviatsis et al., 1994b). Potential neurotoxicity is a third problem inherent to HSV-1 vectors when delivered into the central nervous system. HSV-1 is a neurotrophic human pathogen that can cause a life-threatening encephalitis from primary infection or from reactivation of latent virus. The recombinant HSV-1 viruses that have been studied as anticancer agents fall into three categories. The risk of reactivation was felt to be low based on a study showing that, after adult rats were infected with wild-type HSV-1 and latency established, intracerebral inoculation of hrR3 failed to cause HSV-1 reactivation (Wang et al., 1997). The most thoroughly studied combination has mutations in hrR3 and 34.5, a combination found in G207, a vector that completed phase I safety trials in brain tumor patients.
Wild-type subgroup C causes a mild upper respiratory infection, which resolves uneventfully in healthy individuals. The adenoviral genome is divided into E1A, E1B, E2, E3, and E4 regions, which regulate a temporal cascade of gene expression. To generate an adenoviral vector, a transgene is cloned into a plasmid bearing the adenovirus packaging signal, an E1 deletion, and some adenovirus sequences downstream from the E1 region.
This plasmid is introduced into E1-expressing 293 cells along with a second plasmid bearing a packaging signal and E1 deletion. The viral genome is maintained as an extra-chromosomal element that is rapidly lost in dividing cells, but this is not a major impediment during lytic infections of tumor cells. Adenovirus only infects cells expressing coxsackievirus and adenovirus receptors (CARs) on their surface (Figure 2).
CAR is only expressed by some human tumor cells and, without genetic engineering to alter viral molecules that bind CAR, adenovirus therapy can only be used to treat CAR-expressing tumors like prostate cancer, whose CAR expression increases with Gleason score (Rauen et al., 2002). Oncolytic adenoviruses are highly immunogenic, which can be advantageous if it leads to an antitumor immune response, but can also be a disadvantage if the immune response blocks viral propagation or leads to toxicity.
Indeed, the immunogenic nature of adenovirus may have contributed to the death of an 18-year-old patient after an arterial infusion of a replication-defective adenovirus vector during a gene therapy trial for ornithine transcarbamylase deficiency (Assessment of adenoviral vector safety and toxicity: report of the National Institutes of Health Recombinant DNA Advisory Committee, 2002). The E1B deletion in ONYX-015 restricts viral replication to cells lacking a normal p53 protein since E1B's ability to sequester p53 is essential to viral replication (Bischoff et al., 1996).
This vector was initially appealing because of potential applicability in the 40% of human cancers carrying p53 mutations (Vogelstein and Kinzler, 2004). However, the virus proved capable of infecting some cultured cells lacking p53 mutations (Goodrum and Ornelles, 1998).
Vaccinia virus was named because it was felt to arise around 1930 as a natural derivative of a cowpox strain that was serially passaged while being used as a smallpox vaccine. Unlike adenovirus, vaccinia virus can infect cells from a variety of animal models and a variety of cell types. Vaccinia virus can be stored as dry power for prolonged periods of time without significant loss of infectivity. Other benefits include large DNA size capability (up to 25 kb) and easy manipulability, replication exclusively in the cytoplasm eliminating any risk of integration, and short replication cycle. Initial concerns about vaccinia virus' immunogenicity making repeat injections impossible were alleviated by the finding that vaccinia treatment was as effective in vaccinated as nonvaccinated animals (Lee et al., 1994).
Vaccinia virus' ability to replicate in a wide spectrum of human cells raises concerns about toxic side effects if the virus were shed into the bloodstream, which could affect not only treated patients, but also their relatives and contacts. Should unwanted replications occur, vaccinia immunoglobulin (Enserink, 2002) or the antiviral agent cidofovir may offer protection against vaccinia replication, but further study will be necessary to definitively determine their efficacy.RNA viruses whose wild-type form or natural attenuated mutants exhibit intrinsic tumor selectivityDouble-stranded RNA formation is a hallmark of the life cycle of RNA viruses.
Double-stranded RNA also stimulates the release of interferons, which activate PKR in adjacent uninfected cells, thereby protecting these cells from viral infection. Reoviruses contain 10 segments of double-stranded RNA and are apparently nonpathogenic to humans, causing only mild infections limited to the gastrointestinal or respiratory tract. Reoviruses achieve tumor selectivity because they can replicate relatively selectively in cells with an activated Ras pathway, and approximately 30% of human tumors possess an activating mutation of the Ras pathway. Thus, in cells with an activated Ras pathway, the PKR-mediated responses to double-stranded RNA and interferon are defective. In nontumorous cells, early reovirus transcripts trigger PKR phosphorylation, which in turn leads to inhibition of translation of viral genes and control of virus infection.
In contrast to the other viruses described here, there is still no satisfactory system to generate recombinant reoviruses with specifically engineered mutations, due in part to technical challenges posed by the presence of 10 double-stranded RNA segments in the reoviral genome. Tumor selectivity is believed to arise from viral induction of tumor necrosis factor (TNF)- secretion by peripheral blood mononuclear cells (PBMCs) and viral enhancement of sensitivity of neoplastic cells to the cytotoxic effects of TNF- (Lorence et al., 1988). The most characterized oncolytic strain of NDV is 73-T, so named because it was passaged through mouse ascites tumor cells 73 times in vitro. Because it has undergone the most clinical investigation, important lessons can be drawn from the general strategy utilized for ONYX-015. The strategy has involved a progression from demonstrating safety of intratumoral administration, followed by intracavitary installation (intraperitoneal), intra-arterial infusion (hepatic artery), and eventually intravenous administration. Finally, as a result of results in more clinical trials than any other oncolytic virus demonstrating its safety, ONYX-015 became the first virus to undergo clinical trials combined with chemotherapy.Because oncolytic viruses were initially conceived of as local therapies, the first studies of ONYX-015 occurred in patients with recurrent head and neck carcinomas because of their poor prognosis, the tendency to succumb to local rather than metastatic disease, and the superficial readily accessible tumors, would be easily biopsied and would tolerate inflammation better than deeper cavities. Doses were safely escalated up to 2 1012 viral particles (equivalent to approximately 1011 plaque-forming units (PFU)) daily for 5 consecutive days (Ganly et al., 2000).
Because of difficulties accessing these tumors, biopsy evidence for viral replication was not obtained on these trials.Tumor types that spread within specific body cavities were felt to be appropriate targets for intracavitary inoculation. Therefore, intraperitoneal administration to patients with advanced refractory ovarian carcinoma was performed (Vasey et al., 2002), followed by intraesophageal instillation in patients with Barrett's esophagus.
Finally, premalignant oral dysplasias were targeted through administration as a mouthwash (Rudin et al., 2003). Intraperitoneal administration proved to have dose-limiting toxicity at 1011 PFU daily for 5 consecutive days. Viral genomes were detected in the peritoneum up to 15 days post-treatment but infection of tumor cells in ascitic fluid was not demonstrated.
Colorectal carcinoma causes much of its morbidity and mortality through liver metastases, and these metastases receive over 90% of their blood supply from the hepatic artery. This led to the first trial of ONYX-015 administered through the hepatic artery for colorectal metastases to the liver. Safety was shown at doses up to 2 1012 viral particles given on days 1, 8, 22, 50, and 78, followed by a 5-fluorouracil (5-FU)-based chemotherapy regimen every 4 weeks (Reid et al., 2001). Viral replication was demonstrated in patients receiving the two highest doses by using PCR to detect an increase in genome concentrations in the blood.
No dose-limiting toxicity was noted with doses up to 2 1012 viral particles per injection.HSVBecause of their known ability to replicate in neural tissue, oncolytic HSV were first tested in recurrent malignant glioma patients.
Between 1997 and 1999, two groups performed phase I dose-escalation safety trials of replication-selective HSV 1716 and G207 in the treatment of malignant brain tumors. No adverse effects, including encephalitis, were seen that could be attributed to the administration of 1716. The thallium SPECT volumes were smaller in one, stable in two, larger in five, and not assessable in one patient.This same group followed that study with another study designed to verify viral replication in gliomas. Two patients had long-term expression of the galactosidase reporter gene found in G207 56 and 157 days after inoculation. However, its safety profile in animal models led to a phase I study in treating nine patients with colorectal cancer metastatic to the liver by hepatic arterial infusion (Fong et al., 2002).
No significant toxicity was noted at doses up to 107 PFU, and viral gene expression was detected exclusively in tumor tissues. Overall response rate was 11%, with another 45% showing stable disease.NDVNDV strain 73-T has been utilized in clinical trials as both a viral oncolysate, a suspension of virus and tumor cells that presumably acts as a tumor vaccine, and as free virus. A recent 15-year follow-up of patients with stage III malignant melanoma treated postsurgically with 73-T oncolysate in 1975 as part of a phase II clinical study revealed a 55% overall 15-year survival (Batliwalla et al., 1998). The overall response rate was 15%, and time to tumor progression ranged from 4 to 30 months.
There was one treatment-related death involving a 55-year-old man with renal carcinoma metastatic to the lungs and compromised pulmonary function as a result of previous lobectomies and an 8 cm metastasis in one of two remaining lung lobes. The first ever clinical trial combining onocolytic virus with chemotherapy was initiated by (Khuri et al., 2000). Cisplatin and 5-FU were then given simultaneously, with treatment cycles repeated every 3 weeks or until tumor grew or side effects were encountered. Out of 37 patients, 19 exhibited a response to treatment and only 15% of injected tumors had progressed 6 months after treatment initiation. This approach is best suited for an oncolytic virus that has been dose escalated to a maximum tolerable dose, such as adenovirus. CV706 is a replication-competent, E3-deleted cytolytic Ad5 adenovirus in which a minimal promoter enhancer of the human PSA gene has been placed between E1A and its promoter, causing PSA-regulated expression of E1A. In a phase I trial, 20 patients with locally recurrent prostate cancer after radiation therapy were treated with intraprostatic injections of up to 1013 viral particles (DeWeese et al., 2001). All five patients who achieved a 50% or more reduction in PSA were treated with the two highest doses of CV706.Top of pageTransgenes used in cancer gene therapyUnlike nononcolytic vectors, oncolytic viruses do not require inserted transgenes with a tumoricidal effect in order to be effective therapeutic agents. However, oncolytic viruses can still gain an extra anticancer effect by the insertion of certain transgenes. Transgene types that have been inserted into oncolytic viruses in clinical trials include immune response-modifying genes (cytokines) and prodrug-activating enzymes.Immune response-modifying genesCytokines as transgenes in oncolytic viruses are best suited for viruses that generate a strong immune response that can potentially extend into an antitumor immune response, such as vaccinia or HSV. No serious toxicity occurred, and the most frequent side effects were local inflammation and flu-like symptoms.
Viral mRNA expression was detected in two-thirds of biopsy samples, but no patients showed detectable GM-CSF in serum. In addition, significant eosinophil, lymphocyte, and macrophage infiltration was found in all tumors. No toxicity occurred, and viral mRNA was detected in two-thirds of tumor biopsy samples 21 days after last treatment. Genes encoding for prodrug-activating enzymes are appealing transgenes in cancer gene therapy because of their prominent bystander effects, generated by the ability of the active metabolite of the prodrug to mediate toxicity of neighboring nontransduced cells. The two examples that have made it to clinical trials with oncolytic viruses are HSV-TK, which phosphorylates the antiherpetic agent GCV, and E.
In a phase I clinical trial, 16 patients with newly diagnosed intermediate- to high-risk prostate cancer received intraprostatic injections escalating up to 1012 viral particles (Freytag et al., 2002). After 2 days, 5-fluorocytosine and valganciclovir were administered for varying amounts of time.
Seven of 16 (44%) patients demonstrated a 25% or higher decrease in serum PSA and three of 16 (19%) demonstrated a 50% or higher decrease in serum PSA (Freytag et al., 2002). A follow-up phase I trial by the same group combining this virus with radiation therapy was described earlier in the section highlighting trials combining viruses with radiation therapy.Top of pageLessons learned and future directionsSince the first clinical trial using oncolytic viruses was initiated with ONYX-015 in 1996, five different species of viruses have entered phase I or II clinical trials on over 300 cancer patients. Encouraging data have led to a phase III clinical trial in which ONYX-015 plus chemotherapy will be compared to chemotherapy alone in approximately 300 patients with recurrent head and neck cancer. Results from such a study will provide the first sense of whether oncolytic viruses warrant consideration as part of certain existing anticancer therapeutic regimens.Considerable safety data have accumulated from the numerous completed phase I or II clinical trials. Of over 300 patients treated, only one treatment-related death has been reported to date, from intravenous NDV, and this death may have resulted from rapid tumor lysis, underscoring the importance of selecting patients with adequate pretreatment functional reserve. While certain levels of toxicity may be acceptable in experimental cancer therapies, the risk of rapid treatment-related mortalities should be minimized by adequate patient selection criteria as well as by having a 'fail-safe' mechanism built into the vector to allow a systemic agent to be administered to abort viral replication.There are issues specific to certain types of tumors. For example, high-grade gliomas are among the least easily accessed tumor types to undergo oncolytic virus clinical trials, given the greater morbidity associated with neurosurgical procedures compared with diagnostic procedures in other cancer types.
Gliomas have undergone oncolytic virus treatment by stereotactic inoculation during needle-guided biopsies, as well as using multiple inoculations during a craniotomy. A craniotomy allows inoculation along multiple needle tracts, causing more widespread viral distribution, but leaves a postsurgical cavity in which virus can accumulate if intraparenchymal pressure drives the inoculum out of its needle tracts.
Stereotactic inoculation limits viral distribution and total dose, but is a safer less-expensive procedure, an important factor if a follow-up craniotomy is required to obtain tissue to assess viral replication. The relative merits of both approaches will become better understood as more clinical data are reported.
Treating gliomas with oncolytic viruses will likely be far more challenging than other tumors because of the highly invasive nature of glioblastoma. While viruses such as NDV have been dose-escalated up to a maximum tolerable dose, other viruses such as HSV have had a very good safety profile and therefore have yet to define a maximum tolerable dose but have generated sufficient production costs that some trials have had to dose escalate up to a 'maximum affordable dose.' For these types of viruses, defining a maximum tolerable dose will require greater financial support of clinical trials and more cost-efficient technologies for viral production.
An alternative strategy is the exploration of agents that may enhance in vivo viral replication.For that matter, the role of dose in oncolytic virus therapy remains unclear. While viruses such as NDV have caused greater therapeutic benefit at higher doses, the benefit of higher doses with viruses such as HSV remains unclear.
The inability of some viruses to elicit a therapeutic benefit at higher doses may be immune-mediated, a possibility that should be assessed using data from clinical trials. Alternatively, an immune response against infected tumor cells could also enhance tumor destruction, as specific host immunity develops against tumor antigens.
It is possible that the immune system antagonizes the efficacy of oncolytic viruses administered intravascularly by limiting viral delivery to the tumor. However, once the virus reaches tumor cells, as it does immediately with intratumoral inoculation, the immune response may augment tumor reduction by redirecting the cytotoxic T-cell response from viral antigens to tumor antigens (Todo et al., 1999).
When administering an immunogenic virus in a situation where the immune response is likely to impede viral replication, it may be essential to use a virus with a short replication cycle (Table 1).Given the costs of clinical trials, organizers must maximize data obtained from each trial. Mathematical models that calculate the kinetics of viral replication can be used to determine the number of viral genome copies in the circulation as a function of time based on lab values from available blood samples obtained during clinical trials (Wein et al., 2003). Since nonreplicating viruses can themselves induce an immune response or toxicity, dosing considerations may also include the number of viral particles in addition to plaque-forming units, and relationships between viral particles and plaque-forming units should be made clear when publishing results. In addition, most clinical trials have reported effects on surrogate end points such as PSA levels or transient injection site responses. There is a need for validated end points such as survival and quality of life in order to render data between different trials more readily comparable.Top of pageConclusionsAlthough the concept of using viruses as oncolytic agents dates back nearly a century, formal clinical experience could not be achieved until advances in molecular biology, genetics, and virology enabled engineering DNA viruses to achieve tumor selectivity or identification of RNA viruses with intrinsic tumor selectivity. The 9 years worth of clinical experience that have been achieved with oncolytic viruses have produced enough therapeutic efficacy to trigger optimism for future trials. Although the initial concerns of clinical investigators were for safety, this has proven not to be a common concern in these trials.



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