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The Cell Division Cycle Associated 2 (CDCA2) gene is responsible for encoding a targeting subunit of cell-cycle associated protein. CDCA2 plays a crucial role in various cellular processes, including chromosome segregation and decondensation, nuclear envelope reassembly, microtubule assembly, and DNA damage response. Additionally, CDCA2 is involved in multiple signaling pathways such as the PI3K/Akt pathway and p53 pathway. Undoubtedly, there exists a strong association between CDCA2 and cancer. Numerous studies have reported that elevated levels of CDCA2 are correlated with poor prognosis and several clinicopathological characteristics like tumor size and TNM stage across different types of cancer. Therefore, CDCA2 holds great potential as both a biomarker for diagnosis and a therapeutic target for interventions such as targeted therapies or immunotherapy. Given its promising prospects in scientific research and clinical applications, it is imperative for researchers to delve into the underlying mechanisms of CDCA2 and explore its utilization. • An insight into the basic mechanism for the role of CDCA2 in the cell division process. • Adetailed summary of the complex relationship between CDCA2 and tumor progression. • Feasible ideas to further investigate the oncogeneCDCA2. • Potential strategies to translate the theory of CDCA2 into practical clinical interventions. [ABSTRACT FROM AUTHOR]

320 Background: As targeted therapy options increase in oncology, GTT use is also increasing; however, the strategies and barriers to ordering GTT can vary across clinics. S2108CD is a cluster randomized trial comparing an educationally enhanced genomic tumor board intervention to usual practice to increase evidence-based genome-informed therapy based on GTT results. This analysis seeks to understand the utilization of GTT by physicians in rural and community oncology clinics. Methods: Physicians at sites enrolled on S2108CD completed baseline questionnaires collecting demographics, practice characteristics, and physicians' experience with and use of GTT in practice. We also conducted semi-structured interviews at baseline and mid-study with select physicians in both arms to understand how and when physicians are ordering GTT and how it guides treatment decision making. Descriptive statistics were generated for survey data. Interviews were analyzed using conventional content analysis to identify recurring themes. Results: Surveys were completed by 117 physicians across 18 Recruitment Centers, with 57 from the usual practice and 60 from the intervention arm. Interviews were conducted with 10 physicians at baseline and 10 within 12-18 months of start of the study. Physicians reported feeling confident in determining whether GTT is clinically appropriate for a patient (42% moderately confident, 50% very confident). Some physicians utilize GTT from multiple vendors, with the following vendors used most frequently: Tempus (50% of physicians), Caris Life Sciences (61%), Foundation Medicine (62%) and Guardant Health (69%). Over two-thirds of physicians reported that professional guidelines were "very important" in the decision to utilize GTT. Reasons for not ordering GTT included "not relevant for the patient" (36%) and "difficulty in obtaining sufficient tissue" (20%) as "often" reasons. Notably, lack of access and cost/insurance coverage were "never" or "rarely" a reason for not ordering GTT in 80% physicians. Long waits to receive GTT results reportedly caused a delay in making patient care decisions (47% sometimes and 26% often). Physicians rely on the following sources to learn about new GTT panels: scientific meetings (91%), peer-reviewed literature (92%), and professional societies (90%). Interview data confirmed that physicians are generally confident ordering GTT but there is variability in the processes for ordering GTT and receipt of GTT results amongst clinics. Conclusions: Physicians enrolled on S2108CD self-reported high genomic confidence in ordering GTT. Access to GTT and coverage of GTT do not appear to be barriers to utilization. However, physicians did report delays in decision-making due to result turn-around times, which were sometimes attributed to length of time to tissue sendout and receipt of results into health record. Funding : NIH/NCI/NCORP grant UG1CA189974. Clinical trial information: NCT05455606. [ABSTRACT FROM AUTHOR]

Background: Next-generation sequencing (NGS) of tumor genomes has changed and improved cancer treatment over the past few decades. It can inform clinicians on the optimal therapeutic approach in many of the solid and hematologic cancers, including non-small lung cancer (NSCLC). Our study aimed to determine the costs of NGS assays for NSCLC diagnostics. Methods: We performed a micro-costing study of four NGS assays (Trusight Tumor 170 Kit (Illumina), Oncomine Focus (Thermo Fisher), QIAseq Targeted DNA Custom Panel and QIASeq Targeted RNAscan Custom Panel (Qiagen), and KAPA HyperPlus/SeqCap EZ (Roche)) at the StemCore Laboratories, the Ottawa Hospital, Canada. We used a time-and-motion approach to measure personnel time and a pre-defined questionnaire to collect resource utilization. The unit costs were based on market prices. The cost data were reported in 2019 Canadian dollars. Results: Based on a case throughput of 500 cases per year, the per-sample cost for TruSight Tumor 170 Kit, QIASeq Targeted DNA Custom Panel and QIASeq Targeted RNAscan Custom Panel, Oncomine Focus, and HyperPlus/SeqCap EZ were CAD 1778, CAD 599, CAD 1100 and CAD 1270, respectively. The key cost drivers were library preparation (34–60%) and sequencing (31–51%), followed by data analysis (6–13%) and administrative support (2–7%). Conclusions: Trusight Tumor 170 Kit was the most expensive NGS assay for NSCLC diagnostics; however, an economic evaluation is required to identify the most cost-effective NGS assay. Our study results could help inform decisions to select a robust platform for NSCLC diagnostics from fine needle aspirates, and future economic evaluations of the NGS platforms to guide treatment selections for NSCLC patients. [ABSTRACT FROM AUTHOR]

PURPOSE Enhanced cancer risk reduction measures are recommended for patients with hereditary predispositions to cancer. Providing these services within a healthcare institution (HI) generates downstream revenue (DSR). We evaluated the DSR for our institution after patients were identified to have a pathogenic variant by a genetic counselor (GC). METHODS Retrospective chart review identified patients with hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) seen in the UT Southwestern Medical Center Cancer Genetics Clinic between November 1, 2009, and January 31, 2019. All billable encounters were recorded. Total revenue and work relative value units were calculated after patients met with a GC. RESULTS Four hundred twenty-five patients with HBOC and LS had financial data available for analysis. After GC visit, DSR totaled $32,798,000 in US dollars (USD). Patients unaffected with cancer (n 5 176) generated $8,453,000 (USD). Patients (n 5 96) whose first visit to the institution were for GC consultation (naïve patients) generated $5,933,000 (USD). Unaffected, naïve patients (n 5 64) generated $3,190,000 (USD) in DSR. The 425 total patients generated 73,957 work relative value units at the institution after their appointment with a GC. CONCLUSION GCs bring in substantial DSR for their HI by identifying patients with HBOC or LS. Institution naïve and unaffected patients who continue care at the institution provide additional opportunities to generate DSR. If applied to additional pathogenic variant carriers, GCs can further increase DSR for an HI. [ABSTRACT FROM AUTHOR]

Sarcomas are rare, ubiquitous and heterogeneous tumors usually treated with surgery, chemotherapy, target therapy, and radiotherapy. However, 25-50% of patients experience local relapses and/or distant metastases after chemotherapy with an overall survival about 12-18 months. Recently, immuno-therapy has revolutionized the cancer treatments with initial indications for non-small cell lung cancer (NSCLC) and melanoma (immune-checkpoint inhibitors).Here, we provide a narrative review on the topic as well as a critical description of the currently available trials on immunotherapy treatments in patients with sarcoma. Given the promising results obtained with anti-PD-1 monoclonal antibodies (pembrolizumab and nivolumab) and CAR-T cells, we strongly believe that these new immunotherapeutic approaches, along with an innovative characterization of tumor genetics, will provide an exciting opportunity to ameliorate the therapeutic management of sarcomas. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is one of the most common cancers worldwide and has a high mortality rate following disease recurrence. Treatment efficacy is maximized by providing tailored cancer treatment, ideally involving surgical resection and personalized neoadjuvant and adjuvant therapies, including chemotherapy, radiotherapy and increasingly, targeted therapy. Early detection of recurrence or disease progression results in more treatable disease and is essential to improving survival outcomes. Recent advances in the understanding of tumor genetics have resulted in the discovery of circulating tumor DNA (ctDNA). A growing body of evidence supports the use of these sensitive biomarkers in detecting residual disease and diagnosing recurrence as well as enabling targeted and tumor-specific adjuvant therapies. Methods: A literature search in Pubmed was performed to identify all original articles preceding April 2019 that utilize ctDNA for the purpose of monitoring response to colorectal cancer treatment. Results: Ninety-two clinical studies were included. These studies demonstrate that ctDNA is a reliable measure of tumor burden. Studies show the utility of ctDNA in assessing the adequacy of surgical tumor clearance and changes in ctDNA levels reflect response to systemic treatments. ctDNA can be used in the selection of targeted treatments. The reappearance or increase in ctDNA, as well as the emergence of new mutations, correlates with disease recurrence, progression, and resistance to therapy, with ctDNA measurement allowing more sensitive monitoring than currently used clinical tools. Conclusions: ctDNA shows enormous promise as a sensitive biomarker for monitoring response to many treatment modalities and for targeting therapy. Thus, it is emerging as a new way for guiding treatment decisions—initiating, altering, and ceasing treatments, or prompting investigation into the potential for residual disease. However, many potentially useful ctDNA markers are available and more work is needed to determine which are best suited for specific purposes and for improving specific outcomes. [ABSTRACT FROM AUTHOR]

At the root of the so-called precision medicine or precision oncology, which is our focus here, is the hypothesis that cancer treatment would be considerably better if therapies were guided by a tumor’s genomic alterations. This hypothesis has sparked major initiatives focusing on whole-genome and/or exome sequencing, creation of large databases, and developing tools for their statistical analyses—all aspiring to identify actionable alterations, and thus molecular targets, in a patient. At the center of the massive amount of collected sequence data is their interpretations that largely rest on statistical analysis and phenotypic observations. Statistics is vital, because it guides identification of cancer-driving alterations. However, statistics of mutations do not identify a change in protein conformation; therefore, it may not define sufficiently accurate actionable mutations, neglecting those that are rare. Among the many thematic overviews of precision oncology, this review innovates by further comprehensively including precision pharmacology, and within this framework, articulating its protein structural landscape and consequences to cellular signaling pathways. It provides the underlying physicochemical basis, thereby also opening the door to a broader community. [ABSTRACT FROM AUTHOR]

Purpose The implementation, benefits, and challenges of clinical pharmacist services within a Precision Medicine Program for cancer patients are described. By relating the practice model that was developed, this report may further encourage pharmacists at cancer centers nationally to be involved and lead precision-based care in the oncology setting. Summary A clinical pharmacist was integrated into a Precision Medicine Program for oncology patients using somatic testing to identify actionable mutations and apply targeted therapy to malignancies. This pharmacist served as a drug resource for the program's molecular tumor board and oncologists seeking precision-based oncologic strategies. The pharmacist was a facilitator of drug assistance and dispensing in collaboration with the specialty pharmacy and provided care to 14 oncology patients receiving precision-based therapies. The clinical pharmacist was readily accepted as an addition to the team by both oncologists and patients and the experience served as an important learning opportunity. Conclusion The success of integrating this precision medicine pharmacist into a newly formed Precision Medicine Program and the model it can serve as may be considered for other cancer centers that may or may not have easily accessible pharmacogenomic experts and resources. This service highlights the importance of pharmacist care in such a program and the various opportunities for integration. Oncology clinical pharmacists should seek to integrate into Precision Medicine Programs and systems directing this care and develop their knowledge and understanding of genomics to continue providing the highest level of cancer care as a pivotal member of the cancer care team. [ABSTRACT FROM AUTHOR]

The comprehensive screening of intracellular and extracellular microRNAs was performed to identify novel tumor suppressors. We found that miR-8073 was present in exosome and predominantly exported from colorectal cancer cells. Treatment with a synthetic miR-8073 mimic resulted in a dramatic decrease in the proliferation of various types of cancer cells, which was not observed in similarly treated normal cells. As little is known about the biological functions of miR-8073, its target mRNAs were analyzed by both mRNA expression and in silico sequence analyses, leading to five probable target candidates (FOXM1, MBD3, CCND1, KLK10, and CASP2) that enhance survival during the regulation of the cell cycle, cell proliferation, and apoptosis. We experimentally confirmed that miR-8073 binds the 3’-UTR of each of these mRNA target candidates and that the introduction of a synthetic miR-8073 mimic into cancer cells reduced levels of protein expression. Finally, the antiproliferative effects of miR-8073 were validated in vivo: the subcutaneous injection of a synthetic miR-8073 mimic suppressed colorectal tumor volume to 43% in tumor-bearing xenografted mice. These results suggest that because miR-8073 binds, and thus reduces the levels of, these oncogenic targets, cancer cells must actively downregulate miR-8073 as a survival mechanism. The introduction of miR-8073 into tumors could thus inhibit tumor growth, indicating its great potential for cancer therapeutics. [ABSTRACT FROM AUTHOR]

Background: The anti-programmed death receptor-1 (anti–PD-1) pembrolizumab is approved as first-line monotherapy for metastatic non-small cell lung cancer (mNSCLC) with PD-ligand 1 (PD-L1) tumor expression ≥50%. Most studies comparing PD-L1 results by immunohistochemistry (IHC) assay type have been conducted by prespecified and, in most cases, highly experienced, trained pathologists; however, knowledge is limited regarding the current use and concordance of PD-L1 assays in the real-world clinical setting. Our aim was to study the distribution of PD-L1 tumor expression by IHC assay type among patients with mNSCLC in US oncology practices. Methods: This retrospective observational study utilized de-identified, longitudinal data from a large US electronic medical record database. Eligible patients were adults (≥18 years) with histologically/cytologically confirmed initial diagnosis of metastatic or recurrent NSCLC from October 2015 through December 2017. We determined PD-L1 testing trends and distribution of PD-L1 tumor expression (percentage of tumor cells staining for PD-L1) by IHC assay type. Results: The 12,574 eligible patients (mean age, 69 years) included 6,620 (53%) men and 86% with positive smoking history. Of 4,868 evaluable tests, 3,799 (78%), 195 (4%), 165 (3%), and 709 (15%) used the Agilent 22C3 pharmDx, Agilent 28–8 pharmDx, Ventana PD-L1 (SP142) Assay, and laboratory-developed tests (LDTs, including SP263), respectively. The percentages of tests scoring PD-L1 tumor expression of ≥50% were 33%, 32%, 10%, and 23%, respectively. Measured PD-L1 tumor expression varied across the four assay types (χ2 p < 0.001) and across three assay types excluding SP142 (p < 0.001), with no significant difference between 22C3 and 28–8 assays (p = 0.96). The PD-L1 testing rate increased from 18% in the fourth quarter of 2015 to 71% in the fourth quarter of 2017. Conclusions: In the real-world clinical setting, we observed that measured PD-L1 tumor expression is concordant using the 22C3 and 28–8 assays; however, the SP142 assay and LDTs appear discordant and could underestimate high PD-L1 positivity. Further study is needed to evaluate the association between PD-L1 tumor expression and response to therapy. [ABSTRACT FROM AUTHOR]

The optimal management of breast cancer susceptibility gene (BRCA)1/2 carriers with isolated serous tubal intraepithelial carcinoma (STIC) found at risk-reducing salpingo-oophorectomy (RRSO) is unclear. The prevalence of occult carcinoma and STIC in a consecutive series of BRCA1/2 carriers undergoing RRSO is reported. The outcome of staging procedures in BRCA1/2 carriers with isolated STIC at RRSO as well as the relationship between staging, chemotherapy treatment and risk of recurrence was assessed via a systematic review of the literature. Our series included 235 BRCA1/2 carriers who underwent RRSO. Federation of Gynaecology and Obstetrics stage IA carcinoma or STIC was found at RRSO in three (1.3%) and two (0.9%) patients, respectively. A systematic review of the literature included 82 BRCA1/2 carriers with isolated STIC found at RRSO. In 13/82 (16%) cases with STIC, staging was reported. In none of these cases staging revealed more advanced disease. Recurrent disease was found in four of 36 patients with reported follow-up. The estimated risk of recurrence in patients with isolated STIC at RRSO was about 11% (95% confidence interval 3–26%) after a median follow-up of 42 months (range 7–138). No recurrences were reported in those patients with STIC at RRSO who underwent staging or received chemotherapy. We found 1.3% occult carcinoma and 0.9% STIC at RRSO in our cohort of BRCA1/2 carriers. A systematic review of the literature suggests that additional treatment after RRSO, i.e. staging and/or chemotherapy, is associated with a lower risk of recurrence. However, data on staging and follow-up are limited. [ABSTRACT FROM AUTHOR]

Purpose: Currently, there are only a few software tools designed to assist physicians to translate molecular abnormalities in the cancer genome into potential treatment options. There is a pressing need to develop software to reliably identify known targeted therapies and experimental treatments for patients on the basis of the results of tumor DNA sequencing. Methods: The TQuest platform includes a data layer, data acquisition layer, search engine, and user interface. It identifies associations between one or more molecular targets and therapeutic options. The data layer consists of indexed interventional clinical trials and an expert-curated database of clinically or experimentally validated associations between mutations and drug response. The data acquisition layer includes an information-harvesting module that keeps an up-to-date full-text index of clinical trials by crawling clinicaltrials.gov and combining it with US Food and Drug Administration label data. The user interface is a Web-based module that allows users to upload genomic variants, tumor morphology, and diagnosis. The search results are qualified and ranked by a relevance score. Results: We have manually curated information for 368 distinct genomic variants of 162 gene targets corresponding to 863 drug and target interactions. The platform currently contains a full-text index of approximately 80,000 interventional clinical trials. We applied TQuest to molecular data from 73 metastatic breast cancers. TQuest identified a total of 276 drugs as potential therapeutic options, ranging from one to 103 per patient. Conclusion: TQuest correctly identified all US Food and Drug Administration–approved drugs and routine indications for all cases and also identified many additional drugs that were used in the context of a given molecular abnormality in various clinical trials. The prototype Web application is available at www.tquest.us, and the source code is open and available on GitHub. [ABSTRACT FROM AUTHOR]

The hallmarks of tumor tissue are not only genetic aberrations but also the presence of metabolic and oxidative stress as a result of hypoxia and lactic acidosis. The stress activates several prosurvival pathways including metabolic remodeling, autophagy, antioxidant response, mitohormesis, and glutaminolysis, whose upregulation in tumors is associated with a poor survival of patients, while their activation in healthy tissue with statins, metformin, physical activity, and natural compounds prevents carcinogenesis. This review emphasizes the dual role of stress response pathways in cancer and suggests the integrative understanding as a basis for the development of rational therapy targeting the stress response. [ABSTRACT FROM AUTHOR]

Angiogenesis is known as one of the hallmarks in cancer which could play a key role in providing oxygen and nutrients for tumor cells. It has been shown that tumor cannot grow without sufficient development of new blood vessels. Accordingly, targeting angiogenesis, especially endothelial cells, could be considered as a common therapeutic target in tumors and more investigation on already existing biomarkers and potentially new biomarkers of endothelial cells seems to be necessary in cancer therapy. Moreover, the use of effective targeting approaches such as proteins and peptides, aptamers, and small molecules is an important step for targeting biomarkers associated with endothelial cells and angiogenesis in cancer therapy. These agents are FDA approved, or are currently under investigation in pre-clinical and clinical studies. Among various biomarkers for angiogenesis microRNAs are suitable candidates for target therapy. These molecules play key roles in tumor angiogenesis which exert their effect via targeting a variety of cellular and molecular pathways involved in tumor angiogenesis. Here, we summarize a variety of biomarkers which their expressions or their functions could change the function of endothelial cells in tumor microenvironments. Moreover, we highlighted various therapeutic agents which could target these biomarkers. [ABSTRACT FROM AUTHOR]

microRNAs (miRs) are targets for genomic aberrations and emerging treatments against cancer. It has been demonstrated that targeting miR-569 may potentially benefit patients with ovarian or breast cancer. However, the exact roles of miR-569 remain unclear in human lung cancer cells. Using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR), it was demonstrated that miR-569 expression was consistently decreased in lung cancer cells. As well as cell proliferation and migration inhibition, apoptosis and cell arrest at the G1 phase were induced following reversion of miR-569 expression in lung cancer cells. The present study demonstrated that miR-569 was able to downregulate FOS and high mobility group A2 mRNA and protein expression using RT-qPCR and western blot analysis. The observed role of miRNA-569 in lung cancer cells in the present study suggested that it may be a novel and promising therapeutic target, and a novel biomarker for detecting lung cancer. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have important roles in all biological pathways in multicellular organisms. Over 1,400 human miRNAs have been identified, and many are conserved among vertebrates and invertebrates. Regulation of miRNA is the most common mode of post-transcriptional gene regulation. The miRNAs that are involved in the initiation and progression of cancers are termed oncomiRs and several of them have been identified in canine and human cancers. Similarly, several miRNAs have been reported to be down-regulated in cancers of the two species. In this review, current information on the expression and roles of miRNAs in oncogenesis and progression of human and canine cancers, as well the roles miRNAs have in cancer stem cell biology, are highlighted. The potential for the use of miRNAs as therapeutic targets in personalized cancer therapy in domestic dogs and their possible application in human cancer counterparts are also discussed. [ABSTRACT FROM AUTHOR]

Gastric cancer is the second most common cause of cancer-related mortality worldwide. Accurate prediction of disease progression is difficult, and new biomarkers for clinical use are essential. Recently, we reported that the proteasome-associated deubiquitinating enzyme UCHL5/Uch37 is a new prognostic marker in both rectal cancer and pancreatic ductal adenocarcinoma. Here, we have assessed by immunohistochemistry UCHL5 tumor expression in gastric cancer. The study cohort comprised 650 patients, who underwent surgery in Helsinki University Hospital, Finland, between 1983 and 2009. We investigated the association of cytoplasmic UCHL5 tumor expression to assess clinicopathological parameters and patient survival. Positive cytoplasmic UCHL5 tumor immunoexpression is linked to increased survival of patients with small (<5 cm) tumors (p = 0.001), disease stages I-II (p = 0.025), and age 66 years or older (p = 0.037). UCHL5 is thus a potential marker in gastric cancer with new prognostic relevance. [ABSTRACT FROM AUTHOR]

It has been recognized that miR-181a expression is dysregulated and intimately associated with clinical prognosis in a variety of human cancers. However, the direct role of miR-181a in tumor progression has been elusive. Moreover, mounting evidence has demonstrated that cellular apoptosis, a physiological process of programmed cell death, is disrupted in various categories of human malignancies. Multiple apoptosisrelated genes have been proven to act as the target genes of miR-181a. In this study, we hypothesize that miR-181a probably plays a potential role in modulating the procession and apoptosis of cancer cells. We performed a literature review and elucidated how miR-181a modulated cellular apoptosis, especially the malignant neoplasm cells. We also unraveled the potential role of miR-181a in the diagnosis, treatment and clinical prognosis of multiple human malignancies - miR-181a plays a pivotal role in the development, treatment and prognosis of patients suffering from malignant tumors. It also participates in the development of cancer partially by modulating cellular apoptosis. [ABSTRACT FROM AUTHOR]

Objectives Lung cancer is one of the most common malignant tumors worldwide, and its morbidity and mortality rates continue to rise. The role of lncRNAs in lung cancer has become an emerging area of research. Materials and methods The expression of CAV-1 and HOTAIR was determined in lung cancer tissues and cell lines by western blot and RT-qPCR. Cell proliferation, migration and invasion were analysed in lung cell following knockdown or overexpression of CAV-1 or HOTAIR by transfection with small interfering RNA (siRNA) or plasmid. Results The expression of CAV-1 and HOTAIR in lung cancer tissues and cell lines was higher than in normal lung tissue or normal lung cell lines. We discovered that CAV-1 could regulate cell proliferation, migration and invasion. At the same time, CAV-1 could regulate the expression of HOTAIR. In addition, knockdown of the expression of HOAIR partially reverses the promotion of cell viability and invasion induced by CAV-1. Conclusions Our results indicated that CAV-1 coordinate the lung cancer through HOTAIR. And HOTAIR may become a novel target for lung cancer therapy. [ABSTRACT FROM AUTHOR]

Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated relationships between neuroblastomas (NBs) imaging phenotypes, tumor genomic profile and patient outcome. Patients and methods: This IRB-approved retrospective observational study included 133 NB patients (73 M, 60 F; median age 15 months, range 0–151) treated in a single institution between 1998 and 2012. A consensus review of imaging (CT-scan, MRI) categorized tumors according to both the primarily involved compartment (i.e., neck, chest, abdomen or pelvis) and the sympathetic anatomical structure the tumors rose from (i.e., cervical, paravertebral or periarterial chains, or adrenal gland). Tumor shape, volume and image-defined surgical risk factors (IDRFs) at diagnosis were recorded. Genomic profiles were assessed using array-based comparative genomic hybridization and divided into three groups: “numerical-only chromosome alterations” (NCA), “segmental chromosome alterations” (SCA) and “MYCN amplification” (MNA). Statistical analyses included Kruskal–Wallis, Chi2 and Fisher’s exact tests and the Kaplan-Meier method with log-rank tests and Cox model for univariate and multivariate survival analyses. Results: A significant association between the sympathetic structure origin of tumors and genomic profiles was demonstrated. NBs arising from cervical sympathetic chains were all NCA. Paravertebral NBs were NCA or SCA in 75% and 25%, respectively and none were MNA. Periarterial NBs were NCA, SCA or MNA in 33%, 56% and 11%, respectively. Adrenal NBs were NCA, SCA or MNA in 16%, 36% and 48%, respectively. Among MNA NBs, 92% originated from the adrenal gland. The sympathetic anatomical classification was significantly better correlated to overall survival than the compartmental classification (P < .0003). The tumor volume of MNA NBs was significantly higher than NCA or SCA NBs (P < .0001). Patients with initial volume less than 160 mL had significantly better overall survival (P < .009). A “single mass” pattern was significantly more frequent in NCA NBs (P = .0003). The number of IDRFs was significantly higher in MNA NBs (P < .0001). Conclusion: Imaging phenotypes of neuroblastomas, including tumor origin along the sympathetic system, correlate with tumor genomic profile and patient outcome. [ABSTRACT FROM AUTHOR]

Therapeutic options for the treatment of an increasing variety of cancers have been expanded by the introduction of a new class of drugs, commonly referred to as checkpoint blocking agents, that target the host immune system to positively modulate anti-tumor immune response. Although efficacy of these agents has been linked to a pre-existing level of tumor immune infiltrate, it remains unclear why some patients exhibit deep and durable responses to these agents while others do not benefit. To examine the influence of tumor genetics on tumor immune state, we interrogated the relationship between somatic mutation and copy number alteration with infiltration levels of 7 immune cell types across 40 tumor cohorts in The Cancer Genome Atlas. Levels of cytotoxic T, regulatory T, total T, natural killer, and B cells, as well as monocytes and M2 macrophages, were estimated using a novel set of transcriptional signatures that were designed to resist interference from the cellular heterogeneity of tumors. Tumor mutational load and estimates of tumor purity were included in our association models to adjust for biases in multi-modal genomic data. Copy number alterations, mutations summarized at the gene level, and position-specific mutations were evaluated for association with tumor immune infiltration. We observed a strong relationship between copy number loss of a large region of chromosome 9p and decreased lymphocyte estimates in melanoma, pancreatic, and head/neck cancers. Mutations in the oncogenes PIK3CA, FGFR3, and RAS/RAF family members, as well as the tumor suppressor TP53, were linked to changes in immune infiltration, usually in restricted tumor types. Associations of specific WNT/beta-catenin pathway genetic changes with immune state were limited, but we noted a link between 9p loss and the expression of the WNT receptor FZD3, suggesting that there are interactions between 9p alteration and WNT pathways. Finally, two different cell death regulators, CASP8 and DIDO1, were often mutated in head/neck tumors that had higher lymphocyte infiltrates. In summary, our study supports the relevance of tumor genetics to questions of efficacy and resistance in checkpoint blockade therapies. It also highlights the need to assess genome-wide influences during exploration of any specific tumor pathway hypothesized to be relevant to therapeutic response. Some of the observed genetic links to immune state, like 9p loss, may influence response to cancer immune therapies. Others, like mutations in cell death pathways, may help guide combination therapeutic approaches. [ABSTRACT FROM AUTHOR]

The article discusses the efficacy of AZD4785 as treatment for KRAS-driven human cancers and tumors. It mentions that AZD4785 is a constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting KRAS mRNA. It notes that AZD4785 is an attractive treatment for KRAS mutant non-small cell lung cancer patients.

Ovarian cancer (OC) is one of the three types of malignant tumors in the female reproductive system, and epithelial ovarian cancer (EOC) is its most typical form. Due to the asymptomatic nature of the early stages and resistance to chemotherapy, EOC has both a poor prognosis and a high fatality rate. Current treatments for OC are very limited, and the 5-years survival rate is approximately 30%. Exosomes, which are microvesicles ranging from approximately 30-100 nm in size that are secreted by living cells, can be produced from different cell types and detected in various body fluids. Cancer cells can secrete more exosomes than healthy cells, and more importantly, the content of cancer cell-derived exosomes is distinct. The exosomes shedding from tumor cells are considered to be involved in tumor progression and metastasis. As such, exosomes are expected to be potential tools for tumor diagnosis and treatment. In this review, we briefly present the emerging roles of exosomes in OC and summarize related articles about their roles as diagnostic or prognostic biomarkers and in the treatment and drug resistance of OC. [ABSTRACT FROM AUTHOR]

Background: Single gene tests to predict whether cancers respond to specific targeted therapies are performed increasingly often. Advances in sequencing technology, collectively referred to as next generation sequencing (NGS), mean the entire cancer genome or parts of it can now be sequenced at speed with increased depth and sensitivity. However, translation of NGS into routine cancer care has been slow. Healthcare stakeholders are unclear about the clinical utility of NGS and are concerned it could be an expensive addition to cancer diagnostics, rather than an affordable alternative to single gene testing.Methods and Findings: We validated a 46-gene hotspot cancer panel assay allowing multiple gene testing from small diagnostic biopsies. From 1 January 2013 to 31 December 2013, solid tumour samples (including non-small-cell lung carcinoma [NSCLC], colorectal carcinoma, and melanoma) were sequenced in the context of the UK National Health Service from 351 consecutively submitted prospective cases for which treating clinicians thought the patient had potential to benefit from more extensive genetic analysis. Following histological assessment, tumour-rich regions of formalin-fixed paraffin-embedded (FFPE) sections underwent macrodissection, DNA extraction, NGS, and analysis using a pipeline centred on Torrent Suite software. With a median turnaround time of seven working days, an integrated clinical report was produced indicating the variants detected, including those with potential diagnostic, prognostic, therapeutic, or clinical trial entry implications. Accompanying phenotypic data were collected, and a detailed cost analysis of the panel compared with single gene testing was undertaken to assess affordability for routine patient care. Panel sequencing was successful for 97% (342/351) of tumour samples in the prospective cohort and showed 100% concordance with known mutations (detected using cobas assays). At least one mutation was identified in 87% (296/342) of tumours. A locally actionable mutation (i.e., available targeted treatment or clinical trial) was identified in 122/351 patients (35%). Forty patients received targeted treatment, in 22/40 (55%) cases solely due to use of the panel. Examination of published data on the potential efficacy of targeted therapies showed theoretically actionable mutations (i.e., mutations for which targeted treatment was potentially appropriate) in 66% (71/107) and 39% (41/105) of melanoma and NSCLC patients, respectively. At a cost of £339 (US$449) per patient, the panel was less expensive locally than performing more than two or three single gene tests. Study limitations include the use of FFPE samples, which do not always provide high-quality DNA, and the use of "real world" data: submission of cases for sequencing did not always follow clinical guidelines, meaning that when mutations were detected, patients were not always eligible for targeted treatments on clinical grounds.Conclusions: This study demonstrates that more extensive tumour sequencing can identify mutations that could improve clinical decision-making in routine cancer care, potentially improving patient outcomes, at an affordable level for healthcare providers. [ABSTRACT FROM AUTHOR]

The unfolded protein response (UPR) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. PERK, a UPR protein kinase, regulates protein synthesis and while linked with cell survival, exhibits activities associated with both tumor progression and tumor suppression. For example, while cells lacking PERK are sensitive to UPR-dependent cell death, acute activation of PERK triggers both apoptosis and cell cycle arrest, which would be expected to contribute tumor suppressive activity. We have evaluated these activities in the BRAF-dependent melanoma and provide evidence revealing a complex role for PERK in melanoma where a 50% reduction is permissive for BrafV600E-dependent transformation, while complete inhibition is tumor suppressive. Consistently, PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function and pro-tumorigenic. Strikingly, we demonstrate that small molecule PERK inhibitors exhibit single agent efficacy against BrafV600E-dependent tumors highlighting the clinical value of targeting PERK. [ABSTRACT FROM AUTHOR]

Identifying appropriate preclinical cancer models remains a major challenge in increasing the efficiency of drug development. A potential strategy to improve patient outcomes could be selecting the 'right' treatment in preclinical studies performed in patient-derived xenografts (PDXs) obtained by direct implants of surgically resected tumours in mice. These models maintain morphological similarities and recapitulate molecular profiling of the original tumours, thus representing a useful tool in evaluating anticancer drug response. In this review, we will present the state-of-art use of PDXs as a reliable strategy to predict clinical findings. The main advantages and limitations will also be discussed. [ABSTRACT FROM AUTHOR]

In cancer drug discovery, it is important to investigate the genetic determinants of response or resistance to cancer therapy as well as factors that contribute to adverse events in the course of clinical trials. Despite the emergence of new technologies and the ability to measure more diverse analytes (e.g., circulating tumor cell (CTC), circulating tumor DNA (ctDNA), etc.), tumor tissue is still the most common and reliable source for biomarker investigation. Because of its worldwide use and ability to preserve samples for many decades at ambient temperature, formalin-fixed, paraffin-embedded tumor tissue (FFPE) is likely to be the preferred choice for tissue preservation in clinical practice for the foreseeable future. Multiple analyses are routinely performed on the same FFPE samples (such as Immunohistochemistry (IHC), in situ hybridization, RNAseq, DNAseq, TILseq, Methyl-Seq, etc.). Thus, specimen prioritization and optimization of the isolation of analytes is critical to ensure successful completion of each assay. FFPE is notorious for producing suboptimal DNA quality and low DNA yield. However, commercial vendors tend to request higher DNA sample mass than what is actually required for downstream assays, which restricts the breadth of biomarker work that can be performed. We evaluated multiple genomics service laboratories to assess the current state of NGS pre-analytical processing of FFPE. Significant differences in pre-analytical capabilities were observed. Key aspects are highlighted and recommendations are made to improve the current practice in translational research. [ABSTRACT FROM AUTHOR]

Background. Mutations in the BRCA1 and BRCA2 genes are associated with increased risk of breast, ovarian, and several other cancers. The purpose of the present study was to evaluate the incidence of cancer in first- and second-degree relatives of BRCA mutation carriers compared with the general population. Materials and Methods. A total of 1,086 pedigrees of BRCA mutation carriers was obtained from a prospectively maintained, internal review board-approved study of persons referred for clinical genetic counseling at the University of Texas MD Anderson Cancer Center. We identified 9,032 first-and second-degree relatives from 784 pedigrees that had demonstrated a clear indication of parental origin of mutation. Standardized incidence ratios (SIRs) were used to compare the observed incidence of 20 primary cancer sites to the expected incidence of each cancer based on the calculated risk estimates according to each subject's age, sex, and ethnicity. Results. BRCA1 families had increased SIRs for breast and ovarian cancer (p < .001) and decreased SIRs for kidney, lung, prostate, and thyroid cancer and non-Hodgkin's lymphoma (p < .001). BRCA2 families had increased SIRs for breast, ovarian, and pancreatic cancer (p <.001) and decreased SIRs for kidney, lung, thyroid, and uterine cancer and non-Hodgkin's lymphoma (p < .0025). Analysis of only first-degree relatives (n = 4,099) identified no decreased SIRs and agreed with the increased SIRs observed in the overall study population. Conclusion. We have confirmed previous reports of an association between breast, ovarian, and pancreatic cancers with BRCA mutations. Additional research to quantify the relative risks of these cancers for BRCA mutation carriers can help tailor recommendations for risk reduction and enhance genetic counseling. [ABSTRACT FROM AUTHOR]

The JAK2 V617F mutation can be detected with a high frequency in patients with myeloproliferative neoplasms (MPN). MPN treatment efficiency can be assessed by JAK2 V617F quantification. Real-time quantitative PCR (qPCR) is widely used for JAK2 V617F quantification. Emerging alternative technologies like digital droplet PCR (ddPCR) have been described to overcome inherent qPCR limitations. The purpose of this study was to evaluate the utility of ddPCR for JAK2 V617F quantification in patient samples with MPN. Sensitivity and specificity were established by using DNA artificial mixtures. In addition, 101 samples from 59 patients were evaluated for JAK2 V617F mutation. Limit of detection was 0.01 % for both qPCR and ddPCR. The JAK2 V617F mutation was detected in 43 out of 59 patients by both PCR platforms. However, in 14 % of the samples, JAK2 V617F mutation was detected only with ddPCR. This 14 % of discrepant samples were from patients shortly after allogeneic stem cell transplantation. Percentage of JAK2 V617F mutation measured by qPCR and ddPCR in clinical samples showed a high degree of correlation (Spearman r: 0.9637 p < 0.001) and an excellent agreement assessed by Bland-Altman analysis. In conclusion, ddPCR is a suitable, precise, and sensitive method for quantification of the JAK 2 V617F mutation. [ABSTRACT FROM AUTHOR]

Background: Few exceptional responses in cancer treatment were attributed to a genetic predisposition of the tumor. Methods: We analyzed a cohort of 3105 patients from 12 different cancer types and systematically sought the existence of a correlation between overall survival and the interaction of 21 antineoplastic treatments with 6 tumor mutations. Results: We identified a single significant correlation resulting in increased overall survival from temozolomide in lower-grade glioma with IDH1 R132H mutations. The trend could not be attributed to either the treatment or the mutation alone. Univariate and multivariate Cox regression demonstrated that this interaction stood as an independent prognostic predictor of survival. Conclusion: Our results suggest infrequent instances of exceptional responses ascribable to tumor genomics yet corroborate the existence of an interaction of temozolomide with IDH1 mutations in lower-grade glioma. [ABSTRACT FROM AUTHOR]

The use of patient-specific data in drug and dose selection is becoming an increasingly important component in cancer therapy. Basing drug choice on molecular aspects of the tumor is consistent with the identification of cancer as a molecular disease or diseases, even within the same histological type, and its treatment specific to the background from which it arose and exists. Multiple examples exist of single-gene mutations, and over- or underexpression that convey either sensitivity or resistance to a given agent. What about the picture that global gene expression in a cancer presents regarding drug sensitivity or resistance? Coexpression extrapolation (COXEN) is a methodology that acts as a Rosetta stone between patterns of gene expression that correlate to drug responses in vitro and those in tumors of untreated patients to predict chemosensitivity in such tumors even to drugs that are not specifically indicated for that histotype. Further applications of COXEN in drug discovery allow for in silico screens correlating drug response and gene expression in a genetically diverse cell panel to gene expression patterns in a target tumor with the potential for identifying and repurposing compounds. Here we discuss how COXEN is being developed and tested for application in drug selection, repositioning, and repurposing in oncology. [ABSTRACT FROM AUTHOR]

Intratumoral heterogeneity is a recently recognized but important feature of cancer that underlies the various biocharacteristics of cancer tissues. The advent of next-generation sequencing technologies has facilitated large scale capture of genomic data, while the recent development of single-cell sequencing has allowed for more in-depth studies into the complex molecular mechanisms of intratumoral heterogeneity. In this review, the recent advances and current challenges in single-cell sequencing methodologies are discussed, highlighting the potential power of these data to provide insights into oncological processes, from tumorigenesis through progression to metastasis and therapy resistance. [ABSTRACT FROM AUTHOR]

Advances in engineered recombinant nuclease have provided facile and reliable methods for genome editing. Especially with the development of the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein-9 nuclease) system, the discovery of various versions of Cas9 proteins and delivery carriers, it is now practicable to introduce desired mutations into the genome, to correct disease-related mutations, and to activate or suppress genes of interest. Epigenetic regulators are often disturbed in cancer cells and are essential for the transformation of normal to cancerous cells. Tumor-related epigenetic alterations or epigenetic factor mutations play a major part during the various steps of carcinogenesis and affect a variety of cancer-related genes and a wide range of cancerous phenotypes. Therefore, epigenetic regulatory enzymes might be candidate targets for cancer therapy. In this review, we discuss prospects of CRISPR/Cas9-based genome editing in targeting epigenetics for cancer gene therapy. [ABSTRACT FROM AUTHOR]

In the last decade, proteomic analysis has become an integral tool for investigation of tumor biology, complementing the genetic analysis. The idea of proteomics is to characterize proteins by evaluation of their expressions, functions, and interactions. Proteomics may also provide information about post-translational modifications of proteins and evaluate their value as specific disease biomarkers. The major purpose of clinical proteomics studies is to improve diagnostic procedures including the precise evaluation of biological features of tumor cells and to understand the molecular pathogenesis of cancers to invent novel therapeutic strategies and targets. This review briefly describes the latest reports in proteomic studies of NSCLC. It contains a summary of the methods used to detect proteomic markers in different types of biological material and their clinical application as diagnostic, prognostic, and predictive biomarkers compiled on the basis of the most recent literature and our own experience. [ABSTRACT FROM AUTHOR]

The article discusses how the liquid biopsy medical innovation could potentially be used to examine the genetic aspects of tumor cells from blood samples, and it mentions the detection of cancer biomarkers in blood and the treatment of solid tumors. Circulating cell-free tumor DNA (ctDNA) and circulating tumor cells (CTCs) are addressed, along with the prognosis and treatment response in metastatic cancers. The noninvasive nature of a liquid biopsy procedure is assessed.

The development of high-throughput sequencing technologies has advanced our understanding of cancer. However, characterizing somatic structural variants in tumor genomes is still challenging because current strategies depend on the initial alignment of reads to a reference genome. Here, we describe SMUFIN (somatic mutation finder), a single program that directly compares sequence reads from normal and tumor genomes to accurately identify and characterize a range of somatic sequence variation, from single-nucleotide variants (SNV) to large structural variants at base pair resolution. Performance tests on modeled tumor genomes showed average sensitivity of 92% and 74% for SNVs and structural variants, with specificities of 95% and 91%, respectively. Analyses of aggressive forms of solid and hematological tumors revealed that SMUFIN identifies breakpoints associated with chromothripsis and chromoplexy with high specificity. SMUFIN provides an integrated solution for the accurate, fast and comprehensive characterization of somatic sequence variation in cancer. [ABSTRACT FROM AUTHOR]

Previous work has shown that prostate cancer in a Pten-null murine model is dependent on the p110β isoform of phosphatidylinositol 3-kinase (PI3K), while breast cancer driven by either polyoma middle T antigen (MT) or HER2 is p110α dependent. Whether these differences in isoform dependence arise from tissue specificity or from the nature of the oncogenic signal activating the PI3K pathway is important, given increasing interest in using isoform-specific PI3K inhibitors in cancer therapy. To approach this question, we studied the PI3K isoform dependence of our recently constructed prostate cancer model driven by MT. Since MT activates a number of signaling pathways, we first confirmed that the MT-driven prostate cancer model was actually dependent on PI3K. A newly generated transgenic prostate line expressing an MT allele (Y315F) known to be defective for PI3K binding displayed a markedly reduced ability to drive tumor formation. We next selectively ablated expression of either p110α or p110β in mice in which wild-type MT was expressed in the prostate. We found that tumor formation driven by MT was significantly delayed by the loss of p110α expression, while ablation of p110β had no effect. Since the tumor formation driven by MT is p110α dependent in the prostate as well as in the mammary gland, our data suggest that PI3K isoform dependence is driven by the mode of PI3K pathway activation rather than by tissue type. [ABSTRACT FROM AUTHOR]

Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future. [ABSTRACT FROM AUTHOR]

Genetic variation influences the response of an individual to drug treatments. Understanding this variation has the potential to make therapy safer and more effective by determining selection and dosing of drugs for an individual patient. In the context of cancer, tumours may have specific disease-defining mutations, but a patient's germline genetic variation will also affect drug response (both efficacy and toxicity), and here we focus on how to study this variation. Advances in sequencing technologies, statistical genetics analysis methods and clinical trial designs have shown promise for the discovery of variants associated with drug response. We discuss the application of germline genetics analysis methods to cancer pharmacogenomics with a focus on the special considerations for study design. [ABSTRACT FROM AUTHOR]

The appearance, progression, and potential role for circadian rhythms during early development have previously focused mainly on the suprachiasmatic nucleus (SCN) and peri- and postnatal expression of canonical clock genes. More recently, gene expression studies in embryonic stem cells have shown that some clock genes are expressed in undifferentiated cells; however rhythmicity was only established when cells are directed toward a neural fate. These studies also concluded that a functional clock is not present in ESCs, based solely on their gene expression. The null hypothesis underlying the present study is that embryonic stem cells become rhythmic in both clock gene expression and glucose utilization only when allowed to spontaneously differentiate. Undifferentiated stem cells (ESCs, n = 6 cultures/timepoint for all experiments) were either maintained in their pluripotent state or released into differentiation (dESCs, n = 6 cultures/timepoint for all experiments). Glucose utilization was assayed through 2-deoxyglucose uptake measurement, and clock gene and glucose transporter expression was assayed every 4 hours for 2 days in ESCs and dESCs by quantitative PCR (qPCR) in the same cell lysates. Undifferentiated stem cells expressed a self-sustained rhythm in glucose uptake that was not coincident with rhythmic expression of clock genes. This physiological rhythm was paralleled by glucose transporter mRNA expression. Upon differentiation, circadian patterns of some but not all clock genes were expressed, and the amplitude of the glucose utilization rhythm was enhanced in dESCs. These data provide the earliest evidence of a functional circadian clock, in addition to further challenging the idea that rhythmic transcription of clock genes are necessary for rhythmic physiological output and suggest a role for a clock-controlled physiology in the earliest stages of development. [ABSTRACT FROM AUTHOR]

The article reports on research which was conducted to evaluate a multimedia informed consent tool which was developed for a biobank called the University of North Carolina Health Registry/Cancer Survivorship Cohort. Researchers found that most research participants who viewed the tool found it to be appealing and useful and felt that its benefits outweighed its risks.

The regulatory sequences upstream of E1a, the first viral protein expressed upon infection of cells with adenovirus, have binding sites for multiple transcription factors including two binding sites for E2f and five binding sites for Pea3. We evaluated the impact of deletions, which remove one or more of these transcription factor-binding sites on the expression of E1a in a panel of tumor cells and non-transformed cells. We demonstrated that specific deletions in the E1a enhancer markedly reduced the expression of E1a in growth-arrested cells while having a minimal impact on the expression of E1a in a panel of tumor cells. In particular, deletion of a 50-bp region located from −305 to −255 upstream of the E1a initiation site resulted in marked reduction of E1a and E1b expression and cytolytic activity in growth-arrested cells, while retaining near wild-type of expression of E1a and E1b and cytolytic activity in tumor cells. This deletion removed two Pea3 sites and one E2f site. The characteristics of this vector, TAV-255, was compared with dl1520 (Onyx-015) and demonstrated restricted cytolytic activity in growth-arrested cells similar to dl1520 and superior cytolytic activity in a panel of tumor cell lines. In this current study, we demonstrate that TAV-255, an E1a enhancer deletion vector, possesses tumor selective expression of both E1a and E1b along with potent tumor-selective oncolytic activity. [ABSTRACT FROM AUTHOR]