Health care access, psychosocial outcomes and mental health in adults living with epilepsy during the COVID-19 pandemic.

PURPOSE: People living with epilepsy (PLWE) have a higher prevalence of mental health comorbidities and poorer psychosocial outcomes compared to the general population. The aim of this study was to examine psychosocial outcomes, mental health, healthcare accessibility, and seizure burden in PLWE during the COVID-19 pandemic. METHODS: We conducted a cross-sectional study of adults with epilepsy treated in an urban multicenter health system from 2021 to 2022. A standardized questionnaire assessed for COVID-19 history, comorbidities, access to antiseizure medications (ASMs) and neurological care, seizure burden, and psychosocial outcomes (e.g., employment, social and financial support). The Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) were administered to evaluate for depression and anxiety. Frequency and proportions for categorical variables and median and interquartile ranges for continuous variables were calculated. RESULTS: Fifty-five PLWE participated (95 % response rate). Median age was 40 years (IQR 31.5-66.5), 61.8 % were women, 47.3 % had a bachelor's degree or higher and 29.1 % each had Medicaid and Medicare insurance. Race (from highest to lowest %) was: 32.7 % White, 20 % Black, 20 % Latinx, 14.5 % Asian, and 12.7 % selected "other" or "prefer not to say." COVID-19 had been diagnosed in 21.8 % of participants. Symptoms of anxiety and depression were self-reported by 43.6 % and 34.5 % of patients, respectively, with many describing this symptom as new post-pandemic (37.5 % and 31.6 %, respectively). Using validated scales, 52.7 % had depression (PHQ-9 score ≥ 5) with 30.9 % having moderate/severe depression (PHQ-9 score ≥ 10), while 29.1 % had probable generalized anxiety disorder (GAD-7 score ≥ 8). Seizure burden increased in 21.8 % of participants, while 20 % reported fewer seizures and 29.1 % were seizure free since the COVID-19 pandemic. Economic impacts of the pandemic included job loss (25 % amongst those employed at onset of pandemic), new or worsened financial difficulties (40 %), and new or worsened social support issues (30.9 %). Of all participants, 18.2 % reported difficulties accessing ASMs and 25.5 % cancelled visits, but of those with cancelled visits, 78.6 % had their appointments rescheduled as a telehealth visit. CONCLUSION: Our cohort of PLWE experienced some challenges during the COVID-19 pandemic including poorer mental health and financial and employment-related stressors. Encouragingly, healthcare access was relatively spared during the COVID-19 crisis, with some patients even reporting a reduction in seizure burden. However, PLWE require ongoing psychosocial support with particular attention to decompensation of mental health and social stressors that may be exacerbated by the COVID-19 pandemic.

MIG-6 negatively regulates STAT3 phosphorylation in uterine epithelial cells.

Endometrial cancer is the most common malignancy of the female genital tract. Progesterone (P4) has been used for several decades in endometrial cancer treatment, especially in women who wish to retain fertility. However, it is unpredictable which patients will respond to P4 treatment and which may have a P4-resistant cancer. Therefore, identifying the mechanism of P4 resistance is essential to improve the therapies for endometrial cancer. Mitogen-inducible gene 6 (Mig-6) is a critical mediator of progesterone receptor (PGR) action in the uterus. In order to study the function of Mig-6 in P4 resistance, we generated a mouse model in which we specifically ablated Mig-6 in uterine epithelial cells using Sprr2f-cre mice (Sprr2fcre+Mig-6f/f). Female mutant mice develop endometrial hyperplasia due to aberrant phosphorylation of signal transducers and activators of transcription 3 (STAT3) and proliferation of the endometrial epithelial cells. The results from our immunoprecipitation and cell culture experiments showed that MIG-6 inhibited phosphorylation of STAT3 via protein interactions. Our previous study showed P4 resistance in mice with Mig-6 ablation in Pgr-positive cells (Pgrcre/+Mig-6f/f). However, Sprr2fcre+Mig-6f/f mice were P4-responsive. P4 treatment significantly decreased STAT3 phosphorylation and epithelial proliferation in the uterus of mutant mice. We showed that Mig-6 has an important function of tumor suppressor via inhibition of STAT3 phosphorylation in uterine epithelial cells, and the antitumor effects of P4 are mediated by the endometrial stroma. These data help to develop a new signaling pathway in the regulation of steroid hormones in the uterus, and to overcome P4 resistance in human reproductive diseases, such as endometrial cancer.

Dual-gate operation and carrier transport in SiGe p-n junction nanowires.

We investigate carrier transport in silicon-germanium nanowires with an axial p-n junction doping profile by fabricating these wires into transistors that feature separate top gates over each doping segment. By independently biasing each gate, carrier concentrations in the n- and p-side of the wire can be modulated. For these devices, which were fabricated with nickel source-drain electrical contacts, holes are the dominant charge carrier, with more favorable hole injection occurring on the p-side contact. Channel current exhibits greater sensitivity to the n-side gate, and in the reverse biased source-drain configuration, current is limited by the nickel/n-side Schottky contact.

Comparison of the paediatric blade of the Pentax-AWS and Ovassapian airway in fibreoptic tracheal intubation in patients with limited mouth opening and cervical spine immobilization by a semi-rigid neck collar: a randomized controlled trial.

BACKGROUND: We compared the performances of the paediatric blade of a Pentax Airway Scope and an Ovassapian airway in fibreoptic tracheal intubation in patients whose necks were stabilized by semi-rigid neck collars. METHODS: Ninety patients were enrolled in this prospective, open-label, randomized controlled trial. Patients were randomly allocated to one of two groups (Group OVA-FOB and Group AWS-FOB). The time to tracheal intubation, success rate of tracheal intubation, number of optimization manoeuvres (jaw thrust), and difficulty of manipulation of the fibreoptic bronchoscope were compared between the groups. RESULTS: The time to tracheal intubation was significantly shorter (32 vs 50 s; median difference 19 s; 95% confidence interval 14-25 s; P<0.001) and manipulation of the fibreoptic bronchoscope was significantly easier for Group AWS-FOB. Optimization manoeuvres were rarely required to facilitate fibreoptic tracheal intubation in Group AWS-FOB [jaw thrust, 0 (0%); jaw thrust with anterior neck collar removal, 1 (2%)] compared with that required in Group OVA-FOB [jaw thrust, 39 (87%); jaw thrust with anterior neck collar removal, 2 (4%)]. There was no significant difference in the success rate of tracheal intubation on the first attempt between groups [Group AWS-FOB, 45 (100%); Group OVA-FOB, 44 (98%)]. CONCLUSIONS: Combined use of the paediatric blade of a Pentax Airway Scope and a fibreoptic bronchoscope enabled rapid tracheal intubation, minimizing the use of external manoeuvres of the airway, in patients with limited mouth opening and cervical spine immobilization by semi-rigid neck collars, compared with use of the Ovassapian airway and the fibreoptic bronchoscope. CLINICAL TRIAL REGISTRATION: NCT02827110.

PRMT5-PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurosphere cells.

Glioblastoma (GBM) represents the most common and aggressive histologic subtype among malignant astrocytoma and is associated with poor outcomes because of heterogeneous tumour cell population including mature non-stem-like cell and immature stem-like cells within the tumour. Thus, it is critical to find new target-specific therapeutic modalities. Protein arginine methyltransferase enzyme 5 (PRMT5) regulates many cellular processes through its methylation activity and its overexpression in GBM is associated with more aggressive disease. Previously, we have shown that silencing of PRMT5 expression in differentiated GBM cell lines results in apoptosis and reduced tumour growth in mice. Here, we report the critical role of PRMT5 in GBM differentiated cells (GBMDC) grown in serum and GBM neurospheres (GBMNS) grown as neurospheres in vitro. Our results uncover a very significant role for PRMT5 in GBMNS self-renewal capacity and proliferation. PRMT5 knockdown in GBMDC led to apoptosis, knockdown in GBMNS led to G1 cell cycle arrest through upregulation of p27 and hypophoshorylation of retinoblastoma protein, leading to senescence. Comparison of impact of PRMT5 on cellular signalling by the Human Phospho-Kinase Array and chromatin immunoprecipitation-PCR revealed that unlike GBMDC, PRMT5 regulates PTEN expression and controls Akt and ERk activity in GBMNS. In vivo transient depletion of PRMT5 decreased intracranial tumour size and growth rate in mice implanted with both primary tumour-derived GBMNS and GBMDC. This is the first study to identify PTEN as a potential downstream target of PRMT5 and PRMT5 is vital to support both mature and immature GBM tumour cell populations.

Surface modulation and back reflection from foil targets irradiated by a Petawatt femtosecond laser pulse at oblique incidence.

A significant level of back reflected laser energy was measured during the interaction of ultra-short, high contrast PW laser pulses with solid targets at 30° incidence. 2D PIC simulations carried out for the experimental conditions show that at the laser-target interface a dynamic regular structure is generated during the interaction, which acts as a grating (quasi-grating) and reflects back a significant amount of incident laser energy. With increasing laser intensity above 1018 W/cm2 the back reflected fraction increases due to the growth of the surface modulation to larger amplitudes. Above 1020 W/cm2 this increase results in the partial destruction of the quasi-grating structure and, hence, in the saturation of the back reflection efficiency. The PIC simulation results are in good agreement with the experimental findings, and, additionally, demonstrate that in presence of a small amount of pre-plasma this regular structure will be smeared out and the back reflection reduced.

Factors affecting the trajectory of health-related quality of life in COPD patients.

BACKGROUND: Health-related quality of life (HR-QoL) is an important issue in patients with chronic obstructive pulmonary disease (COPD), as in other chronic illness groups. However, there is limited information on longitudinal changes in HR-QoL over time with the illness trajectory model. OBJECTIVE: To identify different patterns of HR-QoL changes in longitudinal data, and reveal potential predictors affecting these trajectories. METHODS: Subjects with COPD (n = 249) were drawn from the Korean Obstructive Lung Disease cohort, which was conducted from 2005 to 2012. Longitudinal data were drawn from the St George's Respiratory Questionnaire and clinical measures. Growth mixture modelling was used to estimate distinct patterns, and binary and ordinal logistic regression were used to determine factors affecting different trajectory HR-QoL patterns using STATA 12.0. RESULTS: Five distinct HR-QoL patterns were identified. Results show that the level of baseline HR-QoL was significantly associated with age, the BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index at baseline, sleep disturbance, experience of exacerbation in previous year and level of depression. Distinct patterns in HR-QoL that improved vs. worsened were significantly associated with BODE index, number of respiratory symptoms and depression level. CONCLUSIONS: These findings suggest that comprehensive assessment and individualised management programmes are needed to improve HR-QoL in COPD patients.

cAMP-Response Element-Binding 3-Like Protein 1 (CREB3L1) is Required for Decidualization and its Expression is Decreased in Women with Endometriosis.

Endometriosis is a major cause of infertility and pelvic pain, affecting more than 10% of reproductive-aged women. Progesterone resistance has been observed in the endometrium of women with this disease, as evidenced by alterations in progesterone-responsive gene and protein expression. cAMPResponse Element-Binding 3-like protein 1 (Creb3l1) has previously been identified as a progesterone receptor (PR) target gene in mouse uterus via high density DNA microarray analysis. However, CREB3L1 function has not been studied in the context of endometriosis and uterine biology. In this study, we validated progesterone (P4) regulation of Creb3l1 in the uteri of wild-type and progesterone receptor knockout (PRKO) mice. Furthermore, we observed that CREB3L1 expression was significantly higher in secretory phase human endometrium compared to proliferative phase and that CREB3L1 expression was significantly decreased in the endometrium of women with endometriosis. Lastly, by transfecting CREB3L1 siRNA into cultured human endometrial stromal cells (hESCs) prior to hormonal induction of in vitro decidualization, we showed that CREB3L1 is required for the decidualization process. Interestingly, phosphorylation of ERK1/2, critical factor for decidualization, was also significantly reduced in CREB3L1-silenced hESCs. It is known that hESCs from patients with endometriosis show impaired decidualization and that dysregulation of the P4-PR signaling axis is linked to a variety of endometrial diseases including infertility and endometriosis. Therefore, these results suggest that CREB3L1 is required for decidualization in mice and humans and may be linked to the pathogenesis of endometriosis in a P4-dependent manner.

The median effective dose of dexmedetomidine for laryngeal mask airway insertion with propofol 2.0 mg/kg.

BACKGROUND: Dexmedetomidine can be used as a co-induction agent to facilitate laryngeal mask airway (LMA) insertion with minimal effect on respiratory function. The purpose of the study was to determine the median effective dose (ED50) of dexmedetomidine to facilitate LMA insertion during anaesthesia induction with propofol 2.0 mg/kg without neuromuscular blockade. METHODS: Twenty-two patients, whose American Society of Anesthesiologists physical status was I or II with ages between 18 and 60 years undergoing minor orthopaedic or gynaecological surgery, were enrolled. After an injection of pre-determined bolus dose of dexmedetomidine over 2 min, anaesthesia was induced with propofol 2.0 mg/kg. The modified Dixon's up-and-down method was used to determine the bolus dose of dexmedetomidine, starting from 0.5 µg/kg (step size; 0.1 µg/kg). LMA insertion was conducted 90 s after the propofol injection, and the response of patients was categorized as either 'success' or 'failure.' RESULTS: Insertion of the LMA was unsuccessful in 12 of 22 patients. The ED50 (95% confidence interval) of dexmedetomidine for successful LMA insertion with propofol 2.0 mg/kg was 0.55 (0.44-0.66) µg/kg. Bradycardia occurred in four patients, and seven patients had an apneic episode. CONCLUSION: The single dose of dexmedetomidine for successful LMA insertion to be feasible in 50% of patients was 0.55 µg/kg during anaesthesia induction with propofol 2 mg/kg.

Uterine angiomyolipoma with metastasis in a woman with tuberous sclerosis: a case report.

Extrarenal angiomyolipomas (AMLs) have been reported at various anatomical sites such as the liver, spleen, abdominal wall, retroperitoneum, oral cavity, penis, spermatic cord, skin, and lung but are infrequently described in gynecological regions. However, only a few cases of extrarenal AML in the uterus have been reported. The authors describe a case of uterine AML in a 41-year-old woman with evidence of tuberous sclerosis. Initial diagnosis concluded with myoma based on the interpretation of imaging and other pathological parameters. However, after successful laparoscopic surgical staging, AML was diagnosed. To date, the feasibility of laparoscopic surgical diagnosis and the risks associated with this technique have not been reported. The authors briefly review the implementation of laparoscopic surgical staging to diagnose uterine AML.

Quantum Faraday and Kerr rotations in graphene.

Graphene, a monolayer sheet of carbon atoms, exhibits intriguing electronic properties that arise from its massless Dirac dispersion of electrons. A striking example is the half-integer quantum Hall effect, which endorses the presence of Dirac cones or, equivalently, a non-zero (π) Berry's (topological) phase. It is curious how these anomalous features of Dirac electrons would affect optical properties. Here we observe the quantum magneto-optical Faraday and Kerr effects in graphene in the terahertz frequency range. Our results detect the quantum plateaus in the Faraday and Kerr rotations at precisely the quantum Hall steps that hallmark the Dirac electrons, with the rotation angle defined by the fine-structure constant. The robust quantum Hall plateaus in the optical regime, besides being conceptually interesting, may open avenues for new graphene-based optoelectronic applications.

Transverse stability of the proximal segment after bilateral sagittal split ramus osteotomy for mandibular setback surgery.

This study aimed to evaluate the correlation between the transverse displacement of the proximal segment after bilateral sagittal osteotomy for mandibular setback and the amount and design of the mandibular setback. Patients who underwent either bilateral sagittal split ramus osteotomy (BSSRO) alone or two-jaw surgery were selected, and cephalographic postero-anterior (PA) measurements were taken pre-operatively (T1), immediately post-operatively (T2), and at follow-up (T3). The inter-gonal (IG) and inter-ramal (IR) width increased immediately after surgery, but decreased to the initial value during follow-up (P=0.002; IR, P=0.046). Only the immediate IG changes after surgery correlated with the amount of mandibular setback (P=0.009). The IG changes were significant in the symmetric group, but not in the asymmetric group. There was no difference in the IG and IR changes between the symmetric group and the asymmetric group. The immediate IG change in two-jaw patients with symmetric setback showed correlation with the setback amount. The gonial width of the deviated group showed more significant changes than that of the non-deviated group. There was no difference in the unilateral gonial width between the deviated and the non-deviated group, but the difference was significant for the unilateral ramal angle between the two groups. These correlations will be helpful in predicting post-surgical results for patients.

Response of dietary substitution of fishmeal with various protein sources on growth, body composition and blood chemistry of olive flounder (Paralichthys olivaceus, Temminck & Schlegel, 1846).

Animal and/or plant protein sources substituting fishmeal in the diets keep being developed due to its high price. The purpose of this study is to determine response of dietary substitution of fishmeal with silkworm pupae meal, promate meal®, meat and bone meal and/or their combination on the performance of juvenile olive flounder. A 60% fish meal was used as the main protein source, used as the control (Con) diet. The 10 and 20% fishmeal were substituted with silkworm pupae meal and meat and bone meal, referred to as the SPM10, SPM20, MBM10 and MBM20 diets, respectively. And the 10, 20 and 40% fishmeal were substituted with promate meal®, referred to as the PM10, PM20 and PM40 diets, respectively. Finally, the 10 and 20% fishmeal were substituted with combined silkworm pupae meal and promate meal®, refereed to as the SPM + PM10 and SPM + PM20 diets, respectively. Weight gain and specific growth rate of fish fed the MBM10 diet were higher than those of fish fed the Con, SPM20, PM20, PM40 and SPM + PM20 diets. Feed efficiency ratio of fish fed the SPM10, MBM10, MBM20, PM10 and SPM + PM10 diets was higher than that of fish fed the SPM + PM20 and PM40 diets. Protein efficiency ratio of fish fed the MBM10 and MBM20 diets was higher than that of fish fed the SPM20, PM20, PM40 and SPM + PM20 diets. In conclusion, dietary substitution of fishmeal with 10% SPM, 20% MBM, 10% PM and 10% SPM + PM could be made.

The incidence of postoperative nausea and vomiting after thyroidectomy using three anaesthetic techniques.

The choice of anaesthetics can affect the incidence of postoperative nausea and vomiting (PONV). This study compared the incidence of PONV in 177 female patients who underwent thyroidectomy, with anaesthesia induced and maintained using one of three regimens: (i) sevoflurane (thiopental sodium 4 - 5 mg/kg and sevoflurane 2.0 - 2.5 vol% in 50% air); (ii) total intravenous anaesthesia (TIVA; propofol-remifentanil [target blood concentrations 2.5 - 3.5 µg/ml and 3.5 - 4.5 ng/ml, respectively]); or (iii) combined inhalation and intravenous anaesthesia (sevoflurane 1.0 vol% in 50% air plus propofol-remifentanil [target blood concentrations 1.5 - 2.5 µg/ml and 2.5 - 3.5 ng/ml, respectively]). The incidence and severity of PONV and the need for rescue antiemetics were assessed at 0 - 24 h postoperatively. Overall, the incidence of PONV was significantly lower in the TIVA and combined groups compared with the sevoflurane group (33.9%, 39.0% and 64.4%, respectively). In conclusion, the maintenance of anaesthesia with propofol-remifentanil or sevoflurane-propofol-remifentanil decreased the incidence of PONV compared with sevoflurane alone.

Inhibition of swine leukocyte antigen-I presentation in transgenic mini-pig cell lines by expressing human cytomegalovirus US6.

Xenotransplantation using porcine organs may resolve the chronic shortage of donor organs for clinical transplantation if significant immunologic barriers can be overcome. A xenograft can be rejected by T cells, especially CD8(+) cytotoxic T lymphocytes (CTL)-mediated responses, as these cells show cytotoxicity against xenografts by recognition of swine leukocyte antigen (SLA)-I. Peptide translocation is inhibited by the endoplasmic reticulum-resident human cytomegalovirus (HCMV) glycoprotein unique short (US) 6, due to alterations of the transporter associated with antigen processing loading onto MHC class I for antigen presentation to CD8(+) CTL. In this study we transfected the US6 gene into minipig fetal fibroblasts establishing three US6 clonal cell lines. Flow cytometry analysis of US6 clonal cell lines demonstrated a substantial reduction in SLA-I expression. The level of SLA-I expression in US6 clones was decreased to 56.3% compared with the control 42.7%. In CTL assays, the rate of CD8(+) CTL-mediated cytotoxicity was significantly reduced to 35.2% ± 11.7% compared with the control, 79.9% ± 6.5%, (P < .01). These results suggested that HCMV viral protein US6 suppresses the presentation of SLA-I on pig fetal fibroblast cells. This strategy might be used in transgenic pig production to protect porcine organs from CTL-mediated immune rejection.

Ischemic stroke in an adult with glycogen storage disease type I.

Glycogen Storage Disease Type I (GSD-I) is a metabolic disorder characterized by deficiency of glucose-6-phosphatase resulting in ineffective glycogen metabolism to glucose. These patients frequently have hyperlipidemia, among many other metabolic derangements. There is no consensus regarding the risk of developing atherosclerosis. We report an adult male with GSD-I who presented with cerebral infarction and a history of prior ischemic stroke and multiple coronary stent placements. We suggest that patients with GSD-I do have an increased risk of atherosclerosis and its complications and predict that these complications will be seen more frequently since patients with GSD-I are living longer as a result of better treatment.

Prognosis of extremity osteosarcoma in patients aged 40-60 years: a cohort/case controlled study at a single institute.

BACKGROUND: The outcome of older osteosarcoma patients with multi-disciplinary management has not been clearly defined. METHODS: We conducted a cohort (n=375) and a case-control (n=78) study on 26 older age patients (40-60 years) with localized osteosarcoma of extremity. In the case-control study, controls were matched for location and initial tumor volume. RESULTS: Compared to 349 younger patients, older age patients showed an osteolytic pattern on plain radiographs (P=0.05), fibroblastic subtype (P<0.01), and poor histologic response (P=0.03). Multivariate analysis revealed that a large absolute tumor volume (P<0.01), a tumor location in the proximal humerus (P=0.02), and a poor histologic response to preoperative chemotherapy (P<0.01) independently predicted poorer metastasis-free survival. However, an older age showed marginal significance (P=0.09). A case-control study showed a higher proportion of the fibroblastic subtype and poor histologic response in the case group. Five-year metastasis-free survival rates for the 26 cases and 52 controls were 40.1+/-10.1% and 61.5+/-6.8%, respectively (P=0.02). CONCLUSIONS: Older age osteosarcoma patients showed an unfavorable histologic response to chemotherapy and lower survival than younger patients. Nevertheless, a further larger-scale study is required to confirm our observations.

Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy.

The pressing challenge for contemporary gene therapy is to deliver enough therapeutic genes to enough cancer cells in vivo. With the aim of improving viral distribution and tumor penetration, we explored the use of decorin to enhance viral spreading and tumor tissue penetration. We generated decorin-expressing replication-incompetent (dl-LacZ-DCNG, dl-LacZ-DCNQ and dl-LacZ-DCNK) and replication-competent (Ad-DeltaE1B-DCNG, Ad-DeltaE1B-DCNQ and Ad-DeltaE1B-DCNK) adenoviruses (Ads). Point mutants of decorin gene (DCNG), DCNK and DCNQ, have a negative and moderate binding affinity to type-I collagen fibril, respectively. In both tumor spheroids and established solid tumors in vivo, tissue penetration potency of dl-LacZ-DCNG was greatly enhanced than those of dl-LacZ, dl-LacZ-DCNQ and dl-LacZ-DCNK, and this enhanced tissue penetration effect derived from decorin-expressing Ad was dependent on the binding affinity of decorin to collagen fibril. Expression of DCNG enhanced viral spread of replicating Ad, leading to improved tumor reduction and survival benefit. Moreover, the tumoricidal effects of Ad-DeltaE1B-DCNQ and Ad-DeltaE1B-DCNK were lessened, as the binding affinity to collagen was decreased, showing that the increased cancer cell cytotoxicity was driven by the action of decorin on extracellular matrix (ECM). Furthermore, Ad-DeltaE1B-DCNG substantially decreased ECM components within the tumor tissue. Finally, intratumoral injection of Ad-DeltaE1B-DCNG in primary tumor site greatly reduced the formation of B16BL6 melanoma cell pulmonary metastases in mice. Taken together, these data show the utility of decorin as a dispersion agent and highlight its utility and potential in improving the efficacy of replicating Ad-mediated cancer gene therapy.

Double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus in combination with radiotherapy elicits an enhanced anti-tumor effect.

Radiation therapy, a mainstay for anti-tumor therapeutic regimens for a variety of tumor types, triggers tumor cell apoptotic pathways by either directly eliciting DNA damage or indirectly inducing the formation of oxygen radicals. In an effort to augment radiation therapy, we generated a double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus (Ad-DeltaE1B19/55). In combination with radiotherapy, greater cytotoxicity was observed for Ad-DeltaE1B19/55 than for the single E1B 55 kDa-deleted oncolytic Ad (Ad-DeltaE1B55). Consistent with this observation, higher levels of p53, phospho-p53, phospho-Chk1, phospho-Chk2, PI3K (phosphatidylinositol-3-kinase), phospho-AKT, cytochrome c, and cleavage of PARP (poly (ADP-ribose) polymerase) and caspase-3 were observed in cells treated with Ad-DeltaE1B19/55 compared with those treated with Ad-DeltaE1B55, indicating that the E1B 19 kDa present in Ad-DeltaE1B55 may partially block radiation-induced apoptosis. A significant therapeutic benefit was also observed in vivo when oncolytic Ads and radiation were combined. Tumors treated with Ad-DeltaE1B19/55 and radiation showed large areas of necrosis and apoptosis with the corresponding induction of p53. Finally, consistent with in vitro observations, the combination of Ad-DeltaE1B19/55 and radiation was more efficacious than the combination of Ad-DeltaE1B55 and radiation. Taken together, these results present a strong therapeutic rationale for combining radiation therapy with E1B 19 kDa-deleted oncolytic Ad.