322 research outputs found
Correction to: BRG1 regulation by miR-155 in human leukemia and lymphoma cell lines.
No full textFollowing the publication of the original article the author listed as Antonio Herrera contacted the Publisher to state that his correct and full name is Antonio Herrera-Merchan. Antonio Herrera-Merchan has agreed to the publication of this erratum
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Abstract 3293: In vitro cellular and molecular effects of oncolytic vaccinia virus in clear and non-clear cell renal cell carcinoma
No full textAbstract Oncolytic vaccinia virus has several advantages over other OV platforms, including an efficient life cycle, multiple mechanisms of viral spread, large genome, allowing acceptance of foreign therapeutic DNA inserts, and proven safety in humans, due to its use as smallpox vaccine. JX-594 (Pexavec, SillaJen) is an attenuated (TKdeactivated ) oncolytic vaccinia VV, engineered to express GM-CSF and to selectively target tumor over non-tumor tissues. It is currently being investigated as a novel therapeutic option in patients with advanced Renal Cell Carcinoma (RCC, NCT03294083). The present study was undertaken to investigate the effects of JX-954 in a panel of clear and non-clear cell RCC cell lines and characterize the potential mechanisms of JX-594 oncolysis in vitro. We evaluated the oncolytic potency of JX-594 in human clear cell RCCs (VHL mutant 786-0, A498, VHL wild type Caki-1), non-clear cell RCC (ACHN, papillary RCC, and UOK-262, an FH deficient papillary RCC cell) and murine renal cancer cells (RENCA). Potent and persistent cytotoxic effects were induced by JX-594 in all human RCC cells, regardless of the histological subtype, and by mJX-594 (a Western Reserve strain of vaccinia virus expressing murine GMCSF) in RENCA cells. Moreover, we observed efficient viral replication in human (786-0, ACHN) and murine (RENCA) cells, confirming RCC permissiveness to viral infection. Functional proteomics analysis of JX-594 treated 786-0 cells was performed by reverse phase protein array (RPPA) to gain knowledge on potential mechanisms of viral oncolysis. JX-594 treatment had significant effects on the expression levels of proteins related to inducing cell cycle, apoptosis, necrosis, Akt signaling, MAPK signaling, autophagy and stress induction. In particular, the proteins related to cell cycle (Wee1, Cdc25c, CHK1/2, and Cyclin B1) and Akt signaling (PI3K, mTOR, Rictor and FOXO), MAPK signaling (JAK2, PAK1, FAK and MEK1) were down regulated, while proteins involved in apoptosis and necrosis were upregulated. In summary, our studies show that human and murine renal cancer cells are permissive to infection and replication by JX-594 and mJX-594, which induce potent oncolytic effects in clear and non-clear cell RCC, effects associated with significant modulation of RCC pathways associated with cell cycle, proliferation, and survival and stress responses. Citation Format: Yuqi Jing, F Bustamante Guerrero, Jaime Merchan. In vitro cellular and molecular effects of oncolytic vaccinia virus in clear and non-clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3293
Organisational risks matter and should be discussed during consent: survey of 980 neurosurgery patients from the UK
No full textIntroduction
During consent, surgeons discuss surgical and anaesthetic risks with patients. We investigated whether patients also wish to be informed about hospital organisational risks.
Methods
We used a cross-sectional survey. A questionnaire with three real-life scenarios of hospital organisational problems likely to increase the risk of surgery was given to 1,003 patients in neurosurgical departments of three United Kingdom (UK) teaching hospitals. The scenarios were: (1) computer failure in the operating room; (2) lack of surgical equipment; and (3) bed shortage or lack of operating capacity causing postponement of surgery. We quantified how strongly participants wish to be informed about organisational risks, whether this information alters a patient’s decision to have surgery, and the desire of patients to discuss these risks further.
Results
In total, 980 of 1,003 (97.7%) questionnaires were returned and 84.3%–88.5% of patients wished to be informed about hospital organisational risks – more women than men (odds ratio [OR] 1.6–1.8, p < 0.05). Knowledge of the hospital organisational risks would influence 69.2%–70.4% of participants’ decisions to have surgery; 74.9%–78.3% of participants wished to discuss the organisational risks with surgeons and 50.0%–60.8% with hospital managers before surgery. Some 69.4% of patients were concerned about organisational risks vs 77.1% who were concerned about surgical risks.
Conclusions
Most neurosurgery patients consider hospital organisational risks to be material. To comply with the Montgomery ruling in UK medicolegal case law, neurosurgeons and hospital managers should discuss with patients the organisational risks in addition to the surgical and anaesthetic risks during consent
Abstract 4581: A novel virus-drug combination to enhance oncolysis in renal cell carcinoma
No full textAbstract Background: Oncolytic viruses (OVs) represent a promising option for treatment of advanced cancers. There are few studies assessing the effects of oncolytic viruses in renal cell carcinoma. Oncolytic measles virus (MV) is a novel viral platform that previously been shown to induce cell fusion and cytotoxicity in a CD46-dependent manner. The goals of our study are to identify a pharmacological agent that used in combination with oncolytic MV will enhance the virus cytotoxic effects in renal cell carcinoma (RCC) models. Results: To achieve this goal, we performed in vitro assays combining the Edmonston strain of Measles virus expressing eGFP (MV-GFP), whose oncolytic activity in vitro and in vivo has been demonstrated, with several targeted novel agents that include a new generation multikinase inhibitor used in the treatment of RCC, bromodomain inhibitors associated with epigenetic regulation and Triptolide (T) which has been reported as an apoptosis, ER stress, and oxidative stress inducer and inhibitor of angiogenesis. 786-0 (VHL-mut), A498 (VHL mutant), Caki-1 (VHL-wt) and ACHN (VHL-wt) RCC cells were seeded and treated with oncolytic MV, and the compounds including T. Cell viability as well as cytotoxicity were quantitated at 24, 48 and 72h. Evaluation of single agent activity showed that MV and T were associated with the most significant growth inhibitory or cytotoxic effects. Among the MV-drug combinations, we found that low dose of T was associated with the most significant augmentation of MV oncolysis in RCC cell lines, demonstrated by both viability cell count and by real time monitoring of cell growth by xCELLigence based assays. We found that the treatment sequence (virus infection followed by T treatment) was an important determinant of the combined tumor cytotoxic effects. In addition to enhanced tumor cytotoxicity, we also observed that T enhanced viral replication in RCC, which may explain in part the mechanisms of drug synergy. Finally, we investigated the molecular changes associated with RCC oncolysis by MV alone and in combination with T with RPPA (Reverse Phase Protein Array) and western blot validation and enhanced viral oncolysis induced by the MV-T combination was found to be associated with increased apoptosis (PARP cleavage), ER stress induction (pEIF2a, CHOP) and down regulation of survival and proliferation pathways (pAKT) 36h post-treatment. Conclusion: We identified a novel strategy to enhance RCC viral oncolysis by MV-T combination, by mechanisms that include enhanced viral replication with subsequent increase in the cell death, ER stress pathways and down regulation of pAKT. Current efforts are focused on identifying in vivo antitumor effects and mechanisms of this combination that will open new horizons for the development of rational combinations to improve oncolytic measles virotherapies in RCC, which could lead to long term responses/cures in this disease. Citation Format: Valery A. Chavez, Natasha Khatwani, Ashok Saluja, Jaime Merchan. A novel virus-drug combination to enhance oncolysis in renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4581
Abstract 5103: The dark cancer kinome - untapped opportunities for the development of novel drugs
No full textAbstract Kinases are firmly established drug targets in cancer. There are currently 44 FDA approved kinase drug and hundreds of compounds are in clinical development. However, less than 10% of the Kinome is currently targeted and a large proportion is considered understudied by the NIH Illuminating the Druggable Genome Program (https://druggablegenome.net/). No small molecule inhibitors are known for these “dark” proteins, yet many may be opportune novel cancer targets.We developed a computational pipeline to identify and prioritize understudied kinases as cancer drug targets. We analyzed the complete set of tumors in The Cancer Genome Atlas (TCGA). For 33 different cancers we performed differential expression analysis and identified 39 dark kinases that exhibit significant upregulation in at least four types. Using co-expression analysis we built functional networks prioritizing drug targets. To identify small molecules that reverse their expression levels, we leveraged transcriptional response signatures obtained from dozens of human cancer cell lines exposed to tens of thousands of small molecules from the Library of Integrated Network-based Cellular Signatures (LINCS). To identify small molecules that directly bind to and inhibit dark kinases, we have have combined an advanced AI (artificial intelligence) model trained on activity data from across the Kinome with structure-based simulations.Using the computational pipeline, we identified the dark Ca2+/Calmodulin dependent kinase PNCK as the most differentially overexpressed kinase in kidney cancer patients. Our analyses have demonstrated statistically significant correlation between PNCK mRNA levels and various clinical and pathological outcomes, including histologic grade, clinical staging and overall survival. We have confirmed high levels of PNCK expression in 5 renal cell carcinoma cell lines (Caki-1, ACHN, 786-O, A704 and A498). Knockdown and overexpression studies have suggested PNCK and the CaMK pathway may contribute to cellular proliferation and cell cycle progression. We have applied our AI-based screening pipeline to a library of >20 million commercially available compounds and confirmed three PNCK inhibiting chemotypes. In summary, using a novel computational pipeline, we have identified and experimentally validated PNCK as a prospective novel drug target in an understudied pathway that is highly upregulated in kidney cancer. We identified first in class small molecules that target this previously dark kinase as prospective starting points for optimization into a clinical candidate. Citation Format: Derek J. Essegian, Rimpi Khurana, Vasileios Stathias, Valery Chavez, Jaime R. Merchan, Stephan Schürer. The dark cancer kinome - untapped opportunities for the development of novel drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5103
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Abstract C121: Epidemiological characteristics and patterns of recurrence of renal cell carcinoma in Hispanics: A single US center cohort study
No full textRenal cell carcinoma (RCC) is amongst the ten most prevalent malignancies in the United States, with 76,000 new cases each year and almost 14,000 deaths. Over the past half-century, RCC has more than doubled in incidence. RCC seems to have a greater incidence among Hispanics with a nearly three-fold increase. The epidemiology of RCC has been studied. However, there is a gap in knowledge on disparities in RCC within minority populations. We aimed to analyze epidemiologic patterns of RCC within our community, where Hispanics alone make up 70% of the population. We conducted a retrospective study to describe characteristics and calculate rates of recurrence of RCC among patients treated at Sylvester Comprehensive Cancer Center in Miami, FL, from June 2010 to April 2020. The patients were aged 18 and older and had a pathologic diagnosis of RCC. We identified ethnicity as Hispanic/Latino (HL) or non-Hispanic/Latino (NHL). Clinical presentation was classified based on information from the last encounter as either local RCC without recurrence, metastatic RCC after nephrectomy, or metastatic RCC at diagnosis/de novo. We analyzed a total of 1168 patients, from which 661 patients (55.7%) were identified as NHL and 507 (42.7%) as HL. A subtotal of 333 patients (28.5%) had metastatic RCC at diagnosis/de novo, from which 199 (59.7%) were NHL, and 134 (40.2%) were HL. A subtotal of 835 patients (71.5%) were diagnosed with local RCC and underwent nephrectomy, from which 462 (55.3%) were identified as NHL and 373 (44.7%) as HL. From the NHL group that underwent nephrectomy, 189 patients (40.9%) had recurrent disease and 273 (59%) did not. From the HL group, 121 patients (32.4%) had recurrent disease and 252 (67.5%) did not. Overall, 310 patients had metastasis after nephrectomy, from which 121 (39%) were HL and 189 (60.9%) were NHL. In this cohort of patients with RCC, four out of every ten patients with metastasis at diagnosis were HL. NHL appeared to have more recurrence of disease after nephrectomy compared to Hispanics. Further histopathologic, clinical, and genomic characteristics will be presented, along with treatment outcomes and clinical trial participation in the NHL and HL cohorts.
Citation Format: Abner Antonio Murray Melo, Jesus Antonio Ocejo Gallegos, Jaime Rafael Merchan. Epidemiological characteristics and patterns of recurrence of renal cell carcinoma in Hispanics: A single US center cohort study [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C121
Calidad de sentencias de primera y segunda instancia sobre nulidad de resolución administrativa, en el expediente Nº 02411-2015-0-2501-JR-LA-04 del distrito judicial del Santa - Chimbote. 2023
No full textLa investigación tuvo como problema: ¿Cuál es la calidad de las sentencias de primera y segunda instancia sobre nulidad de resolución administrativa según los parámetros normativos, doctrinarios y jurisprudenciales pertinentes, en el expediente Nº 02411- 2015-0-2501-JR-LA-04, del Distrito Judicial del Santa – Chimbote. 2023 el objetivo fue: determinar la calidad de las sentencias en estudio. Es de tipo, cuantitativo cualitativo, nivel exploratorio descriptivo, y diseño no experimental, retrospectivo y transversal. La fuente de información fue un expediente judicial, seleccionado mediante muestreo por conveniencia; para recolectar los datos se utilizaron las técnicas de la observación y el análisis de contenido; y como instrumento una lista de cotejo, validado mediante juicio de expertos. Los resultados revelaron que la calidad de la parte expositiva, considerativa y resolutiva, pertenecientes a: la sentencia de primera instancia fue de rango: muy alta, muy alta y muy alta; mientras que, de la sentencia de segunda instancia: muy alta, muy alta y muy alta. En conclusión, la calidad de las sentencias de primera y segunda instancia, fueron de rango muy alta y muy alta, respectivamente
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Abstract 96: A novel virus-drug combination to enhance oncolysis in colorectal cancer (crc)
No full textAbstract Background: While advances in immune and targeted therapies improve outcomes in selected cancers, only a minority of colorectal cancer (CRC) patients benefit from them. Oncolytic viruses (OVs) represent novel cancer biotherapies, and among them, the oncolytic measles virus (MV) has demonstrated safety and antitumor activity in early clinical studies. MV alone does is not associated with cancer cures. Triptolide, a diterpenoid epoxide extracted from the thunder god vine (Tripterygium wilfordii), has been reported to have potent antitumor effects via multiple mechanisms, including anti-proliferative, pro-apoptotic, antiangiogenic, and induction of ER stress. The effects of triptolide on viral colon cancer oncolysis have not been previously investigated. Objectives: To characterize the in vitro and in vivo mechanisms of novel stromal retargeted oncolytic MVs and improve efficacy by combining MVs with triptolide. Methods: The in vitro effects of triptolide alone, MV-GFP (Edmonston strain of Measles virus expressing eGFP, for human cancer cells), MV-m-uPA (MV retargeted against the murine uPA receptor, for murine cancer cells), or virus-triptolide combinations on tumor cell cytotoxicity were assessed by cell count (Vi cell counter) or xCelligence assays, on HT-29, HCT116, SW620, CT26, and MC38 cells. Molecular and mechanistic characterization of Triptolide’s effects alone and combination with MV in HT29 cells will be analyzed by the (Reverse Phase Protein Array (RPPA) and validated by western blot analysis (experiment undergoing). In vivo effects (tumor progression and survival) of minnelide (M) (water-soluble version of Triptolide) alone and in combination with Measles Virus were assessed in Balb/C mice bearing CT26. Results: While MV and T had dose-dependent cytotoxic activity as single agents, significant augmentation of MV oncolysis was induced by co-treatment with triptolide. In vivo experiments showed similar effects observed in vitro, with potent antitumor activity of triptolide and enhanced in vivo antitumor activity when minnelide was combined with MV vectors. Conclusions: our results strongly suggest that triptolide or minnelide enhances measles virus oncolysis in vitro and in vivo models of colorectal cancer. In vitro and in vivo mechanistic studies are underway to characterize the molecular mechanisms by which triptolide enhances MV oncolysis and will be presented at the meeting. Citation Format: Valery A. Chavez, Floritza Bustamante, Abner Murray, Ashok Saluja, Jaime Merchan. A novel virus-drug combination to enhance oncolysis in colorectal cancer (crc) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 96
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Abstract C024: Trial in progress: Phase 1 study of BAL0891 as monotherapy and in combination with chemotherapy in patients with advanced solid tumors
No full textAbstract Background: BAL0891 is a first-in-class small-molecule mitotic checkpoint inhibitor (MCI) that targets threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) to disrupt spindle assembly checkpoint (SAC) regulation and induce tumor cell death. It has a more potent anti-tumor activity as compared to TTK-specific inhibitors due to its combined prolonged effect on TTK and transient effect on PLK1. In preclinical studies, BAL0891 demonstrated potent anti-tumor activity as a monotherapy and in combination with paclitaxel and carboplatin. In the first-in-human microdose study of TTK-CS-001 in healthy subjects, key BAL0891 pharmacokinetic (PK) parameters were investigated (i.e., clearance, half-life, exposure), and no safety signals were detected. Trial design: This clinical trial is a multiple-cohort, open-label phase 1 study with 3 dose-escalation substudies, investigating intravenous (IV) BAL0891 as monotherapy, and in combination with carboplatin or paclitaxel, in patients with advanced solid tumors. Primary objectives: 1) To evaluate safety/tolerability 2) To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BAL0891 monotherapy and in combination with carboplatin/paclitaxel. Eligibility: Patients ages ≥18 years with advanced/metastatic solid tumors that are refractory to, or intolerant of existing therapy may participate in this study. Patients enrolled in dose level ≥4 of Substudy 1 and all patients in Substudies 2 and 3 must have measurable disease. Substudy 1: Monotherapy BAL0891: IV doses of BAL0891 on Days 1 (D1) and 8 (D8) every 3 weeks (Q3W). A Bayesian logistic regression model (BLRM) will guide dose escalations, with 8 nominal DLs of 5/10/20/40/80/160/320/480 mg. Substudy 2: Phase 1 BAL0891 D1, D8 + carboplatin AUC5-6 D1 Q3W. Substudy 3: Phase 1 BAL0891 D1, D15 + paclitaxel 70-80 mg/m2 D1, D8, D15 Q4W. Substudies 2 and 3 may begin once the maximum tolerated dose (MTD) of BAL0891 monotherapy has been established or at the first signs of expected target toxicity and/or efficacy with monotherapy. Enrollment began in February 2023 and is ongoing in the United States and South Korea. Clinical trial information; NCT05768932 Citation Format: Shivaani Kummar, Minal Barve, Eric Feldman, Seunghyun Ma, Jaime Merchan, Seock-Ah Im, Sun Young Rha. Trial in progress: Phase 1 study of BAL0891 as monotherapy and in combination with chemotherapy in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C024
Adolescentes infractores reincidentes en Ecuador: Subprogramas de reinserción con base en la naturaleza de la infracción.
No full textLos adolescentes infractores, al ser parte de un grupo de atención prioritaria deben gozar de sistemas especiales para la protección de sus derechos. En razón de esto son inimputables relativamente, lo que implica que si cometen un delito se les aplicará una justicia especial. Este sistema especial de justicia no parte de la idea de castigar como con los mayores de edad, sino de proteger al adolescente y de disuadir los comportamientos delictivos en él. En tal sentido, no solo la normativa aplicable y el juzgamiento deben tener un sistema especial, sino también los programas de rehabilitación de los que vayan a ser parte los adolescentes. Por lo tanto y por la baja efectividad de los programas vigentes en el país, es necesario replantearse los mismos. En España se han implementado subprogramas que responden a la naturaleza
de la infracción cometida, con distintas formas de abarcar la rehabilitación de los menores; programas que han dado excelentes resultados sobre todo para disminuir las cifras de reincidencia en este grupo etario. Esto responde a que el programa se diseña en razón de las motivaciones y realidad de cada adolescente para cometer los ilícitos, y por ende, saber qué aspectos particulares trabajar. Esto es importante, puesto que se podría aplicar en Ecuador, para disminuir los índices de reincidencia de tal manera garantizar de manera efectiva los derechos de los adolescentes.Adolescent offenders, as part of a priority attention group, should benefit from special systems to protect their rights. Therefore, they are relatively immune from prosecution, which means that if they commit a crime, special justice will be applied to them. This special justice system is not based on the idea of punishing, as with adults, but instead on protecting the adolescent and discouraging criminal behavior. In this sense, not only the applicable legislation and the trial must have a special system, but also the rehabilitation programs the adolescents will be part of. Therefore, considering the low effectiveness of the current programs in the country, it is necessary to reconsider them. In Spain, various sub-programs that respond to the nature of the committed offense have been implemented, they offer different ways of dealing with underage rehabilitation and the results have been excellent, especially in terms of lowering the repeated infringements rate in this age group. This is
because the program is designed according to the motivations and reality of each adolescent to commit the offenses, and thus, determine which aspects to work on. This is important since it could be applied in Ecuador to reduce recidivism rates to effectively guarantee the adolescents' rights
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