Ethanol has been shown to exhibit therapeutic properties as an ablative agent alone and in combination with thermal ablation. Ethanol may also increase sensitivity of cancer cells to certain physical ...and chemical antitumoral agents. The aim of our study was to assess the potential influence of nontoxic concentrations of ethanol on hyperthermia therapy, an antitumoral modality that is continuously growing and that can be combined with classical chemotherapy and radiotherapy to improve their efficiency. Human leukemia cells were included as a model in the study. The results indicated that ethanol augments the cytotoxicity of hyperthermia against U937 and HL60 cells. The therapeutic benefit of the hyperthermia/ethanol combination was associated with an increase in the percentage of apoptotic cells and activation of caspases-3, -8 and -9. Apoptosis triggered either by hyperthermia or hyperthermia/ethanol was almost completely abolished by a caspase-8 specific inhibitor, indicating that this caspase plays a main role in both conditions. The role of caspase-9 in hyperthermia treated cells acquired significance whether ethanol was present during hyperthermia since the alcohol enhanced Bid cleavage, translocation of Bax from cytosol to mitochondria, release of mitochondrial apoptogenic factors, and decreased of the levels of the anti-apoptotic factor myeloid cell leukemia-1 (Mcl-1). The enhancement effect of ethanol on hyperthermia-activated cell death was associated with a reduction in the expression of HSP70, a protein known to interfere in the activation of apoptosis at different stages. Collectively, our findings suggest that ethanol could be useful as an adjuvant in hyperthermia therapy for cancer.
Elucidation of the relationships between genotype, diet, and health requires accurate dietary assessment. In intervention and epidemiological studies, dietary assessment usually relies on ...questionnaires, which are susceptible to recall bias. An alternative approach is to quantify biomarkers of intake in biofluids, but few such markers have been validated so far. Here we describe the use of metabolomics for the discovery of nutritional biomarkers, using citrus fruits as a case study. Three study designs were compared. Urinary metabolomes were profiled for volunteers that had (a) consumed an acute dose of orange or grapefruit juice, (b) consumed orange juice regularly for one month, and (c) reported high or low consumption of citrus products for a large cohort study. Some signals were found to reflect citrus consumption in all three studies. Proline betaine and flavanone glucuronides were identified as known biomarkers, but various other biomarkers were revealed. Further, many signals that increased after citrus intake in the acute study were not sensitive enough to discriminate high and low citrus consumers in the cohort study. We propose that urine profiling of cohort subjects stratified by consumption is an effective strategy for discovery of sensitive biomarkers of consumption for a wide range of foods.
RATIONALE:Adoptive transfer of cardiac progenitor cells (CPCs) has entered clinical application, despite limited mechanistic understanding of the endogenous response after myocardial infarction (MI). ...Extracellular matrix undergoes dramatic changes after MI and therefore might be linked to CPC-mediated repair.
OBJECTIVE:To demonstrate the significance of fibronectin (Fn), a component of the extracellular matrix, for induction of the endogenous CPC response to MI.
METHODS AND RESULTS:This report shows that presence of CPCs correlates with the expression of Fn during cardiac development and after MI. In vivo, genetic conditional ablation of Fn blunts CPC response measured 7 days after MI through reduced proliferation and diminished survival. Attenuated vasculogenesis and cardiogenesis during recovery were evident at the end of a 12-week follow-up period. Impaired CPC-dependent reparative remodeling ultimately leads to continuous decline of cardiac function in Fn knockout animals. In vitro, Fn protects and induces proliferation of CPCs via β1-integrin-focal adhesion kinase-signal transducer and activator of transcription 3-Pim1 independent of Akt.
CONCLUSIONS:Fn is essential for endogenous CPC expansion and repair required for stabilization of cardiac function after MI.
To improve cancer disparities among under-represented minority (URM) populations, better representation of URM individuals in cancer research is needed. The San Diego State University and University ...of California San Diego Moores Cancer Center Partnership is addressing cancer disparities through an educational program targeting undergraduate URM students. The Partnership provides a paid intensive summer research internship enriched with year-round activities that include educational sessions, a journal club, mentorship, social activities, and poster sessions and presentations. Program evaluation through follow-up surveys, focus groups, and other formal and informal feedback, including advisory and program steering committees, are used to improve the program. Long-term follow-up among scholars (minimum of 10 years) provides data to evaluate the program’s long-term impact on scholars’ education and career path. Since 2016, 63 URM undergraduate students participated in the scholar program. At the year-2 follow-up (2016 cohort;
n
= 12), 50% had completed their Graduate Record Examination (GRE) and/or applied to graduate or medical school.
Lessons learned
during the course of the program led to implementation of changes to provide a better learning experience and increase overall program satisfaction. Updates were made to recruitment timeline, improvements of the recruitment processes, refinement of the program contracts and onboarding meetings, identification of essential program coordinator skills and responsibilities, adjustments to program components, and establishment of a well-mapped and scheduled evaluation plan. The Partnership identified best practices and lessons learned for implementing lab-based internship scholar programs in biomedical and public health fields that could be considered in other programs.
The development of 64Cu-based immuno-PET radiotracers requires the use of copper-specific bifunctional chelators (BFCs) that contain functional groups allowing both convenient bioconjugation and ...stable copper complexes to limit in vivo bioreduction, transmetallation and/or transchelation. The excellent in vivo kinetic inertness of the pentaazamacrocyclic 64CuCu-15-5 complex prompted us to investigate its potential for the 64Cu-labelling of monoclonal antibodies (mAbs), compared with the well-known NODAGA and DOTA chelators. To this end, three NODAGA, DOTA and 15-5-derived BFCs, containing a pendant azadibenzocyclooctyne moiety, were synthesised and a robust methodology was determined to form covalent bonds between them and azide-functionalised trastuzumab, an anti-HER2 mAb, using strain-promoted azide-alkyne cycloaddition. Unlike the DOTA derivative, the NODAGA- and 15-5-mAb conjugates were radiolabelled with 64Cu, obtaining excellent radiochemical yields, under mild conditions. Although all the radioimmunoconjugates showed excellent stability in PBS or mouse serum, 64CuCu-15-5- and 64CuCu-NODAGA-trastuzumab presented higher resistance to transchelation when challenged by EDTA. Finally, the immunoreactive fraction of the radioimmunoconjugates (88–94%) was determined in HER-2 positive BT474 human breast cancer cells, confirming that the bioconjugation and radiolabelling processes implemented had no significant impact on antigen recognition.
Identifying compounds that are neurotoxic either toward the central or the peripheral nervous systems (CNS or PNS) would greatly benefit early stages of drug development by derisking liabilities and ...selecting safe compounds. Unfortunately, so far assays mostly rely on histopathology findings often identified after repeated-dose toxicity studies in animals. The European NeuroDeRisk project aimed to provide comprehensive tools to identify compounds likely inducing neurotoxicity. As part of this project, the present work aimed to identify diagnostic non-invasive biomarkers of PNS toxicity in mice. We used two neurotoxic drugs in vivo to correlate functional, histopathological and biological findings. CD1 male mice received repeated injections of oxaliplatin or paclitaxel followed by an assessment of drug exposure in CNS/PNS tissues. Functional signs of PNS toxicity were assessed using electronic von Frey and cold paw immersion tests (oxaliplatin), and functional observational battery, rotarod and cold plate tests (paclitaxel). Plasma concentrations of neurofilament light chain (NF-L) and vascular endothelial growth factor A (VEGF-A) were measured, and histopathological evaluations were performed on a comprehensive list of CNS and PNS tissues. Functional PNS toxicity was observed only in oxaliplatin-treated mice. Histopathological findings were observed dose-dependently only in paclitaxel groups. While no changes of VEGF-A concentrations was recorded, NF-L concentrations were increased only in paclitaxel-treated animals as early as 7 days after the onset of drug administration. These results show that plasma NF-L changes correlated with microscopic changes in the PNS, thus strongly suggesting that NF-L could be a sensitive and specific biomarker of PNS toxicity in mice.
•Plasma NF-L concentrations rose with peripheral nerve lesion grade.•Plasma VEGF-A concentrations were not related to peripheral nerve lesion.•Despite toxicity and nociceptive signs, oxaliplatin did not produce nerve lesion.•For each drug, tissue exposure increased with dose, higher in PNS than CNS.
A green HPLC method for lamivudine (3TC), zidovudine (AZT) and nevirapine (NVP) determination in fixed-dose combination tablets was developed using ethanol as both one of the mobile phases and the ...solvent for sample preparation. This method was validated according to ICH Q2(R1) guideline. Additionally, the method was adapted to complete the analysis of five related substances described in the International Pharmacopoeia (Ph. Int.), five other known related substances and two excipients. The separation was obtained with a C18 column (ARV4 5 µm 250 × 3.0 mm, Interchim) using a gradient mode with 0.1M ammonium acetate buffer (pH 4.5) and ethanol as mobile phase at 35°C, a flow rate of 0.4 mL/min, at 270 nm and an injection volume of 10 µL. The combination of ethanol (biodegradable and low-cost alternative solvent) with the use of a column diameter of 3 mm instead of 4.6 mm as used in pharmacopoeias, makes the wastes of the analysis more environmentally friendly and allows the use of a conventional HPLC pump (<400 bar) for easy implementation in quality control in countries with limited resources. Assessment of the method greenness was evaluated using three analytical tools: Analytical Eco-scale, AGREE metrics and Analytical Method Greenness Score (AMGS).
The efficiency in the management of patients with suspected malignant lesions represents the main objective of the oncology of head and neck. Flexible nasopahyngolaryngoscopy with working channel ...allows to quickly and safely assess and obtain histological samples of this type of lesion. Our objective is to describe the usefulness of this technique in lesions suggestive of malignancy in terms of efficiency, sensitivity and specificity. A retrospective study was carried out over a period of time from December 2014 to December 2019, including patients biopsied with flexible fibroscopy of lesions of debut suspected of malignancy. Here we assess the location of the lesion, the histological results, the diagnostic time and the epidemiological variables. 104 patients were included in the study. More than half of the lesions, 55.2% (57), were located in the larynx; 57.7% (60) resulted positive for malignancy in the flexible fiberscope biopsy; 19.2% (20) were taken to the operating room to get biopsied under general anesthesia resulting in 7.4% (14) positive for malignancy, which shows a sensitivity of the test of 81%. In our sample, a diagnostic time of 15 days was obtained. Considering our results, the few complications and the revised literature, flexible fiberscope biopsy with working channel is an efficient procedure for the management of oncological patients of head and neck.
To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor ...radioresistance.
For TRT, we used a melanin radiotracer (
IICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAF
SK-MEL-3, murine NRAS
1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRAS
1007 syngeneic model.
TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRAS
spheroids were highly radiosensitive towards
IICF01012-TRT. In mice bearing NRAS
1007 melanoma,
IICF01012 induced a significant extended survival (92 vs. 44 days,
< 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation.
Our data suggest that
IICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that
IICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.
Considerar la actividad turística como fenómeno potencial generador de desarrollo sostenible es estratégico dentro de un proceso de planificación urbana. La planificación del desarrollo turístico de ...una localidad y la planificación del desarrollo urbano son procesos que pueden aportar mayor beneficio a un distrito o provincia si se realizan bajo una mirada intersectorial. Entonces, ¿cómo pueden los activos turísticos de un territorio en vías de crecimiento urbano como Moche jugar un rol en la planificación urbana del entorno y contribuir a mejorar sus condiciones espaciales desde el enfoque de desarrollo sostenible? Para ello, se propone que el desarrollo urbano sostenible considere los componentes sociales, económicos y ambientales como atractivos turísticos y activos para el desarrollo urbano. Se revisa la problemática de Moche con relación al turismo y su desarrollo urbano, y se llega a una propuesta de lineamientos para el desarrollo urbano sostenible de Moche, que va desde la identificación de los activos, estrategias de desarrollo urbano, identificación de proyectos estratégicos para el desarrollo urbano de Moche y esquema de intervención de actores. Esta metodología contribuye a visibilizar el potencial regenerador y ordenador del desarrollo de un entorno turístico, así como el valor que tiene incorporar la problemática sobre el crecimiento turístico como insumo para la elaboración de lineamientos que hagan frente a la problemática del desarrollo urbano. Por último, valorar los activos turísticos de una localidad, genera una toma de conciencia sobre su rol en el proceso de planificación urbana del mismo.
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