Autocrine Down-Regulation of Basic Fibroblast Growth Factor Receptors Causes Mitotoxin Resistance in a Human Melanoma Cell Line

The ability of melanoma to develop resistance to mitotoxins, growth-factor- directed anti-neoplastic agents that offer potential for the treatment of this highly refractory disease, may limit therapeutic efficacy. To address this problem, we developed a subcloned human melanoma cell line that is resistant to the mitotoxin composed of basic fibroblast growth factor conjugated to the ribosome-inactivating protein saporin. Resistance was caused by autocrine FGF ligands, which down-regulate bFGF receptors and reduce bFGF-saporin binding. Inhibiting the autocrine loop with suramin or with neutralizing antibodies to FGF up-regulated receptors and decreased resistance in vitro. Furthermore, suramin restored sensitivity in resistant tumor xenografts. These results suggest the potential of therapeutic modalities combining agents that neutralize growth factors with receptor-directed mitotoxins for targeting malignant melanoma either to prevent emergence of resistance or to circumvent resistance once it occurs

Health care in rural areas: proposal of a new telemedicine program assisted from the reference health centers, for a sustainable digitization and its contribution to the carbon footprint reduction

[EN] Introduction This paper studies and quantifies the environmental benefits of implementing a new telemedicine service for users of the public health system in a rural area of Alicante (Spain). The proposed telemedicine service is based on carrying out 20% of the follow-on consultations with a specialist virtually from the Reference Health Centres with the support of qualified staff. This way of providing medical care remotely will be a good transition to fully online medical services, especially for the elderly. The proposed model avoids the displacement of users to the Alcoy Hospital, reducing the distances to be travelled, which will be directly reflected in a reduction of the emission of pollutants (carbon footprint) generated by patients' vehicles. Methods Data from the Alcoy Health Department were used for 2019, the last year of normal activity of the health centres before Covid-19. Using data from the Department's health management report and the emission factors of the vehicles, we calculated the distances, hours, litres of fuel saved, as well as the tonnes of CO2 equivalent, CO2, CH4 and N2O. Results With the implementation of this type of telemedicine, journeys would be avoided, saving 447,279 km, 7,580 h and 38,019 L of fuel. The emission into the atmosphere of 79.26 metric tons of CO2, 74.5 kg of CH4 and 487.28 kg of N2O per year would be avoided. Conclusions The implementation of this telemedicine service contributes to a high degree to: (a) increasing the environmental sustainability of the rural health sector thanks to the reduction of traffic emissions (saving 9% of pollutants compared to the current system), (b) decongesting the health system by reducing face-to-face visits to specialists, (c) increasing the quality of life of patients by avoiding road travel (d) promoting the digitalisation of the rural population.Silvia Aparisi-Navarro was supported by Universitat Politecnica de Valencia [PAID-01-2020]. Maria Moncho-Santonja was supported by Conselleria d'Educacio, Investigacio, Cultura i Esport [ACIF-20].Moncho-Santonja, M.; Aparisi-Navarro, S.; Defez Garcia, B.; Davol, A.; Peris Fajarnes, G. (2022). Health care in rural areas: proposal of a new telemedicine program assisted from the reference health centers, for a sustainable digitization and its contribution to the carbon footprint reduction. Heliyon. 8(7):1-6. https://doi.org/10.1016/j.heliyon.2022.e09812168

p66 Shc and tyrosine-phosphorylated Shc in primary breast tumors identify patients likely to relapse despite tamoxifen therapy

INTRODUCTION: Shc adapter proteins are secondary messenger proteins involved in various cellular pathways, including those mediating receptor tyrosine kinase signaling and apoptosis in response to stress. We have previously reported that high levels of tyrosine-phosphorylated Shc (PY-Shc) and low levels of its inhibitory p66 Shc isoform are strongly prognostic for identifying both early node-negative and more advanced, node-positive, primary breast cancers with high risk for recurrence. Because aberrant activation of tyrosine kinases upstream of Shc signaling proteins has been implicated in resistance to tamoxifen – the most widely prescribed drug for treatment of estrogen receptor-positive breast cancer – we hypothesized that Shc isoforms may identify patients at increased risk of relapsing despite tamoxifen treatment. METHODS: Immunohistochemical analyses of PY-Shc and p66 Shc were performed on archival primary breast cancer tumors from a population-based cohort (60 patients, 9 relapses) and, for validation, an independent external cohort (31 patients, 13 relapses) in which all patients received tamoxifen as a sole systemic adjuvant prior to relapse. RESULTS: By univariate and multivariate analyses, the Shc proteins were very strong and independent predictors of treatment failure in both the population-based cohort (interquartile hazard ratio = 8.3, 95% confidence interval [CI] 1.8 to 38, P = 0.007) and the validating cohort (interquartile relative risk = 12.1, 95% CI 1.7 to 86, P = 0.013). CONCLUSION: These results suggest that the levels of PY-Shc and p66 Shc proteins in primary tumors identify patients at high risk for relapsing despite treatment with tamoxifen and therefore with further validation may be useful in guiding clinicians to select alternative adjuvant treatment strategies

RANKL inhibition is an effective adjuvant for docetaxel in a prostate cancer bone metastases model

BACKGROUND Docetaxel induces an anti-tumor response in men with advanced prostate cancer (PCa); however, the side effects associated with docetaxel treatment can be severe, resulting in discontinuation of therapy. Thus, identification of an effective adjuvant therapy to allow lower doses of docetaxel is needed. Advanced PCa is typically accompanied by skeletal metastasis. Receptor activator of NFkB ligand (RANKL) is a key pro-osteoclastic factor. Targeting RANKL decreases establishment and progression of PCa growth in bone in murine models. METHODS The efficacy of inhibiting RANKL, using a recombinant soluble RANK extracellular domain fused with the immunoglobulin Fc domain (RANK-Fc), was tested as an adjuvant therapy with docetaxel for PCa bone metastasis in a murine intra-tibial model. RESULT The combination of RANK-Fc and docetaxel reduced tumor burden in bone greater than either treatment alone. CONCLUSION The combination of docetaxel with a RANKL-inhibiting agent merits further investigation for treatment of advance PCa. Prostate 68:820–829, 2008. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58561/1/20744_ftp.pd

Anti-interleukin-6 monoclonal antibody induces regression of human prostate cancer xenografts in nude mice

BACKGROUND Despite clinical associations and in vitro data suggesting that autocrine interleukin-6 (IL-6) production contributes to prostate cancer progression or chemotherapy resistance, there have been no reports that explore the role of IL-6 on prostate tumors in vivo. In the present study, we investigated the effect of IL-6 inhibition on the growth of human prostate cancer xenografts in nude mice. METHODS To determine if autocrine IL-6 production contributes to prostate cancer growth and chemotherapy resistance in vivo, xenografts of a human prostate cancer cell line that produces IL-6 (PC-3) were established in nude mice. The mice were randomly divided into four treatment groups: (1) saline (vehicle control) + murine IgG (isotype control); (2) etoposide + murine IgG; (3) saline + anti-IL-6 monoclonal antibody; and (4) etoposide + anti-IL-6 monoclonal antibody. Tumors were measured twice weekly during a 4-week treatment period. At the conclusion of the study, all mice were sacrificed, and in addition to final volume, tumors were evaluated for the degree of apoptosis by TUNEL analysis. RESULTS Anti-IL-6 Ab (with saline or etoposide) induced tumor apoptosis and regression (∼60% compared to initial tumor size). Etoposide alone did not induce tumor regression or apoptosis in this animal model, and there was no synergy between anti-IL-6 Ab and etoposide. CONCLUSIONS These studies suggest that IL-6 contributes to prostate cancer growth in vivo, and that targeting IL-6 may contribute to prostate cancer therapy. Prostate 48:47–53, 2001. © 2001 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34760/1/1080_ftp.pd

Ribosome-Inactivating Proteins: From Plant Defense to Tumor Attack

Ribosome-inactivating proteins (RIPs) are EC3.2.32.22 N-glycosidases that recognize a universally conserved stem-loop structure in 23S/25S/28S rRNA, depurinating a single adenine (A4324 in rat) and irreversibly blocking protein translation, leading finally to cell death of intoxicated mammalian cells. Ricin, the plant RIP prototype that comprises a catalytic A subunit linked to a galactose-binding lectin B subunit to allow cell surface binding and toxin entry in most mammalian cells, shows a potency in the picomolar range. The most promising way to exploit plant RIPs as weapons against cancer cells is either by designing molecules in which the toxic domains are linked to selective tumor targeting domains or directly delivered as suicide genes for cancer gene therapy. Here, we will provide a comprehensive picture of plant RIPs and discuss successful designs and features of chimeric molecules having therapeutic potential

Immunotoxins and Other Conjugates Containing Saporin-S6 for Cancer Therapy

Ribosome-inactivating proteins (RIPs) are a family of plant toxins that permanently damage ribosomes and possibly other cellular substrates, thus causing cell death. RIPs are mostly divided in two types: Type 1 RIPs that are single-chain enzymatic proteins, and type 2 RIPs that consist of an active A chain (similar to a type 1 RIP) linked to a B chain with lectin properties. RIP-containing conjugates have been used in many experimental strategies against cancer cells, often showing great efficacy in clinical trials. Saporin-S6, a type 1 RIP extracted from Saponaria officinalis L. seeds, has been extensively utilized to construct anti-cancer conjugates because of its high enzymatic activity, stability and resistance to conjugation procedures, resulting in the efficient killing of target cells. This review summarizes saporin-S6-containing conjugates and their application in cancer therapy, considering in-vitro and in-vivo studies both in animal models and in clinical trials. The review is structured on the basis of the targeting of hematological versus solid tumors and on the antigen recognized on the cell surface