The estrogen receptor (ER) is a well-known predictor of breast cancer response to endocrine therapy. ER+ progesterone receptor (PR)− breast tumors have a poorer response to endocrine therapy and a ...more aggressive phenotype than ER+PR+ tumors. A comparative genomic hybridization array technique was used to examine 25 ER+PR+ and 23 ER+PR− tumors. Tissue microarrays composed of 50 ER+PR+ and 50 ER+PR− tumors were developed to validate the comparative genomic hybridization array results. The genes of interest were analyzed by fluorescence in situ hybridization. The ER+PR− group had a slightly different genomic profile when compared with ER+PR+ tumors. Chromosomes 17 and 20 contained the most overlapping gains, and chromosomes 3, 8, 9, 14, 17, 21, and 22 contained the most overlapping losses when compared with the ER+PR+ group. The gained regions, 17q23.2-q23.3 and 20q13.12, and the lost regions, 3p21.32-p12.3, 9pter-p13.2, 17pter-p12, and 21pter-q21.1, occurred at different alteration frequencies and were statistically significant in the ER+PR− tumors compared with the ER+PR+ tumors. ER+PR− breast tumors have a different genomic profile compared with ER+PR+ tumors. Differentially lost regions in the ER+PR− group included genes with tumor suppressor functions and genes involved in apoptosis, mitosis, angiogenesis, and cell spreading. Differentially gained regions included genes such as MAP3K3 , RPS6KB1 , and ZNF217. Amplification of these genes could contribute to resistance to apoptosis, increased activation of the PI3K/Akt/mTOR pathway, and the loss of PR in at least some ER+PR− tumors.
Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or ...sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells.
Background
Information on vaccine effectiveness in a context of novel variants of concern (VOC) emergence is of key importance to inform public health policies. This study aimed to estimate a measure ...of comparative vaccine effectiveness between Omicron (BA.1) and Delta (B.1.617.2 and sub‐lineages) VOC according to vaccination exposure (primary or booster).
Methods
We developed a case–case study using data on RT‐PCR SARS‐CoV‐2‐positive cases notified in Portugal during Weeks 49–51, 2021. To obtain measure of comparative vaccine effectiveness, we compared the odds of vaccination in Omicron cases versus Delta using logistic regression adjusted for age group, sex, region, week of diagnosis, and laboratory of origin.
Results
Higher odds of vaccination were observed in cases infected by Omicron VOC compared with Delta VOC cases for both complete primary vaccination (odds ratio OR = 2.1; 95% confidence interval CI: 1.8 to 2.4) and booster dose (OR = 5.2; 95% CI: 3.1 to 8.8), equivalent to reduction of vaccine effectiveness from 44.7% and 92.8%, observed against infection with Delta, to −6.0% (95% CI: 29.2% to 12.7%) and 62.7% (95% CI: 35.7% to 77.9%), observed against infection with Omicron, for complete primary vaccination and booster dose, respectively.
Conclusion
Consistent reduction in vaccine‐induced protection against infection with Omicron was observed. Complete primary vaccination may not be protective against SARS‐CoV‐2 infection in regions where Omicron variant is dominant.
BackgroundPatients with brain metastases (BM) live longer due to improved diagnosis and oncologic treatments. The association of volumetric modulated arc therapy (VMAT) and image-guided radiation ...therapy (IGRT) with brain radiosurgery (SRS) allows complex dose distributions and faster treatment delivery to multiple lesions. Materials and methodsThis study is a retrospective analysis of SRS for brain metastasis using VMAT. The primary endpoints were local disease-free survival (LDFS) and overall survival (OS). The secondary outcomes were intracranial disease-free survival (IDFS) and meningeal disease-free survival (MDFS). ResultsThe average number of treated lesions was 5.79 (range: 2-20) per treatment in a total of 113 patients. The mean prescribed dose was 18 Gy (range: 12-24 Gy). The median LDFS was 46 months. The LDFS in 6, 12, and 24 months was for 86%, 79%, and 63%, respectively. Moreover, brain progression occurred in 50 patients. The median overall survival was 47 months. The OS in 75%, 69%, and 61% patients was 6, 12, and 24 months, respectively. IDFS was 6 and 24 months in 35% and 14% patients, respectively. The mean MDFS was 62 months; it was 6 and 24 months for 87% and 83% of patients. Acute severe toxicity was relatively rare. During follow-up, the rates of radionecrosis and neurocognitive impairment were low (10%). ConclusionThe use of VMAT-SRS for multiple BM was feasible, effective, and associated with low treatment-related toxicity rates. Thus, treatment with VMAT is a safe technique to plan to achieve local control without toxicity.
Intrinsic and acquired resistance to conventional and targeted therapeutics is a fundamental reason for treatment failure in many cancer patients. Targeted approaches to overcome chemoresistance as ...well as resistance to targeted approaches require in depth understanding of the underlying molecular mechanisms. The anti-cancer activity of a drug can be limited by a broad variety of molecular events at different levels of drug action in a cell-autonomous and non-cell-autonomous manner. This review summarizes recent insights into the adaptive mechanisms used by tumours to resist therapy including cellular phenotypic plasticity, dynamic alterations of the tumour microenvironment, activation of redundant signal transduction pathways, modulation of drug target expression levels, and exploitation of pro-survival responses.
Intrinsic and acquired resistance to conventional and targeted therapeutics is a fundamental reason for treatment failure in many cancer patients.
The present study is focused on the ultrafast and green synthesis, via the co-precipitation method, of magnetic nanoparticles (MNPs) based on iron oxides using design of experiments (DOE) and high ...energy sonochemical approach, considering two main factors: amplitude (energy) of the ultrasound probe and sonication time. The combination of these techniques allowed the development of a novel one-minute green synthesis, which drastically reduced the amount of consumed energy, solvents, reagents, time and produced residues. This green sonochemical synthesis permitted to obtain mean particle sizes of 11 ± 2 nm under the optimized conditions of amplitude = 40% (2826 J) and time = 1 min. Their composition, structure, size, morphology and magnetic properties were assessed through X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), scanning and transmission electron microscopy (SEM & TEM), and vibrating sample magnetometry (VSM). The characterization results indicate the proper formation of MNPs, and the correct functionalization of MNPs with different coating agents. The functionalized MNPs were used as: i) biosensor, which could detect mercury in water in the range of 0.030–0.060 ppm, and ii) support onto which polyclonal antibodies were anchored and successfully bound to an osteosarcoma cell line expressing the target protein (TRIB2-GFP), as part of an immunoprecipitation assay.
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•MNPs synthesis via co-precipitation methodology was enhanced by DOE and high energy ultrasound.•A one-minute, green and reproducible synthesis was developed obtaining 11 ± 2 nm MNPs.•Composition, size, morphology and magnetic properties suggested MNPS proper formation.•MNPs were functionalized with several coverages.•MNPs proved their usefulness in the environmental field and biomedical sciences.
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