One of the greatest challenges facing humanity is the development of sustainable strategies to ensure food availability in response to population growth and climate change. One approach that can ...contribute to increase food security is to close yield gaps and enhancing genetic gain; to such end, what is known as “molecular breeding” plays a fundamental role. Since a crop breeding program is mainly based on the quality of the germplasm, its detailed genetic characterization is mandatory to ensure the efficient use of genetic resources and accelerating development of superior varieties. Deep genotyping is an essential tool for a comprehensive characterization of the germplasm of interest and, fortunately, the technology is now accessible at a reasonable cost. What must be ensured is the correct interpretation of the genotypic information and on that basis develop efficient practical molecular crop breeding strategies that respond to the real needs of the breeding program.
Key words: breeding population, genetic resources, marker assisted selection, Single Nucleotide Polymorphism (SNP)
Even when conventional breeding was effective in achieving a continuous improvement in yield, Molecular Genetics tools applied in plant breeding contributed to maximize genetic gain. Thus, the use of ...DNA technology applied in agronomic improvement gave rise to Molecular Breeding, discipline which groups the different breeding strategies where genotypic selection, based on DNA markers, are used in combination with or in replacement of phenotypic selection. These strategies can be listed as: marker-assisted selection; marker-assisted backcrossing; marker assisted recurrent selection; and genomic selection. Strong arguments have been made about the potential advantages that Molecular Breeding brings, although little has been devoted to discussing its feasibility in practical applications. The consequence of the lack of a deep analysis when implementing a strategy of Molecular Breeding is its failure, leading to many undesirable outcomes and discouraging breeders from using the technology. The aim of this work is to trigger a debate about the convenience of the use of Molecular Breeding strategies in a breeding program considering the DNA technology of choice, the complexity of the trait of agronomic interest to be improved, the expected accuracy in the selection, and the demanded resources.
The aim of the present study was to evaluate the effect of the hydroxyethyl-methacrylate (HEMA) concentration and solvent content of dental adhesives on cell viability and cytokine (IL-1b, IL-6, ...IL-10, TNF-α) release by human dental pulp cells (HDPCs). HDPCs were obtained from fresh extracted human third molars. Experimental adhesives were prepared containing different concentrations of HEMA (0%, 10%, and 20%) with and without solvent (ethanol 10%). Cylindrical specimens were immersed on culture medium during 24 h to obtain the extracts. The cells were incubated with extracts (culture medium + components leached from the adhesives) of different adhesives, and cell viability and cytokine release were evaluated after 6 and 24 h of exposure. Adhesives containing HEMA promoted high cell viability reduction after 6 h of exposure; but after 24 h, the results were similar to the ones found among control group cells. These effects on cell viability were prominently increased with the addition of solvent. Although IL-1b release was not affected by exposure to eluates, other cytokines (IL-10, IL-6, TNF-α) were modulated by the different experiment conditions, directly influenced by the HEMA concentration and presence of solvent. Higher HEMA concentrations, combined with the presence of solvent, can promote significant reduction on HDPC viability, increasing the release of anti- and pro-inflammatory mediators.
Purpose
HER2-low breast cancer (BC) is a novel entity with relevant therapeutic implications, especially in hormone receptor (HR) positive BC. This study examines whether HER2 mRNA through the ...21-gene assay, Oncotype DX (ODX), can refine the diagnosis of HER2-low and HER2-
zero
, obtained by immunohistochemistry (IHC).
Methods
Between Jan 2021 and Jan 2023, 229 consecutive HR-positive HER2-negative early BC (T1-3 N0-1) have been characterised by IHC and ODX. HER2 status by IHC was either zero (IHC-0) or low (IHC-1 + and IHC-2 + /ISH-negative) while HER2-zero was further divided into HER2-null (IHC-0) and HER2-ultralow (IHC-1–10%). HER2 gene expression by ODX was negative if lower 10.7.
Results
The distribution of HER2 IHC was as follows: 53.3% HER2-0, 29.25% HER2-1 + , and 17.5% HER2-2 + . The clinicopathological characteristics were similar in the three groups, with higher PgR-negative rate in HER2-zero (13.9% vs 3% vs 5%). The distribution of RS was homogeneous in the three groups with the median HER2 gene expression of 9.20 IQR: 8.70–9.60. HER2 gene expression gradually increased as the IHC score, with substantial overlap. After adjusting for confounders, HER2-1 + and HER2 2 + had a significant positive correlation between HER2 gene expression and IHC OR 1.42, 95% CI 1.21 to 1.68,
p
< 0.001; OR 1.96, 95% CI 1.61 to 2.37,
p
< 0.001 compared to the HER2-
zero
group. HER2 gene expression did not differ between HER2-null and HER2-ultralow subgroups.
Conclusion
Due to the substantial overlap, the HER2 gene expression is unable to properly distinguish HER2-low and HER2-
zero
IHC whose accurate identification is critical in the context of HER2-negative BC.
Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening ...arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers.
In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib.
A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias.
These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.
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•A careflow mining approach designed to analyze heterogeneous longitudinal data is proposed.•Temporal electronic phenotyping of EHR and billing data is performed.•Better insights on ...the health care processes of breast cancer patients are obtained.
In this work we present a careflow mining approach designed to analyze heterogeneous longitudinal data and to identify phenotypes in a patient cohort. The main idea underlying our approach is to combine methods derived from sequential pattern mining and temporal data mining to derive frequent healthcare histories (careflows) in a population of patients. This approach was applied to an integrated data repository containing clinical and administrative data of more than 4000 breast cancer patients. We used the mined histories to identify sub-cohorts of patients grouped according to healthcare activities pathways, then we characterized these sub-cohorts with clinical data. In this way, we were able to perform temporal electronic phenotyping of electronic health records (EHR) data.
AurkA overexpression was previously found in breast cancer and associated to its ability in controlling chromosome segregation during mitosis, however whether it may affect breast cancer cells, ...endorsed with stem properties (BCICs), is still unclear. Surprisingly, a strong correlation between AurkA expression and β-catenin localization in breast cancer tissues suggested a link between AurkA and Wnt signaling. In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells. As a consequence, the amount of BCICs and their migratory capability dramatically decreased. Conversely, wnt3a mRNA stabilization and increased CD44(+)/CD24(low/-) subpopulation was found in AurkA-overexpressing MCF7 cells. In vivo, AurkA-overexpressing primary breast cancer cells showed higher tumorigenic properties. Interestingly, we found that AurkA suppressed the expression of miR-128, inhibitor of wnt3a mRNA stabilization. Namely, miR-128 suppression realized after AurkA binding to Snail. Remarkably, a strong correlation between AurkA and miR-128 expression in breast cancer tissues confirmed our findings. This study provides novel insights into an undisclosed role for the kinase AurkA in self-renewal and migration of BCICs affecting response to cancer therapies, metastatic spread and recurrence. In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.
Hormone-receptor positive (HR+), Human-Epidermal-growth Factor negative (HER2-) breast cancer, including the Luminal A and the Luminal B subtypes, is the most common in women diagnosed with ...early-stage BC. Despite the advances in screening, surgery and therapies, recurrence still occurs. Therefore, it is important to identify early those factors that significantly impact the recurrence risk. Based on current evidence and their professional expertise, a Panel of oncologists discussed the definition of high risk of recurrence in early breast cancer. Histological grade, nodal involvement, genomic score, histological grade, tumor size, and Ki-67 proliferation index were rated as the most important factors to define the high risk in patients with early breast cancer. All these factors should be considered comprehensively to tailor the choice of treatment to the peculiar characteristics of each patient.
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•Recurrence still occurs in early HR+ HER2- breast cancer.•Determination of recurrence risk is required to optimize the therapeutic approach.•Histological grade and nodal involvement are the most important factors.•Genomic score, Ki-67, and tumor size are also relevant to define the risk.
The majority of patients with stage III–IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in ...drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S).
Matched biopsies (33) taken at Ft-S and Sd-S were selected from the ‘Pandora’ tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated.
A total of 2270 somatic mutations were identified (89.85% base substitutions 8.19% indels, and 1.92% unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction.
There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.
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