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Abstract: Background. When treating patients with advanced non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors and chemotherapy, intercalated schedule with time separation between the two classes of drugs should avoid their mutual antagonism. In a survey of published trials, we focus on relation between eligibility criteria and effectiveness of intercalated treatment. Methods. Published documents were identified using major medical databases, conference proceedings and references of published trials. Median progression-free survival (PFS) was taken as the basic parameter of treatment efficacy. Correlation between characteristics of patients and median PFS was assessed through the Pearson%s correlation coefficient and the coefficient of determination, separately for first-line and second-line setting. Results. The series includes 11 single-arm trials and 18 randomized phase II or phase III trials with a total of 2903 patients. Treatment-naive patients or those in progression after first-line treatment were included in 16 and 13 trials, respectively. In 14 trials, only patients with non-squamous histology were eligible. Proportion of patients with nonsquamous carcinoma (in first-line setting), proportion of never-smokers (both in first- and second-line setting) and proportion of epidermal growth factor receptor (EGFR) mutant patients (both in first- and second-line setting) showed a moderate or strong correlation with median PFS. In six trials of intercalated treatment applied to treatment-naive EGFR%mutant patients, objective response was confirmed in 83.1% of cases and median PFS was 18.6 months. Conclusions. Most suitable candidates for intercalated treatment are treatment-naive patients with EGFR%mutant tumors, as determined from biopsy or liquid biopsy. For these patients, experience with intercalated treatment is most promising and randomized trials with comparison to the best standard treatment are warranted.
Keywords: lung cancer, NSCLC, intercalated treatment, EGFR, tyrosine -kinase inhibitors
Published in DiRROS: 31.05.2024; Views: 49; Downloads: 33
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Published in DiRROS: 28.10.2022; Views: 483; Downloads: 147
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Abstract: Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene (n = 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the major control serpin of the kallikrein–kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE. SERPING1 variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure–function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs (n = 25). Exonic variants (n = 6) can affect exon splicing. Rare deep-intron variants (n = 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (n = 74). This category includes some homozygous (n = 10) or compound heterozygous variants (n = 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from a de novo variant. Situations with paternal or maternal disomy have been recorded (n = 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any SERPING1 variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy.
Keywords: Hereditary angioedemas -- genetics -- diagnosis, genetic variation, serpins, SERPING1 gene, C1-INH, C1-INH-HAE, C1 inhibitor, serpinopathy
Published in DiRROS: 06.04.2022; Views: 913; Downloads: 539
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Abstract: Within the ROBOMINERS project an innovative technology for the future exploitation of small and difficult to access mineral deposits is being studied. The project has two main objectives. First, the development of a bioinspired reconfigurable robotic miner prototype, able to navigate, explore and mine selectively with a certain degree of autonomy. The robot-miner will be able to work under different conditions, making the exploitation of many mineral deposits economically feasible, while reducing social and environmental impacts associated with conventional mining methods. The second objective is the creation of a vision of a new mining ecosystem, its function, parts, research roadmaps and visions for years 2030 and 2050, including creation of novel ideas from other sectors, particularly robotics. The robotic ecosystem concept will be tested in representative sites across Europe with simulations, showcasing the different mining environments and conditions where it can be applied.
Keywords: avtonomni robot, rudniki, prospekcija, mineralne surovine
Published in DiRROS: 06.01.2021; Views: 1632; Downloads: 692
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