Clinical significance of TP53 alterations in advanced NSCLC patients treated with EGFR, ALK and ROS1 tyrosine kinase inhibitors: An update.

 The development of targeted therapies for non-small cell lung cancer (NSCLC), such as the epidermal growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and ROS proto-oncogene 1 (ROS1), has improved patients' prognosis and significantly extended progression-free survival. However, it remains unclear why some patients do not benefit from the treatment as much or have a rapid disease progression. It is considered that, apart from the oncogenic driver gene, molecular alterations in a number of caretaker and gatekeeper genes significantly impact the efficacy of targeted therapies. The tumor protein 53 (TP53) gene is one of the most frequently mutated genes in NSCLC. To date, numerous studies have investigated the influence of various TP53 alterations on patient prognosis and responsiveness to therapies targeting EGFR, ALK, or ROS1. This review focuses on the latest data concerning the role of TP53 alterations as prognostic and/or predictive biomarkers for EGFR, ALK, and ROS1 tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients. Since the presence of TP53 mutations in NSCLC has been linked to its decreased responsiveness to EGFR, ALK, and ROS1 targeted therapy in most of the referenced studies, the review also discusses the impact of TP53 mutations on treatment resistance. It seems plausible that assessing the TP53 mutation status could aid in patient stratification for optimal clinical decision-making. However, drawing meaningful conclusions about the clinical value of the TP53 co-mutations in EGFR-, ALK- or ROS1-positive NSCLC is hampered mainly by an insufficient knowledge regarding the functional consequences of the TP53 alterations. The integration of next-generation sequencing into the routine molecular diagnostics of cancer patients will facilitate the detection and identification of targetable genetic alterations along with co-occurring TP53 variants. This advancement holds the potential to accelerate understanding of the biological and clinical role of p53 in targeted therapies for NSCLC.

FGFR1-4 RNA-Based Gene Alteration and Expression Analysis in Squamous Non-Small Cell Lung Cancer.

While fibroblast growth factor receptors (FGFRs) are involved in several biological pathways and FGFR inhibitors may be useful in the treatment of squamous non-small cell lung cancer (Sq-NSCLC), FGFR aberrations are not well characterized in Sq-NSCLC. We comprehensively evaluated FGFR expression, fusions, and variants in 40 fresh-frozen primary Sq-NSCLC (stage IA3−IV) samples and tumor-adjacent normal tissues using real-time PCR and next-generation sequencing (NGS). Protein expression of FGFR1−3 and amplification of FGFR1 were also analyzed. FGFR1 and FGFR4 median gene expression was significantly (p < 0.001) decreased in tumors compared with normal tissue. Increased FGFR3 expression enhanced the recurrence risk (hazard ratio 4.72, p = 0.029), while high FGFR4 expression was associated with lymph node metastasis (p = 0.036). Enhanced FGFR1 gene expression was correlated with FGFR1 protein overexpression (r = 0.75, p = 0.0003), but not with FGFR1 amplification. NGS revealed known pathogenic FGFR2,3 variants, an FGFR3::TACC3 fusion, and a novel TACC1::FGFR1 fusion together with FGFR1,2 variants of uncertain significance not previously reported in Sq-NSCLC. These findings expand our knowledge of the Sq-NSCLC molecular background and show that combining different methods increases the rate of FGFR aberrations detection, which may improve patient selection for FGFRi treatment.

PROM1, CXCL8, RUNX1, NAV1 and TP73 genes as independent markers predictive of prognosis or response to treatment in two cohorts of high-grade serous ovarian cancer patients.

Considering the vast biological diversity and high mortality rate in high-grade ovarian cancers, identification of novel biomarkers, enabling precise diagnosis and effective, less aggravating treatment, is of paramount importance. Based on scientific literature data, we selected 80 cancer-related genes and evaluated their mRNA expression in 70 high-grade serous ovarian cancer (HGSOC) samples by Real-Time qPCR. The results were validated in an independent Northern American cohort of 85 HGSOC patients with publicly available NGS RNA-seq data. Detailed statistical analyses of our cohort with multivariate Cox and logistic regression models considering clinico-pathological data and different TP53 mutation statuses, revealed an altered expression of 49 genes to affect the prognosis and/or treatment response. Next, these genes were investigated in the validation cohort, to confirm the clinical significance of their expression alterations, and to identify genetic variants with an expected high or moderate impact on their products. The expression changes of five genes, PROM1, CXCL8, RUNX1, NAV1, TP73, were found to predict prognosis or response to treatment in both cohorts, depending on the TP53 mutation status. In addition, we revealed novel and confirmed known SNPs in these genes, and showed that SNPs in the PROM1 gene correlated with its elevated expression.

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer.

Fibroblast growth factor receptor (FGFR) inhibitors (FGFRis) are a potential therapeutic option for squamous non-small cell lung cancer (Sq-NSCLC). Because appropriate patient selection is needed for targeted therapy, molecular profiling is key to discovering candidate biomarker(s). Multiple FGFR aberrations are present in Sq-NSCLC tumors-alterations (mutations and fusions), amplification and mRNA/protein overexpression-but their predictive potential is unclear. Although FGFR1 amplification reliability was unsatisfactory, FGFR mRNA overexpression, mutations, and fusions are promising. However, currently their discriminatory power is insufficient, and the available clinical data are from small groups of Sq-NSCLC patients. Here, we focus on FGFR aberrations as predictive biomarkers for FGFR-targeting agents in Sq-NSCLC. Known and suggested molecular determinants of FGFRi resistance are also discussed.

Detection of EGFR mutations in liquid biopsy samples using allele-specific quantitative PCR: A comparative real-world evaluation of two popular diagnostic systems.

PURPOSE: The detection of epidermal growth factor receptor (EGFR) mutations in plasma cell-free DNA (cfDNA) is an auxiliary tool for the molecular diagnosis of non-small cell lung cancer (NSCLC), especially when an adequate tumor tissue specimen cannot be obtained. We compared the diagnostic accuracy of two commonly used in vitro diagnostic-certified allele-specific quantitative PCR assays for detecting plasma cfDNA EGFR mutations. METHODS: We analyzed EGFR mutations in plasma cfDNA from 90 NSCLC patients (stages I-IV) before treatment (n â€‹= â€‹60) and after clinical progression on EGFR tyrosine kinase inhibitors (n â€‹= â€‹30) using the cobas EGFR mutation test v2 (Roche Molecular Systems, Inc.) and therascreen EGFR Plasma RGQ PCR kit (Qiagen GmbH). RESULTS: There was higher concordance between plasma cfDNA and matched tumor tissue EGFR mutations with cobas (66.67%) compared with therascreen (55.93%). The concordance rate increased to 90.00% with cobas (Cohen's kappa coefficient, κ â€‹= â€‹0.80; p â€‹< â€‹0.0001) and 73.33% with therascreen (κ â€‹= â€‹0.49; p â€‹= â€‹0.0009) in advanced NSCLC patients. In treatment-naïve patients, cobas was superior to therascreen (sensitivity: 82.35% vs. 52.94%; specificity: 100% vs. 100%). In patients with clinical progression on EGFR tyrosine kinase inhibitors, EGFR exon 20 p.T790M was detected in 30% and 23% of cfDNA samples by cobas and therascreen, respectively. CONCLUSIONS: Cobas was superior to therascreen for detection of plasma EGFR mutations in advanced NSCLC. Plasma cfDNA EGFR mutation analysis is complex; therefore, the diagnostic accuracy of commercially available assays should be validated.

Relating Neuroticism to Emotional Exhaustion: A Dynamic Approach to Personality.

We build on a novel model of personality [PersDyn] that captures three sources of individual differences (here applied to neuroticism): (1) one's baseline level of behavior, affect, and cognitions (baseline); (2) the extent to which people experience different neuroticism levels (variability); and (3) the swiftness with which they return to their neuroticism baseline once they deviated from it (attractor strength). To illustrate the model, we apply the PersDyn model to the study of the relationship between neuroticism and emotional exhaustion. In the first study, we conducted a 5-day experience sampling study on 89 employees who reported on their level of state neuroticism six times per day. We found that higher levels of baseline neuroticism and variability were related to increased emotional exhaustion. Furthermore, we found an interaction effect between baseline and attractor strength: people with a high baseline and high attractor strength tend to experience a high degree of emotional exhaustion, whereas people with low levels of baseline neuroticism are less likely to suffer from exhaustion if their attractor strength is high. In the second study, we conducted a laboratory experiment on 163 participants, in which we manipulated state neuroticism via short movie clips. Although the PersDyn parameters were not related to post-experiment emotional exhaustion, the interaction effect between baseline and attractor strength was replicated. It is concluded that a dynamic approach to neuroticism is important in understanding emotional exhaustion.

Clinical importance of FANCD2, BRIP1, BRCA1, BRCA2 and FANCF expression in ovarian carcinomas.

OBJECTIVE: DNA repair pathways are potential targets of molecular therapy in cancer patients. The FANCD2, BRIP1, BRCA1/2, and FANCF genes are involved in homologous recombination DNA repair, which implicates their possible role in cell response to DNA-damaging agents. We evaluated a clinical significance of pre-treatment expression of these genes at mRNA level in 99 primary, advanced-stage ovarian carcinomas from patients, who later received taxane-platinum (TP) or platinum-cyclophosphamide (PC) treatment. METHODS: Gene expression was determined with the use of Real-Time PCR. The BRCA2 and BRIP1 gene sequence was investigated with the use of SSCP, dHPLC, and PCR-sequencing. RESULTS: Increased FANCD2 expression occurred to be a negative prognostic factor for all patients (PC+TP:HR 3.85, p = 0.0003 for the risk of recurrence; HR 1.96, p = 0.02 for the risk of death), and this association was even stronger in the TP-treated group (HR 6.7, p = 0.0002 and HR 2.33, p = 0.01, respectively). Elevated BRIP1 expression was the only unfavorable molecular factor in the PC-treated patients (HR 8.37, p = 0.02 for the risk of recurrence). Additionally, an increased FANCD2 and BRCA1/2 expression levels were associated with poor ovarian cancer outcome in either TP53-positive or -negative subgroups of the TP-treated patients, however these groups were small. Sequence analysis identified one protein truncating variant (1/99) in BRCA2 and no mutations (0/56) in BRIP1. CONCLUSIONS: Our study shows for the first time that FANCD2 overexpression is a strong negative prognostic factor in ovarian cancer, particularly in patients treated with TP regimen. Moreover, increased mRNA level of the BRIP1 is a negative prognostic factor in the PC-treated patients. Next, changes in the BRCA2 and BRIP1 genes are rare and together with other analyzed FA genes considered as homologous recombination deficiency may not affect the expression level of analyzed genes.

Clinical importance of the EMSY gene expression and polymorphisms in ovarian cancer.

EMSY, a BRCA2-associated protein, is amplified and overexpressed in various sporadic cancers. This is the first study assessing the clinical impact of its expression and polymorphisms on ovarian cancer (OvCa) outcome in the context of the chemotherapy regimen used. In 134 frozen OvCa samples, we assessed EMSY mRNA expression with Reverse Transcription-quantitative PCR, and also investigated the EMSY gene sequence using SSCP and/or PCR-sequencing. Clinical relevance of changes in EMSY mRNA expression and DNA sequence was evaluated in two subgroups treated with either taxane/platinum (TP, n=102) or platinum/cyclophosphamide (PC, n=32). High EMSY expression negatively affected overall survival (OS), disease-free survival (DFS) and sensitivity to treatment (PS) in the TP-treated subgroup (p-values: 0.001, 0.002 and 0.010, respectively). Accordingly, our OvCa cell line studies showed that the EMSY gene knockdown sensitized A2780 and IGROV1 cells to paclitaxel. Interestingly, EMSY mRNA expression in surviving cells was similar as in the control cells. Additionally, we identified 24 sequence alterations in the EMSY gene, including the previously undescribed: c.720G>C, p.(Lys240Asn); c.1860G>A, p.(Lys620Lys); c.246-76A>G; c.421+68A>C. In the PC-treated subgroup, a heterozygous genotype comprising five SNPs (rs4300410, rs3814711, rs4245443, rs2508740, rs2513523) negatively correlated with OS (p-value=0.009). The same SNPs exhibited adverse borderline associations with PS in the TP-treated subgroup. This is the first study providing evidence that high EMSY mRNA expression is a negative prognostic and predictive factor in OvCa patients treated with TP, and that the clinical outcome may hinge on certain SNPs in the EMSY gene as well.

Asháninka Palm Management and Domestication in the Peruvian Amazon.

Palms are a natural resource that has been abundantly used by Amerindians for centuries. Only a few palm domestications have been reported in the American tropics, where there is great diversity of the Arecaceae family. We report the results of a survey combining ethnobotanical and ecological methods to study the past and present management and distribution of palms by the Asháninka indigenous people from the Tambo river region in the Peruvian Amazon. Our objectives were to document palm-related traditional ecological knowledge, to examine correlation between palm abundance and Asháninka management practices and social exchange of palm resources, and to address the question of how the Asháninka have modified palm diversity and distribution in their territory. We found that most palm species have multiple uses; the most intensively managed were palms that provide thatch, notably Attalea phalerata, Oenocarpus mapora and Phytelephas macrocarpa. Of these, Attalea phalerata was the most commonly cultivated and was found only in cultivated stands. Our results have implications for understanding the domestication of Attalea weberbaueri, which is a landrace within the Attalea phalerata complex. A closer understanding of this process would require morphometric and genetic methods to compare wild and managed populations.

Germline SMARCA4 mutations in patients with ovarian small cell carcinoma of hypercalcemic type.

BACKGROUND: SMARCA4 mutations have recently been identified as driving lesions of the ovarian small cell carcinoma of hypercalcemic type (SCCHT). Familial occurrence of this neoplasm was described previously. METHODS: We looked for germline SMARCA4 alterations in eight patients with the SCCHT. DNA was extracted from probands' and their relatives' blood. The SMARCA4 coding sequence, previously found altered in all the tumors, was PCR amplified and sequenced in the germline DNA. RESULTS: Two patients carried a heterozygous germline SMARCA4 alteration: c.3760G > T and c.2352insG, respectively. The analysis of the probands' next of kins revealed that the c.3760G > T mutation was inherited by the proband and her sister from their father, and the sisters' four children also carried the mutation. The proband's sister was diagnosed with a carcinoma of the parotid gland at age 2. A brother of the other proband was tested negative. CONCLUSIONS: Our study suggests that some women develop the ovarian SCCHT due to the inherited or possibly de novo-occurring germline alterations in the SMARCA4 gene, however, its penetrance appears limited. Nevertheless, because of high aggressiveness of the SCCHT, a molecular diagnostics of the SMARCA4 gene and careful follow-up should be offered to patients with this cancer and their families.

Size asymmetric hard spheres as a convenient model for the capacitance of the electrical double layer of an ionic liquid.

Even though ionic liquids are composed of nonspherical ions, it is shown here that the general features of the capacitance of an electrical double layer can be obtained using a charged hard sphere model. We have shown in our earlier studies that at high electrolyte concentrations or large magnitudes of the electrode charge density the fact that the ions have a finite size, and are not point ions, cause the capacitance near the potential of zero charge to increase and change from a minimum to a maximum as the ionic concentration is increased and to decrease as the magnitude of the electrode charge density increases. Here, we show that the asymmetry of the capacitance of an ionic liquid can be explained qualitatively by using spherical ions of different size without attempting to introduce the ionic shape in a detailed manner. This means that the general features of the capacitance of the double layer of an ionic liquid can be studied without using a complex model, although the study of the density or charge profiles of an ionic fluid would require one. However, this is often unnecessary in the analysis of many experiments.

Palmeras usadas por los indígenas asháninkas en la Amazonía Peruana / Palm trees used by the indigenous ashaninkas in the Peruvian Amazon

El presente artículo muestra el conocimiento e importancia de las palmeras en la vida de los nativos Asháninkas. Presentamos una descripción cualitativa y cuantitativa de 32 entrevistas, obtenidos durante la visita a siete comunidades nativas ubicadas en los márgenes de los ríos Perené y Tambo en el departamento Junín, Perú. Registramos 15 especies de palmeras usadas por los Asháninkas, agrupadas bajo cinco categorías de uso: alimenticio, construcción, herramienta, ornamental y medicinal. Las especies con usos más amplios son: Attalea phalerata, Bactris gasipaes, Oenocarpus bataua y Socratea exorhiza. Las partes de las palmeras más utilizadas son los frutos, principalmente gracias a su valor comestible. La cercanía de las comunidades Asháninkas del valle del Perené a ciudades, influirían en un cambio en el tipo de vida tradicional, donde las palmeras son los más importantes recursos naturales utilizados por ellos. Sin embargo, en las comunidades del valle Tambo la vida tradicional, el conocimiento y practica en el uso de las palmeras esta aún vital.

American palm ethnomedicine: a meta-analysis.

BACKGROUND: Many recent papers have documented the phytochemical and pharmacological bases for the use of palms (Arecaceae) in ethnomedicine. Early publications were based almost entirely on interviews that solicited local knowledge. More recently, ethnobotanically guided searches for new medicinal plants have proven more successful than random sampling for identifying plants that contain biodynamic ingredients. However, limited laboratory time and the high cost of clinical trials make it difficult to test all potential medicinal plants in the search for new drug candidates. The purpose of this study was to summarize and analyze previous studies on the medicinal uses of American palms in order to narrow down the search for new palm-derived medicines. METHODS: Relevant literature was surveyed and data was extracted and organized into medicinal use categories. We focused on more recent literature than that considered in a review published 25 years ago. We included phytochemical and pharmacological research that explored the importance of American palms in ethnomedicine. RESULTS: Of 730 species of American palms, we found evidence that 106 species had known medicinal uses, ranging from treatments for diabetes and leishmaniasis to prostatic hyperplasia. Thus, the number of American palm species with known uses had increased from 48 to 106 over the last quarter of a century. Furthermore, the pharmacological bases for many of the effects are now understood. CONCLUSIONS: Palms are important in American ethnomedicine. Some, like Serenoa repens and Roystonea regia, are the sources of drugs that have been approved for medicinal uses. In contrast, recent ethnopharmacological studies suggested that many of the reported uses of several other palms do not appear to have a strong physiological basis. This study has provided a useful assessment of the ethnobotanical and pharmacological data available on palms.

American palms used for medicine, in the ethnobotanical and pharmacological publications

The center of diversity of palms (Arecaceae) in tropical America is found in the Amazon basin and along the Panamanian isthmus. The greatest palm species richness has been reported for the Iquitos and Choco areas. Many species of palms are used mainly for construction and due to their edible fruits. In addition, there are 104 palms species that are used for medicinal purposes in many regions of the Americas. Cocos nucifera and Oenocarpus bataua are the most commonly used species for medicinal purposes. The fruit is the most commonly used part of palms for medicinal purposes (57 species). The traditional and medicinal use of plants has deep roots in the indigenous communities of Latin America. The significance of ethnomedicine for health care of local populations can not be ignored anymore because it plays a significant role in basic health care in developing countries. Interdisciplinary research in anthropology, ethnobotany and ethnopharmacology helps gather information on ethnomedicine and desing new drugs for modern medicine. American palms are sources of useful bioactive compounds against diabetes, prostate hyperplasia and leishmaniasis.

El centro de la diversidad de palmeras (Arecaceae) en América tropical se encuentra en la cuenca del Amazonas y a lo largo del istmo de Panamá. La mayor riqueza de especies de palmeras ha sido registrada para las áreas de Iquitos y de Chocó. Numerosas especies de palmeras son útiles, principalmente en la construcción y por sus frutos comestibles. Adicionalmente, 104 especies de palmeras neotropicales han sido reportadas con aplicaciones medicinales en muchas regiones de América. Cocos nucifera y Oenocarpus bataua, son las especies más utilizadas como medicinales. Los frutos, son la parte de la palmera de mayor uso con fines medicinales (57 especies). El uso tradicional y medicinal de plantas, tiene raíces profundas no sólo en comunidades indígenas de Latinoamérica, sino que es practicado en gran parte de la sociedad. El significado de la etnomedicina para la asistencia médica de las poblaciones locales no puede seguir siendo ignorado, porque la etnomedicina juega un papel significativo en la asistencia médica básica en los países en desarrollo. Investigaciones interdisciplinarias, antropológicas, etnobotánicas y etnofarmacológicas ayudan a brindar información sobre etnomedicina y diseñar nuevas drogas para la medicina moderna. Las palmeras americanas son fuentes de compuestos bioactivos útiles que pueden ser usados contra la diabetes, la hiperplasia de la próstata y la leishmaniasis entre otros.