Intense debate surrounds the effects of post‐fire salvage logging (SL) versus nonintervention policies on forest regeneration, but scant support is available from experimental studies. We analyze the ...effect of three post‐fire management treatments on the recruitment of a serotinous pine (Pinus pinaster) at a Mediterranean mountain. Treatments were applied 7 months after the fire and differ in the degree of intervention, ranging from “no intervention” (NI, all trees left standing) to “partial cut plus lopping” (PCL, felling most of the trees, cutting the main branches, and leaving all the biomass in situ without mastication), and “SL” (felling and piling the logs, and masticating the woody debris). Seedling survival after 3 years was the highest in PCL (47.3% versus 38.7% in SL). This was associated with the amelioration of microclimatic conditions under the scattered branches, which reduced radiation and soil temperature while increasing soil moisture. Seedling density after 2 years was approximately 5.5 times higher in PCL than in SL, as in SL a large fraction of seedlings was lost as a consequence of mechanized mastication. The NI treatment showed the lowest seedling survival (17.3%). Nevertheless, seedling density was similar to SL. Seedling growth scarcely differed among treatments. Our results show that branches left onsite acted as nurse objects that improved key microclimatic conditions for seedling recruitment. This creates a facilitative interaction ideal for seedling establishment in moisture‐deficient ecosystems, as it provides the benefit of a shading overstory but without underground competition.
The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. ...We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response.
We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided.
We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval CI = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio HR = 3.02, 95% CI = 1.54 to 5.93, P = .001, and HR = 2.57, 95% CI = 1.30 to 5.09, P = .007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort.
Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.
This work presents the comparison of four advanced oxidation processes driven by UVC-LED radiation (278 nm—2 W/m2) for simultaneous bacteria inactivation (Escherichia coli—106 CFU/mL) and ...microcontaminant removal (imidacloprid—50 µg/L) in simulated wastewater secondary effluent. To this end, the activation of H2O2 and S2O82− as precursors of HO• and SO4•−, respectively, by UVC-LED and UVC-LED/Fe3+–NTA (ferric nitrilotriacetate at 0.1 mM) has been studied at different oxidant concentrations. For the purpose of comparison, conventional chlorination was used as the baseline along with bacterial regrowth 24 h after treatment. Disinfection was achieved within the first 30 min in all of the processes, mainly due to the bactericidal effect of UVC-LED radiation. UVC-LED/H2O2 did not substantially affect imidacloprid removal due to the low HO• generation by UVC irradiation at 278 nm, while more than 80% imidacloprid removal was achieved by the UVC-LED/S2O82−, UVC-LED/Fe3+–NTA/S2O82−, and UVC-LED/Fe3+–NTA/H2O2 processes. The most efficient concentration of both oxidants for the simultaneous disinfection and microcontaminant removal was 1.47 mM. Chlorination was the most effective treatment for bacterial inactivation without imidacloprid removal. These findings are relevant for scaling up UVC-LED photoreactors for tertiary wastewater treatment aimed at removing bacteria and microcontaminants.
Abstract
Background
Gene panel testing by massive parallel sequencing has increased the diagnostic yield but also the number of variants of uncertain significance. Clinical interpretation of genomic ...data requires expertise for each gene and disease. Heterozygous ATM pathogenic variants increase the risk of cancer, particularly breast cancer. For this reason, ATM is included in most hereditary cancer panels. It is a large gene, showing a high number of variants, most of them of uncertain significance. Hence, we initiated a collaborative effort to improve and standardize variant classification for the ATM gene.
Methods
Six independent laboratories collected information from 766 ATM variant carriers harboring 283 different variants. Data were submitted in a consensus template form, variant nomenclature and clinical information were curated, and monthly team conferences were established to review and adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria to ATM, which were used to classify 50 representative variants.
Results
Amid 283 different variants, 99 appeared more than once, 35 had differences in classification among laboratories. Refinement of ACMG/AMP criteria to ATM involved specification for twenty-one criteria and adjustment of strength for fourteen others. Afterwards, 50 variants carried by 254 index cases were classified with the established framework resulting in a consensus classification for all of them and a reduction in the number of variants of uncertain significance from 58% to 42%.
Conclusions
Our results highlight the relevance of data sharing and data curation by multidisciplinary experts to achieve improved variant classification that will eventually improve clinical management.
Establishing the pathogenic nature of variants in ATM, a gene associated with breast cancer and other hereditary cancers, is crucial for providing patients with adequate care. Unfortunately, ...achieving good variant classification is still difficult. To address this challenge, we extended the range of in silico tools with a series of graphical tools devised for the analysis of computational evidence by health care professionals. We propose a family of fast and easy-to-use graphical representations in which the impact of a variant is considered relative to other pathogenic and benign variants. To illustrate their value, the representations are applied to three problems in variant interpretation. The assessment of computational pathogenicity predictions showed that the graphics provide an intuitive view of prediction reliability, complementing and extending conventional numerical reliability indexes. When applied to variant of unknown significance populations, the representations shed light on the nature of these variants and can be used to prioritize variants of unknown significance for further studies. In a third application, the graphics were used to compare the two versions of the ATM-adapted American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, obtaining valuable information on their relative virtues and weaknesses. Finally, a server ATMision (ATM missense in silico interpretation online) was generated for users to apply these representations in their variant interpretation problems, to check the ATM-adapted guidelines' criteria for computational evidence on their variant(s) and access different sources of information.
Previous studies have shown that friendly environments are associated with well-being and higher quality of life in older people. This study aimed to investigate the relationship between friendly ...environments and subjective well-being by segmenting the population according to the need for help in performing activities of daily living (ADLs) in a representative sample of people over 55 years of age in the Basque Country (Spain) (n = 2760). To determine the predictive power of friendliness on subjective well-being, two separate linear regression models were obtained according to the need for help in ADLs. The results obtained show a greater explanatory power of the model in the case of people who required help. However, in the case of people who do not need help, subjective health had a greater weight in the predictions. This paper's findings support the greater importance of the characteristics of the physical and social environment, as people's functional status worsens, with friendliness being an explanatory factor for people's well-being as they age and their dependency increases.
Nowadays, chronic kidney disease (CKD) prevalence keeps increasing worldwide. The management of these patients usually requires renal replacement therapy (RRT). However, the complexity of patients' ...profiles comprises a great challenge to overcome. During the last decades, CKD units have been developed to offer multidisciplinary and coordinated attention to patients, helping in the decision‐making of the RRT. Nevertheless, there is a huge variability in the performance and organization of care practice, implying an existing necessity to homogenize the RRT modality chosen. We propose a test composed of two parts: one to be completed by the medical staff (to evaluate contraindications for the different RRT techniques) and another by the patient or nursing staff (to consider patients' preferences). In this sense, it would be possible to have a common and useful tool to complement patient education in RRT, as well as sharing decision‐making in the ACKD units taking into account patient preferences.
Pompe disease (PD) is a rare disorder caused by mutations in the acid alpha-glucosidase (GAA) gene. Most gene therapies (GT) partially rely on the cross-correction of unmodified cells through the ...uptake of the GAA enzyme secreted by corrected cells. In the present study, we generated isogenic murine GAA-KO cell lines resembling severe mutations from Pompe patients. All of the generated GAA-KO cells lacked GAA activity and presented an increased autophagy and increased glycogen content by means of myotube differentiation as well as the downregulation of mannose 6-phosphate receptors (CI-MPRs), validating them as models for PD. Additionally, different chimeric murine GAA proteins (IFG, IFLG and 2G) were designed with the aim to improve their therapeutic activity. Phenotypic rescue analyses using lentiviral vectors point to IFG chimera as the best candidate in restoring GAA activity, normalising the autophagic marker p62 and surface levels of CI-MPRs. Interestingly, in vivo administration of liver-directed AAVs expressing the chimeras further confirmed the good behaviour of IFG, achieving cross-correction in heart tissue. In summary, we generated different isogenic murine muscle cell lines mimicking the severe PD phenotype, as well as validating their applicability as preclinical models in order to reduce animal experimentation.
Advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (deletion in exon 19 or L858R) show an impressive progression-free survival of 14 ...months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. We hypothesized that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways.
We assessed the T790M mutation in pretreatment diagnostic specimens from 129 erlotinib-treated advanced NSCLC patients with EGFR mutations. The expression of eight genes and two proteins involved in DNA repair and four receptor tyrosine kinases was also examined.
The EGFR T790M mutation was observed in 45 of 129 patients (35%). Progression-free survival was 12 months in patients with and 18 months in patients without the T790M mutation (P = 0.05). Progression-free survival was 27 months in patients with low BRCA1 mRNA levels, 18 months in those with intermediate levels, and 10 months in those with high levels (P = 0.02). In the multivariate analysis, the presence of the T790M mutation (HR, 4.35; P = 0.001), intermediate BRCA1 levels (HR, 8.19; P < 0.0001), and high BRCA1 levels (HR, 8.46; P < 0.0001) emerged as markers of shorter progression-free survival.
Low BRCA1 levels neutralized the negative effect of the T790M mutation and were associated with longer progression-free survival to erlotinib. We advocate baseline assessment of the T790M mutation and BRCA1 expression to predict outcome and provide alternative individualized treatment to patients based on T790M mutations and BRCA1 expression.
Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90% disease-free survival at five years. ...However, some of these treatments do not have a specific cell target, damaging both cancerous and normal cells. Thus, HL survivors have a high risk of developing new primary cancers, both hematologic and solid tumors, which have been related to treatment. Several studies have shown that after treatment, HL patients and survivors present persistent chromosomal instability, including nonclonal chromosomal aberrations. The frequency and type of chromosomal abnormalities appear to depend on the type of therapy and the cell type examined. For example, MOPP chemotherapy affects hematopoietic and germ stem cells leading to long-term genotoxic effects and azoospermia, while ABVD chemotherapy affects transiently sperm cells, with most of the patients showing recovery of spermatogenesis. Both regimens have long-term effects in somatic cells, presenting nonclonal chromosomal aberrations and genomic chaos in a fraction of noncancerous cells. This is a source of karyotypic heterogeneity that could eventually generate a more stable population acquiring clonal chromosomal aberrations and leading towards the development of a new cancer.
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