Copper uptake, accumulation and physiological changes in adult grapevines in response to excess copper in soil.

Publicada online em 24 de setembro

An Exceptional Response to Dostarlimab in Mismatch Repair Deficient, Microsatellite Instability-High and Platinum Refractory Endometrial Cancer

Until recently, effective therapies for advanced endometrial cancer progressing to a platinum-based combination were lacking. In this setting, immunotherapy with anti PD-1/PDL-1 monoclonal antibodies is rising as a new paradigm in particular for patients with microsatellites instability/mismatch repair deficiency. In this case report, we describe an exceptional and rapid response to dostarlimab in a platinum refractory endometrial cancer patient with high disease burden harboring a mismatch repair deficiency

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

Most breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms-TargetScan and miRanda-to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ( P≤5×10-8 ) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3'-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and reinforce the role of miRNA-mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.Funding Agency Portuguese Foundation for Science and Technology CRESC ALGARVE 2020 European Union (EU) 303745 Maratona da Saude Award DL 57/2016/CP1361/CT0042 SFRH/BPD/99502/2014 CBMR-UID/BIM/04773/2013 POCI-01-0145-FEDER-022184info:eu-repo/semantics/publishedVersio

Use of phosphorus fertilization and mycorrhization as strategies for reducingcopper toxicity in young grapevines.

Established vineyard soils may have high copper (Cu) contents due to the ongoing foliar applications of copper-based fungicides. In viticulture, the replacement of old vineyards with new vines is common practice, however,limited by Cu excess in soil and its toxicity to young grapevines. The application of phosphorus (P) and ar-buscular mycorrhizal fungi (AMF) inoculation are potential strategies to reduce Cu toxicity to young grapevines.This study aimed to assess the effects of phosphorus fertilization and AMF (Rhizophagus clarus) inoculation ongrowth and physiological parameters of young grapevines grown in soil with high Cu content. The experimentwas conducted in a greenhouse, where natural grassland soil was artificially contaminated by the addition of60 mg kg−1Cu. The soils were treated with and without AMF inoculation, combined with additions of 0, 40 and100 mg P kg−1. After 90 days of cultivation, grapevine plants were assessed for chlorophyllafluorescence,photosynthetic pigment contents, superoxide dismutase (SOD) activity, plant height, plant biomass, and con-centrations of Cu and P in roots and shoots. Phosphorus fertilization promoted increases in seedling growth(related to the increase of total P concentration in roots and shoots), soluble Pi concentration in leaves, and thequantum yield of the PSII (YII) (associated with a reduction in shoot Cu concentration). The AMF inoculationincreased the concentration of P in roots and shoots, soluble Pi in leaves and electron transport rate (ETR).Phosphorus fertilization and inoculation of grapevines with AMF are strategies capable of reducing Cu toxicity inyoung grapevines

CDKN1B mutation and copy number variation are associated with tumor aggressiveness in luminal breast cancer

The CDKN1B gene, encoding for the CDK inhibitor p27kip1, is mutated in defined human cancer subtypes, including breast, prostate carcinomas and small intestine neuroendocrine tumors. Lessons learned from small intestine neuroendocrine tumors suggest that CDKN1B mutations could be subclonal, raising the question of whether a deeper sequencing approach could lead to the identification of higher numbers of patients with mutations. Here, we addressed this question and analyzed human cancer biopsies from breast (n = 396), ovarian (n = 110) and head and neck squamous carcinoma (n = 202) patients, using an ultra-deep sequencing approach. Notwithstanding this effort, the mutation rate of CDKN1B remained substantially aligned with values from the literature, showing that essentially only hormone receptor-positive breast cancer displayed CDKN1B mutations in a relevant number of cases (3%). However, the analysis of copy number variation showed that another fraction of luminal breast cancer displayed loss (8%) or gain (6%) of the CDKN1B gene, further reinforcing the idea that the function of p27kip1 is important in this type of tumor. Intriguingly, an enrichment for CDKN1B alterations was found in samples from premenopausal luminal breast cancer patients (n = 227, 4%) and in circulating cell-free DNA from metastatic luminal breast cancer patients (n = 59, 8.5%), suggesting that CDKN1B alterations could correlate with tumor aggressiveness and/or occur later during disease progression. Notably, many of the identified somatic mutations resulted in p27kip1 protein truncation, leading to loss of most of the protein or of its C-terminal domain. Using a gene-editing approach in a luminal breast cancer cell line, MCF-7, we observed that the expression of p27kip1 truncating mutants that lose the C-terminal domains failed to rescue most of the phenotypes induced by CDKN1B gene knockout, indicating that the functions retained by the C-terminal portion are critical for its role as an oncosuppressor, at least in luminal breast cancer. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

MicroRNA Fingerprints Identify miR-150 as a Plasma Prognostic Marker in Patients with Sepsis

BACKGROUND: The physiopathology of sepsis continues to be poorly understood, and despite recent advances in its management, sepsis is still a life-threatening condition with a poor outcome. If new diagnostic markers related to sepsis pathogenesis will be identified, new specific therapies might be developed and mortality reduced. Small regulatory non-coding RNAs, microRNAs (miRNAs), were recently linked to various diseases; the aim of our prospective study was to identify miRNAs that can differentiate patients with early-stage sepsis from healthy controls and to determine if miRNA levels correlate with the severity assessed by the Sequential Organ Failure Assessment (SOFA) score. METHODOLOGY/PRINCIPAL FINDINGS: By using genome-wide miRNA profiling by microarray in peripheral blood leukocytes, we found that miR-150, miR-182, miR-342-5p, and miR-486 expression profiles differentiated sepsis patients from healthy controls. We also proved by quantitative reverse transcription-polymerase chain reaction that miR-150 levels were significantly reduced in plasma samples of sepsis patients and correlated with the level of disease severity measured by the SOFA score, but were independent of the white blood counts (WBC). We found that plasma levels of tumor necrosis factor alpha, interleukin-10, and interleukin-18, all genes with sequence complementarity to miR-150, were negatively correlated with the plasma levels of this miRNA. Furthermore, we identified that the plasma levels ratio for miR-150/interleukin-18 can be used for assessing the severity of the sepsis. CONCLUSIONS/SIGNIFICANCE: We propose that miR-150 levels in both leukocytes and plasma correlate with the aggressiveness of sepsis and can be used as a marker of early sepsis. Furthermore, we envision miR-150 restoration as a future therapeutic option in sepsis patients

Chemical properties and protective effect of Rosmarinus officinalis: mitigation of lipid peroxidation and DNA-damage from arsenic exposure

Recent studies have implicated dietary factors in the cause and prevention of important diseases, with strong evidence that plant’s compounds can protect against these diseases. Moreover, food security and environmental contamination are topics in focus at the moment. In this view, contamination by arsenic (As) has received much attention as well as some spices with medicinal properties. Among these plants, the use of Rosmarinus officinalis L. has demonstrated antioxidant properties besides being used for circulatory disorders. Therefore, we measured the mitotic index of Allium cepa L. and characterized the antioxidant effects to determine the capacity of R. officinalis to ameliorate arsenic-induced DNA damage. R. officinalis extract showed no mutagenic effects and exhibited antimutagenic potential, reducing the DNA damage, anaphase-telophase briges and micronuclei chromosome aberrations that result from treatment with the arsenic. Additionally, reduction in arsenic- induced lipid peroxidation was also observed

Kinetic parameters govern of the uptake of nitrogen forms in "Paulsen" and "Magnolia" grapevine rootstocks.

Grapevine rootstocks are selected according to graft compatibility, pathogen tolerance and water stress. However, morphological and kinetic parameters of nutrient absorption, such as nitrate (NO3 −) and ammonium (NH4 +), usually are not considered. The study aimed to select, based on morphological and kinetic absorption parameters, grapevine rootstocks with greater efficiency of N-forms absorption. The study was performed with two grapevine rootstocks (?Paulsen 1103? and ?Magnolia?), grown in Hoagland nutrient solution in a greenhouse. After 21 d, they were placed in 0.05 mol L-1 CaSO4 solution for 20 d to exhaust nutrient internal reserves. The rootstock with highest NO3 − and NH4 + uptake efficiency was ?Paulsen 1103?, since it presented lower Cmin and Km values in the two N forms, allowing N extraction by roots, even in low concentrations in solution, due to the higher transporter affinity for NO3 − and NH4 + in roots from rootstock. ?Paulsen 1103? rootstock also presented better photosynthetic performance and root development, collaborating for greater growth and mass production than 'Magnolia' rootstock. On the other hand, ?Magnolia? rootstock showed higher NO3 − and NH4 + Cmin and Km values than ?Paulsen? rootstock, which shows lower transporters affinity for these ions. Results demonstrate the importance of the use of NO3 − and NH4 + uptake kinetic parameters in grapevine rootstock selection programs, since these may serve as indicator of plant's ability to absorb NO3 − and NH4 + in low concentrations