Why we should take care of the competing risk bias in survival analysis: A phase II trial on the toxicity profile of radiotherapy for prostate cancer

AimThe aim of the present study is to evaluate and quantify the bias of competing risks in an Italian oncologic cohort comparing results from different statistical analysis methods.BackgroundCompeting risks are very common in randomized clinical trials and observational studies, in particular oncology and radiotherapy ones, and their inappropriate management causes results distortions widely present in clinical scientific articles.Materials and methodsThis is a single-institution phase II trial including 41 patients affected by prostate cancer and undergoing radiotherapy (IMRT-SIB) at the University Hospital of Udine.Different outcomes were considered: late toxicities, relapse, death.Death in the absence of relapse or late toxicity was considered as a competing event.ResultsThe Kaplan Meier method, compared to cumulative incidence function method, overestimated the probability of the event of interest (toxicity and biochemical relapse) and of the competing event (death without toxicity/relapse) by 9.36%. The log-rank test, compared to Gray's test, overestimated the probability of the event of interest by 5.26%.The Hazard Ratio's and cause specific hazard's Cox regression are not directly comparable to subdistribution hazard's Fine and Gray's modified Cox regression; nonetheless, the FG model, the best choice for prognostic studies with competing risks, found significant associations not emerging with Cox regression.ConclusionsThis study confirms that using inappropriate statistical methods produces a 10% overestimation in results, as described in the literature, and highlights the importance of taking into account the competing risks bias.     

A global review and meta-analysis of applications of the freshwater Fish Invasiveness Screening Kit

Reviews in Fish Biology and Fisheries - The freshwater Fish Invasiveness Screening Kit (FISK) has been applied in 35 risk assessment areas in 45 countries across the six inhabited continents (11...     

Conomarphins cause paralysis in mollusk: Critical and tunable structural elements for bioactivity

Two conomarphins were purified as the major component of the venom of Conus eburneus. Conomarphins Eb1 and Eb2 showed biological activity in the mollusk Pomacea padulosa, causing sluggishness and retraction of siphon, foot, and cephalic tentacles. To further probe the effects of conserved amino acids and posttranslational modifications in conomarphins, we prepared four synthetic analogues: conomarphin Eb1 Hyp10Pro, Hyp10Ala, d ‐Phe13Ala, and l ‐Phe13 variants. Structure‐activity relationship analysis indicated that d ‐Phe13 is critical to the biological activity of conomarphins. In contrast, amino acid changes at position 10 and removal of posttranslational modification in Hyp10Pro can be tolerated. The high expression level and observed mollusk activity of conomarphins may suggest their potential role as defensive arsenal of Conoidean snails against other predatory gastropods.     

Gastrulation of Gastrotheca riobambae in comparison with other frogs

Blastopore formation, the embryonic disk, archenteron and notochord elongation, and Brachyury expression in the marsupial frog Gastrotheca riobambae was compared with embryos of Xenopus laevis and of the dendrobatids Colostethus machalilla and Epipedobates anthonyi. In contrast with X. laevis embryos, the blastopore closes before elongation of the archenteron and notochord in the embryos of G. riobambae and of the dendrobatid frogs. Moreover, the circumblastoporal collar (CBC) thickens due to the accumulation of involuted cells. An embryonic disk, however, is formed only in the G. riobambae gastrula. We differentiate three gastrulation patterns according to the speed of development: In X. laevis, elongation of the archenteron and notochord begin in the early to mid gastrula, whereas in the dendrobatids C. machalilla and E. anthonyi the archenteron elongates at mid gastrula and the notochord elongates after gastrulation. In G. riobambae, only involution takes place during gastrulation. Archenteron and notochord elongation occur in the post gastrula. In the non-aquatic reproducing frogs, the margin of the archenteron expands anisotropically, resulting in an apparent displacement of the CBC from a medial to a posterior location, resembling the displacement of Hensen's node in the chick and mouse. The differences detected indicate that amphibian gastrulation is modular.     

Base damage and single-strand break repair: mechanisms and functional significance of short- and long-patch repair subpathways

A large variety of DNA lesions induced by environmental agents or arising as an outcome of cellular metabolism are counteracted by a complex network of proteins that belong to the base excision repair/single strand break repair (BER/SSBR) processes. No matter whether the initial lesions are modified DNA bases or single-strand breaks with non-conventional termini these processes are completed either by replacement of a single (short-patch, SP) or more (long-patch, LP) nucleotides by different arrays of proteins. Here, the factors that are involved in the selection between SP- and LP-BER/SSBR are reviewed. The biological significance of these alternative subpathways is also presented as inferred from mutant mouse/cell models.     

Fas-negative osteosarcoma tumor cells are selected during metastasis to the lungs: the role of the Fas pathway in the metastatic process of osteosarcoma

Low expression of Fas by different tumors including osteosarcoma, correlates with poor prognosis. We found that osteosarcoma lung metastases from patients expressed negligible amounts of Fas, but primary tumors often expressed high Fas levels. The reason for this discrepancy is unknown. We hypothesized that because FasL is constitutively expressed in the lungs, Fas-positive (Fas(+)) tumor cells entering the lungs would bind with FasL and die from Fas-induced apoptosis, resulting in the "selection" of Fas-negative (Fas(-)) cells, which would eventually form metastases. To test this hypothesis, we injected K7 osteosarcoma cells, which express functional Fas in vitro, into mice and confirmed that its bone tumors were Fas(+), but lung metastases were Fas(-). Next, to inhibit Fas signaling without affecting Fas expression, we transfected these cells with a FADD-dominant negative (FDN) plasmid and developed K7/FDN cells. Metastases formed by K7/FDN cells contained Fas(+) tumor cells. Moreover, K7/FDN cells were retained in the lungs longer and formed more lung metastases than K7 cells. In addition, the incidence of lung metastases in FasL-deficient mice injected with K7 cells was higher than that in wild-type mice. Metastases from FasL-deficient mice but not from wild-type mice contained Fas(+) tumor cells. Based on that, we conclude that Fas(-) osteosarcoma cells are selected during lung metastases formation and that inhibition of Fas signaling in tumors or lack of FasL in the host environment allows the proliferation of Fas(+) osteosarcoma cells in the lungs and promotes metastases growth. Therefore, Fas may be considered as a new therapeutic target for osteosarcoma treatment.     

A practical guide to interpreting and generating bottom-up proteomics data visualizations

Mass-spectrometry based bottom-up proteomics is the main method to analyze proteomes comprehensively and the rapid evolution of instrumentation and data analysis has made the technology widely available. Data visualization is an integral part of the analysis process and it is crucial for the communication of results. This is a major challenge due to the immense complexity of MS data. In this review, we provide an overview of commonly used visualizations, starting with raw data of traditional and novel MS technologies, then basic peptide and protein level analyses, and finally visualization of highly complex datasets and networks. We specifically provide guidance on how to critically interpret and discuss the multitude of different proteomics data visualizations. Furthermore, we highlight Python-based libraries and other open science tools that can be applied for independent and transparent generation of customized visualizations. To further encourage programmatic data visualization, we provide the Python code used to generate all data figures in this review on GitHub ( https://github.com/MannLabs/ProteomicsVisualization ).     

Emerging role for Ureaplasma parvum serovar 3: Active infection in women with silent high-risk human papillomavirus and in women with idiopathic infertility

Recently, there are controversial opinions on the presence of Mycoplasmas/Ureaplasmas as colonizers or pathogens, and on the use of a targeted therapy. This study aimed to characterize Mycoplasmas/Ureaplasmas infections in reproductive age women, including the acquisition of sexually transmitted (ST) pathogens and poor birth outcomes. A total of 646 healthy Italian women fulfilled the inclusion criteria including 521 infertile women, 65 pregnant women, and 60 fertile women with identified risk factors and symptomatic for vaginitis/cervicitis. Multiplex and quantitative molecular techniques and direct automatic DNA sequencing were performed to assess the genome structure of Mycoplasma/Ureaplasma species and ST infected pathogens. Ureaplasma parvum serovar 3 represented the predominant colonizer of the urogenital tract of this series and the unique species significantly associated with ST pathogens coinfection (p < 0.01). U. parvum load >10⁴ bacteria/ml, suggestive of active infection, has been measured only in asymptomatic high-risk human papillomavirus infected women (24.3%) and in 40% of women with idiopathic infertility. To note, 16% of the follicular fluid from these idiopathic women resulted infected with U. parvum. In conclusion, the present study focused the attention on U. parvum serovar 3 as emerging microorganism in sexually active women that may have the benefit of targeted therapy.