Parapithecines are an extinct subfamily of stem anthropoid primates previously known only from the Jebel Qatrani Formation in Egypt. Here, we describe isolated teeth pertaining to Simonsius harujensis sp. nov., a relatively small-bodied parapithecine from strata near Zallah Oasis in the Sirt Basin of central Libya that is estimated to date to ∼31 Ma on the basis of mammalian biostratigraphy. The dental morphology of S. harujensis sp. nov. is generally intermediate between that of the closely related parapithecines Parapithecus fraasi and Simonsius grangeri, highlighting some of the anatomical features distinguishing the latter taxa and providing further support for their generic separation. A phylogenetic analysis using parsimony methods was performed on a character-taxon matrix incorporating data from the new Libyan parapithecine, virtually all other parapithecids and the proteopithecid Proteopithecus sylviae. Results of this analysis suggest that parapithecids comprise a basal clade consisting of three species of Biretia and a more derived clade including Parapithecinae (Parapithecus and Simonsius) and Qatraniinae (Qatrania, Ucayalipithecus, and Apidium). Body mass estimates for parapithecids were calculated on the basis of regression equations generated to predict body mass from the occlusal area of upper and lower cheek teeth in extant anthropoids. The relatively small body mass of S. harujensis sp. nov. and its reconstructed phylogenetic position as the sister group of S. grangeri, which is the largest known parapithecid, support the convergent acquisition of body mass larger than 500 g among multiple clades of early Oligocene African anthropoids. The new Libyan parapithecine augments previously reported evidence supporting a substantial degree of faunal provincialism across northern Africa/Arabia during the early Oligocene.
The Fragility Indexquantifies the reliability of positive trials by estimating the number of events, which would change statistically significant results to non-significant results.
We identified randomized trials supporting drug approvals by the US FDA between 2009 and 2019 in lung, breast, prostate, and colon cancers and in melanoma. We reconstructed survival tablesand calculated the number of events, which would result in a non-significant result for the primary endpoint. The FI was then compared to the number of patients in each trial who withdrew consent or were lost to follow-up. Regression analyses were used to explore associations between RCT characteristics and FI and trials in which FI was lower or equal to number of participants who withdrew consent or were lost to follow-up.
Among 81 RCTs, the median FI was 28. The median number of patients who withdrew consent or were lost to follow up was 27. FI was equal or lower than the number of patients who withdrew consent or were lost to follow-up in 47 trials (58%). GS-4997 in vivo There was a modest increase in FI over time (p=0.02). Trials with overall survival as the primary endpoint (p=0.006) and those in the palliative setting (p<0.001) had lower FI. There was no association with trial sample size or duration of follow-up.
Statistical significance of RCTs in common solid tumours can be reversed often with a small number of additional events. Post-approval RCTs or real-world data analyses should be performed to ensure results of registration trials are robust.
Statistical significance of RCTs in common solid tumours can be reversed often with a small number of additional events. Post-approval RCTs or real-world data analyses should be performed to ensure results of registration trials are robust.Precision medicine is progressively revolutionizing oncology, through the identification of biomarkers predictive of treatment response in cancer patients. For three of such biomarkers, namely NTRK-fusions, microsatellite instability and high tumor mutational burden, drugs have been approved by regulatory agencies regardless of tumor histology, realizing the paradigm of histology-agnostic actionability. Several additional biomarkers are being studied in a histology-agnostic manner, and may in the future expand this list. However, most available evidence suggest that histology-agnosticism may be the extreme of a continuous spectrum of actionability, rather than a binary quality. The present review recapitulates such evidence, highlighting opportunities and challenges posed by the emergence of the spectrum of biomarker actionability in the context of a prevalently histology-based oncology.Metabolic syndrome (MetS) is a complex, multifactorial disease which lead to an increased risk of cardiovascular disease, type 2 diabetes, and stroke. However, selective, and potent drugs for the treatment of MetS are still lacking. Previous studies have found that Akebia saponin D (ASD) has beneficial effects on metabolic diseases such as obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). Therefore, our study was designed to determine the effect and mechanism of action of ASD against MetS in a high-fat diet (HFD) induced mouse model. ASD significantly decreased plasma lipid and insulin resistance in these mice, and a targeted approach using metabolomic analyses of plasma and feces indicated that glucose and lipids in these mice crossed the damaged intestinal barrier into circulation. Furthermore, ASD was able to increase lipid excretion and inhibit intestinal epithelial lipid absorption. Results for gut microbiota composition showed that ASD significantly reduced HFD-associated Alistipes, Prevotella, and enhanced the proportions of Butyricimonas, Ruminococcus, and Bifidobacterium. After 14 weeks of ASD/fecal microbiota transplantation (FMT) interventions the developed gut barrier dysfunction was restored. Additionally, RNA-seq revealed that ASD reduced the lipid-induced tight junction (TJ) damage in intestinal epithelial cells via down-regulation of the PPAR-γ-FABP4 pathway in vitro and that use of the PPAR-γ inhibitor (T0070907) was able to partially block the effects of ASD, indicating that the PPAR-γ/FABP4 pathway is a critical mediator involved in the improvement of MetS. Our results demonstrated that ASD not only modifies the gut microbiome but also ameliorates the HFD-induced gut barrier disruption via down-regulation of the PPAR-γ-FABP4 pathway. These findings suggest a promising, and novel therapeutic strategy for gut protection against MetS.GS-4997 in vivo
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