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Full Decision of Paraneoplastic Membranous Nephropathy Subsequent Curative Treatment associated with Triple-Negative Breast cancers.
Significant maturation of swimming in zebrafish (Danio rerio) occurs within the first few days of life when fish transition from coiling movements to burst swimming and then to beat-and-glide swimming. This maturation occurs against a backdrop of numerous developmental changes - neurogenesis, a transition from predominantly electrical to chemical-based neurotransmission, and refinement of intrinsic properties. There is evidence that spinal locomotor circuits undergo fundamental changes as the zebrafish transitions from burst to beat-and-glide swimming. Our electrophysiological recordings confirm that the operation of spinal locomotor circuits becomes increasingly reliant on glycinergic neurotransmission for rhythmogenesis governing the rhythm of tail beats. This transition occurred at the same time that we observed a change in rhythmicity of synaptic inhibition to spinal motoneurons (MNs). When we examined whether the transition from weakly to strongly glycinergic dependent rhythmogenesis occurred at a uniform pace across the length of the spinal cord, we found that this transition occurred earlier at caudal segments than at rostral segments of the spinal cord. selleck products Furthermore, while this rhythmogenic transition occurred when fish transition from burst swimming to beat-and-glide swimming, these two transitions were not interdependent. link2 These results suggest that there is a developmental transition in the operation of spinal locomotor circuits that is gradually set in place in the spinal cord in a caudo-rostral temporal sequence. Copyright © 2020 Roussel et al.PURPOSE Fanconi anemia (FA) rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). FA patients with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work we searched and validated two already approved drugs as new potential therapies for HNSCC in FA patients. EXPERIMENTAL DESIGN We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify non-genotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied in vitro and in vivo for efficacy and safety. RESULTS Several FDA/EMA-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in FA HNSCC cell lines. The two best candidates gefitinib and afatinib, EGFR inhibitors approved for non-small-cell lung cancer (NSCLC), displayed non-tumor/tumor IC50 ratios of ~400 and ~100 times, respectively. Neither gefitinib nor afatinib activated the FA signaling pathway or induced chromosomal fragility in FA cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two FA patient-derived HNSCCs. Finally, in vivo toxicity studies in Fanca-deficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side-effects, no toxicity to bone marrow progenitors and did not alter any hematological parameters. CONCLUSIONS Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA approved anticancer drugs exerting cancer specific toxicity for HNSCC in FA patients. Copyright ©2020, American Association for Cancer Research.PURPOSE Recent studies have demonstrated a benefit of adjuvant capecitabine in early breast cancer, particularly in patients with triple negative breast cancer (TNBC). However, TNBC is heterogeneous and more precise predictive biomarkers are needed. EXPERIMENTAL DESIGN Tumor tissues collected from TNBC patients in the FinXX trial, randomized to adjuvant anthracycline-taxane based chemotherapy with or without capecitabine, were analyzed using a 770-gene panel targeting multiple biological mechanisms and additional 30-custom genes related to capecitabine metabolism. Hypothesis-generating exploratory analyses were performed to assess biomarker expression in relation to treatment effect using Cox regression model and interaction tests adjusted for multiplicity. RESULTS 111 TNBC samples were evaluable (57 without capecitabine and 54 with capecitabine). The median follow-up was 10.2 years. Multivariate analysis showed significant improvement in RFS favoring capecitabine in four biologically-important genes and metaPURPOSE Concurrent inhibition of mTOR and PI3K led to improved efficacy in preclinical models and provided the rationale for this phase I study of everolimus and buparlisib (BKM120) in patients with advanced solid tumor. EXPERIMENTAL DESIGN We used the Bayesian EWOC design to test escalating doses of everolimus (5mg or 10mg) and buparlisib (20, 40, 60, 80 and 100 mg) in eligible patients. Pharmacokinetic (PK) assessment was conducted using blood samples collected on cycle 1, days 8 and 15. Pharmacodynamic (PD) impact on mTOR/PI3K pathway modulation evaluated in paired skin biopsies collected at baseline and end of cycle 1. RESULTS We enrolled 43 patients, median age of 63 (39-78) years; 25 (58.1%) females, 35 (81.4%) Caucasians and 8 (18.6%) Blacks. The most frequent toxicities were hyperglycemia, diarrhea, nausea, fatigue and AST elevation. Dose limiting toxicities observed in 7 patients were fatigue (3), hyperglycemia (2), mucositis (1), acute kidney injury (1) and urinary tract infection (1). link3 The RP2D for the combination was established as everolimus (5mg) and buparlisib (60mg). The best response in 27 evaluable patients was progressive disease and stable disease in in three (11%) and 24 (89%) respectively. The median PFS and OS were 2.7 (1.8, 4.2) and 9 (6.4, 13.2) months. Steady-state PK analysis showed dose-normalized maximum concentrations and area-under-the-curve values for everolimus and buparlisib in combination to be comparable with single agent PK. CONCLUSION The combination of everolimus and buparlisib is safe and well-tolerated at the RP2D of 5mg and 60mg on a continuous daily schedule. Copyright ©2020, American Association for Cancer Research.The importance of non-coding RNA sequences has become increasingly clear over the past decade. New RNA families are often detected and analyzed using comparative methods based on multiple sequence alignments. Accordingly, a number of programs have been developed for aligning and deriving secondary structures from sets of RNA sequences. Yet, the best tools for these tasks remain unclear because existing benchmarks contain too few sequences belonging to only a small number of RNA families. RNAconTest (RNA consistency test) is a new benchmarking approach relying on the observation that secondary structure is often conserved across highly divergent RNA sequences from the same family. RNAconTest scores multiple sequence alignments based on the level of consistency among known secondary structures belonging to reference sequences in their output alignment. Similarly, consensus secondary structure predictions are scored according to their agreement with one or more known structures in a family. Comparing the performance of 10 popular alignment programs using RNAconTest revealed that DAFS, DECIPHER, LocARNA, and MAFFT created the most structurally consistent alignments. The best consensus secondary structure predictions were generated by DAFS and LocARNA (via RNAalifold). Many of the methods specific to non-coding RNAs exhibited poor scalability as the number or length of input sequences increased, and several programs displayed substantial declines in score as more sequences were aligned. Overall, RNAconTest provides a means of testing and improving tools for comparative RNA analysis, as well as highlighting the best available approaches. RNAconTest is available from the DECIPHER website . Published by Cold Spring Harbor Laboratory Press for the RNA Society.Lactococcus lactis subsp. cremoris MG1363 is a model for the lactic acid bacteria (LAB) used in the dairy industry. The proteolytic system, consisting of a proteinase, several peptide- and amino acid uptake systems and a host of intracellular peptidases, plays a vital role in nitrogen metabolism and is of eminent importance for flavor formation in dairy products. The dipeptidase PepV functions in the last stages of proteolysis. A link between nitrogen metabolism and peptidoglycan (PG) biosynthesis was underlined by the finding that deletion of the dipeptidase gene pepV (MGΔpepV) results in a prolonged lag phase when the mutant strain was grown with a high concentration of glycine. In addition, most MGΔpepV cells lyse and have serious defects in their shape. This phenotype is due to a shortage of alanine, since adding alanine can rescue the growth and shape defects. Strain MGΔpepV is more resistant to vancomycin, an antibiotic targeting peptidoglycan D-Ala-D-Ala ends, which confirmed that MGΔpepV has an abnormcell wall synthesis in L. lactis. Copyright © 2020 Huang et al.A prominent feature of lactic acid bacteria (LAB) is their ability to inhibit growth of spoilage organisms in food, but hitherto research efforts to establish the mechanisms underlying bioactivity focused on the production of antimicrobial compounds by LAB. We show in this study, that competitive exclusion, i.e, competition for a limited resource by different organisms, is a major mechanism of fungal growth inhibition by lactobacilli in fermented dairy products. The depletion of the essential trace element manganese by two Lactobacillus species was uncovered as the main mechanism for growth inhibition of dairy spoilage yeast and molds. A manganese transporter (MntH1), representing one of the highest expressed gene products in both lactobacilli, facilitates the exhaustive manganese scavenging. Expression of the mntH1 gene was found to be strain-dependent, affected by species co-culturing and growth phase. Further, deletion of the mntH1 gene in one of the strains resulted in loss of bioactivity, proving this gelly understood. In this study, we show that depletion of free manganese is a major bioprotective mechanism of lactobacilli in dairy products. High manganese uptake and intracellular storage provides a link to the distinct non-enzymatic manganese catalyzed oxidative stress defense mechanism, previously described for certain lactobacilli. The evaluation of representative Lactobacillus species in our study identifies multiple relevant species groups for fungal growth inhibition via manganese depletion. Hence, through the natural mechanism of nutrient depletion, the use of dedicated bioprotective lactobacilli constitutes an attractive alternative to artificial preservation. Copyright © 2020 Siedler et al.APSES-type transcription factors (TFs) have analogous and diverse functions in the regulation of fungal morphogenesis processes. However, little is known concerning these functions in microsclerotium formation. In this study, we characterized two orthologous APSES genes (MrStuA and MrXbp) in the entomopathogenic fungus, Metarhizium rileyi Deletion of either MrStuA or MrXbp impaired dimorphic transition, conidiation, fungal virulence, and microsclerotium formation. Compared with the wild-type strain, ΔMrStuA and ΔMrXbp mutants were hypersensitive to thermal and oxidative stress. Furthermore, RNA-seq analysis revealed that MrStuA and MrXbp independently regulate their own distinctive subsets of signaling pathways during dimorphic transition and microsclerotium formation, but also show overlapping regulation of genes during these two distinct morphogenesis processes. These results provide a global insight into vital roles of MrStuA and MrXbp in M. rileyi and aid in dissection of the interacting regulatory mechanisms of dimorphism transition and microsclerotium development.
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