Simultaneously targeting the tumor and tumor microenvironment may hold promise in treating children with refractory solid tumors. Pexidartinib, an oral inhibitor of tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), KIT, and FLT3, is FDA approved in adults with tenosynovial giant cell tumor. A phase I trial was conducted in pediatric and young adult patients with refractory leukemias or solid tumors including neurofibromatosis type 1-related plexiform neurofibromas.
 
  A rolling six design with dose levels (DL) of 400 mg/m
  , 600 mg/m
  , and 800 mg/m
  once daily for 28-day cycles (C) was used. Response was assessed at regular intervals.  https://www.selleckchem.com/products/bp-1-102.html  Pharmacokinetics and population pharmacokinetics were analyzed during C1.
 
  Twelve patients (4 per DL, 9 evaluable) enrolled on the dose-escalation phase and 4 patients enrolled in the expansion cohort median (lower, upper quartile) age 16 (14, 16.5) years. No dose-limiting toxicities were observed. Pharmacokinetics appeared linear over three DLs. Pharmacokinetic modeling and simulation determined a weight-based recommended phase II dose (RP2D). Two patients had stable disease and 1 patient with peritoneal mesothelioma (C49+) had a sustained partial response (67% RECIST reduction). Pharmacodynamic markers included a rise in plasma macrophage CSF (MCSF) levels and a decrease in absolute monocyte count.
 
  Pexidartinib in pediatric patients was well tolerated at all DL tested, achieved target inhibition, and resulted in a weight-based RPD2 dose.
 Pexidartinib in pediatric patients was well tolerated at all DL tested, achieved target inhibition, and resulted in a weight-based RPD2 dose.RNA interference is a powerful tool for dissecting gene function. In Caenorhabditis elegans, ingestion of double stranded RNA causes strong, systemic knockdown of target genes. Further insight into gene function can be revealed by tissue-specific RNAi techniques. Currently available tissue-specific C. elegans strains rely on rescue of RNAi function in a desired tissue or cell in an otherwise RNAi deficient genetic background. We attempted to assess the contribution of specific tissues to polyunsaturated fatty acid (PUFA) synthesis using currently available tissue-specific RNAi strains. We discovered that rde-1(ne219), a commonly used RNAi-resistant mutant strain, retains considerable RNAi capacity against RNAi directed at PUFA synthesis genes. By measuring changes in the fatty acid products of the desaturase enzymes that synthesize PUFAs, we found that the before mentioned strain, rde-1(ne219) and the reported germline only RNAi strain, rrf-1(pk1417) are not appropriate genetic backgrounds for tissue-specific RNAi experiments. However, the knockout mutant rde-1(ne300) was strongly resistant to dsRNA induced RNAi, and thus is more appropriate for construction of a robust tissue-specific RNAi strains. Using newly constructed strains in the rde-1(null) background, we found considerable desaturase activity in intestinal, epidermal, and germline tissues, but not in muscle. The RNAi-specific strains reported in this study will be useful tools for C. elegans researchers studying a variety of biological processes.Optimal plant growth is hampered by deficiency of the essential macronutrient phosphate in most soils. Plant roots can, however, increase their root hair density to efficiently forage the soil for this immobile nutrient. By generating and exploiting a high-resolution single-cell gene expression atlas of Arabidopsis roots, we show an enrichment of TARGET OF MONOPTEROS 5/LONESOME HIGHWAY (TMO5/LHW) target gene responses in root hair cells. The TMO5/LHW heterodimer triggers biosynthesis of mobile cytokinin in vascular cells and increases root hair density during low-phosphate conditions by modifying both the length and cell fate of epidermal cells. Moreover, root hair responses in phosphate-deprived conditions are TMO5- and cytokinin-dependent. Cytokinin signaling links root hair responses in the epidermis to perception of phosphate depletion in vascular cells.
  Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) in non-medullary thyroid carcinoma (TC) and neuroblastoma (NB), being associated with a poor prognosis for patients. However, little is known about how tumors steer the specific metabolic phenotype and function of TAMs.
 
  In a human coculture model, transcriptome, metabolome and lipidome analysis were performed on TC-induced and NB-induced macrophages. The metabolic shift was correlated to functional readouts, such as cytokine production and reactive oxygen species (ROS) production, including pharmacological inhibition of metabolic pathways.
 
  Based on transcriptome and metabolome analysis, we observed a strong upregulation of lipid biosynthesis pathways in TAMs. Subsequently, lipidome analysis revealed that tumor-induced macrophages have an increased total lipid content and enriched levels of intracellular lipids, especially phosphoglycerides and sphingomyelins. Strikingly, this metabolic shift in lipid synthesis contributes to their protumoral functional characteristics blocking key enzymes of lipid biosynthesis in the tumor-induced macrophages reversed the increased inflammatory cytokines and the capacity to produce ROS, two well-known protumoral factors in the TME.
 
  Taken together, our data show that tumor cells can stimulate lipid biosynthesis in macrophages to induce protumoral cytokine and ROS responses and advocate lipid biosynthesis as a potential therapeutic target to reprogram the TME.
 Taken together, our data show that tumor cells can stimulate lipid biosynthesis in macrophages to induce protumoral cytokine and ROS responses and advocate lipid biosynthesis as a potential therapeutic target to reprogram the TME.The global threat posed by the COVID-19 pandemic has highlighted the need to accurately identify the immediate and long-term postdisaster impacts on disaster-relief workers. We examined the case of a local government employee suffering from post-traumatic stress disorder (PTSD) and bipolar II disorder following the Great East Japan Earthquake. The complex and harsh experience provoked a hypomanic response such as elated feelings with increased energy, decreased need for sleep and an increase in goal-directed activity, which allowed him to continue working, even though he was adversely affected by the disaster. However, 3.5 years later, when he suffered further psychological damage, his PTSD symptoms became evident. In addition to treating mood disorders, trauma-focused psychotherapy was required for his recovery. Thereafter, we considered the characteristics of mental health problems that emerge in disaster-relief workers, a long time after the disaster, and the conditions and treatments necessary for recovery.