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The inherent plasticity of tumor cells provides a mechanism of resistance to many molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions seen in prostate and lung cancer. Here we investigate the root cause of this lineage plasticity in a primary murine prostate organoid model that mirrors the lineage transition seen in patients. These cells lose luminal identity within weeks following deletion ofTrp53andRb1, ultimately acquiring an Ar-negative, Syp+ phenotype after orthotopicin vivotransplantation. Single-cell transcriptomic analysis revealed progressive mixing of luminal-basal lineage features after tumor suppressor gene deletion, accompanied by activation of Jak/Stat and Fgfr pathway signaling and interferon-a and -g gene expression programs prior to any morphologic changes. Genetic or pharmacologic inhibition of Jak1/2 in combination with FGFR blockade restored luminal differentiation and sensitivity to antiandrogen therapy in models with residual AR expression. Collectively, we show lineage plasticity initiates quickly as a largely cell-autonomous process and, through newly developed computational approaches, identify a pharmacological strategy that restores lineage identity using clinical grade inhibitors.

Medulloblastoma (MB) and diffuse infiltrative pontine glioma (DIPG) are malignant pediatric tumors. Extracellular vesicles (EVs) and their bioactive cargoes have been implicated in tumorigenesis. Most studies have focused on adult tumors, therefore the role of EVs and the noncoding RNA (ncRNA) landscape in pediatric brain tumors is not fully characterized. The overall aim of this pilot study was to isolate EVs from MB and DIPG patient-derived cell lines and to explore the small ncRNA transcriptome.EVs from 3 DIPG and 4 MB patient-derived cell lines were analyzed. High-throughput next generation sequencing interrogated the short non-coding RNA (ncRNA) transcriptome. Known and novel miRNAs were quantified. Differential expression analysis, in silico target prediction, and functional gene enrichment were performed.EV secretomes from MB and DIPG patient-derived cell lines demonstrated discrete ncRNA biotypes. Notably, miRNAs were depleted and Y RNAs were enriched in EV samples. Hierarchical cluster analysis revealed high discrimination in miRNA expression between DIPG and MB cell lines and RNA-Seq identified novel miRNAs not previously implicated in MB or DIPG pathogenesis. Known and putative target genes of dysregulated miRNAs were identified. Functional annotation analysis of the target genes for differentially expressed EV-and parental-derived miRNAs revealed significant cancer-related pathway involvement.This hypothesis-generating study demonstrated that pediatric brain tumor-derived cell lines secrete EVs comprised of various ncRNA cargoes. Validation of these findings in patient samples may provide new insights into the pediatric brain tumor microenvironment and identification of novel therapeutic candidates.

Alice in Wonderland syndrome is a disorienting perceptual disorder characterized by discrete episodes of bizarre visual illusions and spatial distortions which has been associated with numerous neurologic and psychiatric conditions. Little is known regarding the electrophysiologic correlates of the visual symptoms described in this syndrome. The authors report the unique case of an 8-year-old boy presenting with visual distortions consistent with Alice in Wonderland syndrome, and an electroencephalogram demonstrating bilateral temporo-occipital slowing which correlated with symptoms of micropsia, teleopsia, and dysmorphopsia. Identification of this clinical syndrome and its electroclinical features are important for establishing a proper diagnosis and subsequent reassurance or appropriate treatment directed toward the underlying etiology.

Two ecosystems affected by acidic pollutants (Thana Creek, Bombay and inshore area of Trivandrum, Kerala) and two other ecosystems affected by alkaline pollutants (Cola Bay, Goa and inshore area of Karwar, Karnataka) were studied for pollution effects monitoring through Foraminifera. In the Thana Creek area, Bombay, the magnitude of corrosive effect, lower—than—normal ornamentation, deepening of grooves and sutural thickenings, enlargement of pores, widening of apertures in Foraminifera were taken as indices of pollution effect. In the, Cola bay area, Goa, the environment becomes hypertrophic resulting in large—sized, robust, mostly megalospheric forms of Ammonia. Elphidium and Florilus scaphum are recorded at the proximal zone near the discharge point; miliolids in the transitional zone and dominantly smaller—sized Nonionella, Fursenkoina pontoni, Bulimina marginata at the distal zone quite far from thc discharge point where pollutants are diluted and dissipated. In the Karwär area, Karnataka, pollutant causes reduced diversity with a decrease in foraminiferal population. Moreover, there is a reduction in size followed by test wall thinning in Nonion and Ammonia, increase of agglutinated forms near shore, and dispersal and dilution of the pollutants resulting in foraminiferal abundance. In the Trivandrum area, Kerala, the effluent effect presents morphological anomalies (Operculina, Cibicides), erosion along peripheries, induced growth in last few chambers, inferred dissolution and consequent destruction of small, thin—walled forms suggested by their absence, thus leaving only the larger ones in the entire area. Living/dead ratio is negatively oriented at all sites.

Benthic Foraminifera are highly responsive to subtle changes in the estuarine environment. Keeping this in view, a qualitative analysis of living benthic Foraminifera was made of the samples collected from the Mandovi—Zuari estuaries and the connecting long and narrow Cumbarjua canal of Goa. The lower reaches of the rivers are paved with a substrate consisting mostly of sand while it is silty—sand in the upper estuarine zones and clayey in the canal zone. The living Foraminifera are abundant in the upper estuarine zones of the rivers and the Cumbarjua canal junction zones, and characterised by the Ammonia—Trochammina suite with Miliammina fusca; while the canal zone is enriched by agglutinated formes. The Ammonia—Elphidium suite dominates the lower estuarine zones indicating a typical marine environment. The high organic matter content particularly in the Canal Zone is due to the inflow of pollutan ts from the nearby pesticide factory and the constant contaminating discharge of navigating barges and other mechanised boats of the fishing industry. Ammonia sp. and its variants and other agglutinated species become dominant here. The decline in calcareous species and thinning of the dead tests leading to their eventual destruction may be attributed to their susceptibility to acidity in the waters.

Neuromyelitis optica (NMO) is a primary astrocyte disease associated with central nervous system inflammation, demyelination, and tissue injury. Brain lesions are frequently observed in regions enriched in expression of the aquaporin-4 (AQP4) water channel, an antigenic target of the NMO IgG serologic marker. Based on observations of disease reversibility and careful characterization of NMO lesion development, we propose that the NMO IgG may induce a dynamic immunological response in astrocytes. Using primary rat astrocyte-enriched cultures and treatment with NMO patient-derived serum or purified IgG, we observed a robust pattern of gene expression changes consistent with the induction of a reactive and inflammatory phenotype in astrocytes. The reactive astrocyte factor lipocalin-2 and a broad spectrum of chemokines, cytokines, and stress response factors were induced by either NMO patient serum or purified IgG. Treatment with IgG from healthy controls had no effect. The effect is disease-specific, as serum from patients with relapsing-remitting multiple sclerosis, Sjogren's, or systemic lupus erythematosus did not induce a response in the cultures. We hypothesize that binding of the NMO IgG to AQP4 induces a cellular response that results in transcriptional and translational events within the astrocyte that are consistent with a reactive and inflammatory phenotype. Strategies aimed at reducing the inflammatory response of astrocytes may short circuit an amplification loop associated with NMO lesion development.

Generation of free radicals in the kidney cortex plays an important role in the pathogenesis of cisplatin-induced dysfunction of renal proximal tubule cells. Previous studies carried out showed that an alcohol extract of Crataeva nurvala stem bark possessed antioxidant activity in rats, hence the present work aimed at evaluating the possible effect of the alcohol extract of C. nurvala on cisplatin-induced dysfunction model of renal proximal tubule cells by oxidative stress. The alcohol extract was administered orally for ten days at two dose levels of 250 and 500 mg/kg body weight, five days after administration of a single i.p. dose of cisplatin (5 mg/kg). Renal dysfunction was evaluated histologically by light microscopy and biochemically by measuring the concentrations of blood urea nitrogen, serum creatinine, lipid peroxidation, glutathione and catalase activity in the kidney cortex. The results suggest that the plant extract (250 and 500 mg/kg) was effective in significantly altering the indices of c...

Neuromyelitis optica (NMO) is a primary astrocyte disease associated with central nervous system inflammation, demyelination, and tissue injury. Brain lesions are frequently observed in regions enriched in expression of the aquaporin-4 (AQP4) water channel, an antigenic target of the NMO IgG serologic marker. Based on observations of disease reversibility and careful characterization of NMO lesion development, we propose that the NMO IgG may induce a dynamic immunological response in astrocytes. Using primary rat astrocyte-enriched cultures and treatment with NMO patient-derived serum or purified IgG, we observed a robust pattern of gene expression changes consistent with the induction of a reactive and inflammatory phenotype in astrocytes. The reactive astrocyte factor lipocalin-2 and a broad spectrum of chemokines, cytokines, and stress response factors were induced by either NMO patient serum or purified IgG. Treatment with IgG from healthy controls had no effect. The effect is disease-specific, as serum from patients with relapsing-remitting multiple sclerosis, Sjögren's, or systemic lupus erythematosus did not induce a response in the cultures. We hypothesize that binding of the NMO IgG to AQP4 induces a cellular response that results in transcriptional and translational events within the astrocyte that are consistent with a reactive and inflammatory phenotype. Strategies aimed at reducing the inflammatory response of astrocytes may short circuit an amplification loop associated with NMO lesion development.