Few alterations in clinical pathology and histopathology observed in a CYP2C18&19 humanized mice model

<p>Abstract</p> <p>Background</p> <p>This study was performed to characterize a gene-addition transgenic mouse containing a BAC (bacterial artificial chromosome) clone spanning the human CYP2C18&19 genes (tg-CYP2C18&19).</p> <p>Methods</p> <p>Hemizygous tg-CYP2C18&19, 11 week old mice were compared with wild-type littermates to obtain information regarding clinical status, clinical pathology and anatomical pathology. After one week of clinical observations, blood samples were collected, organs weighed, and tissues collected for histopathology.</p> <p>Results</p> <p>In males, the tissue weights were lower in tg-CYP2C18&19 than in wild-type mice for brain (<it>p </it>≤ 0.05), adrenal glands (<it>p </it>≤ 0.05) and brown fat deposits (<it>p </it>≤ 0.001) while the heart weight was higher (<it>p </it>≤ 0.001). In female tg-CYP2C18&19, the tissue weights were lower for brain (<it>p </it>≤ 0.001) and spleen (<it>p </it>≤ 0.001) compared to wild-type females. Male tg-CYP2C18&19 had increased blood glucose levels (<it>p </it>≤ 0.01) while females had decreased blood triglyceride levels (<it>p </it>≤ 0.01).</p> <p>Conclusion</p> <p>Despite the observed alterations, tg-CYP2C18&19 did not show any macroscopic or microscopic pathology at the examined age. Hence, these hemizygous transgenic mice were considered to be viable and healthy animals.</p

A cluster of genes located in 1p36 are down-regulated in neuroblastomas with poor prognosis, but not due to CpG island methylation

BACKGROUND: A common feature of neuroblastoma tumours are partial deletions of the short arm of chromosome 1 (1p-deletions). This is indicative of a neuroblastoma tumour suppressor gene being located in the region. Several groups including our have been studying candidate neuroblastoma genes in the region, but no gene/genes have yet been found that fulfil the criteria for being a neuroblastoma tumour suppressor. Since frequent mutations have not been detected, we have now analyzed the expression and promoter CpG island methylation status of the genes UBE4B, KIF1B, PGD, APITD1, DFFA and PEX14 in the 1p36.22 region in order to find an explanation for a possible down-regulation of this region. RESULTS: The current study shows that gene transcripts in high stage neuroblastoma tumours are significantly down-regulated compared to those in low stage tumours in the 1p36.22 region. CpG island methylation does not seem to be the mechanism of down-regulation for most of the genes tested, since no methylation was detected in the fragments analyzed. One exception is the CpG island of APITD1. Methylation of this gene is also seen in blood from control individuals and is therefore not believed to participate in tumour development. CONCLUSION: The genes UBE4B, KIF1B, PGD, APITD1, DFFA and PEX14 are down-regulated in high stage NB tumours, a feature that can not be explained by CpG island methylation

Rho-associated kinase is a therapeutic target in neuroblastoma

Source at: http://doi.org/10.1073/pnas.1706011114 Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK)2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3β-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH-MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma

Absence of photophysiological response to iron addition in autumn phytoplankton in the Antarctic sea-ice zone

he high nutrient–low chlorophyll condition of the Southern Ocean is generally thought to be caused by the low bioavailability of micronutrients, particularly iron, which plays an integral role in phytoplankton photosynthesis. Nevertheless, the Southern Ocean experiences seasonal blooms that generally initiate in austral spring, peak in summer, and extend into autumn. This seasonal increase in primary productivity is typically linked to the seasonal characteristics of nutrient and light supply. To better understand the potential limitations on productivity in the Antarctic sea-ice zone (SIZ), the photophysiological response of phytoplankton to iron addition (2.0 nM FeCl3) was investigated during autumn along the Antarctic coast off Dronning Maud Land. Five short-term (24 h) incubation experiments were conducted around Astrid Ridge (68∘ S) and along a 6∘ E transect, where an autumn bloom was identified in the region of the western SIZ. Surface iron concentrations ranged from 0.27 to 1.39 nM around Astrid Ridge, and 0.56 to 0.63 nM along the 6∘ E transect. Contrary to expectation, the photophysiological response of phytoplankton to iron addition, measured through the photosynthetic efficiency and the absorption cross-section for photosystem II, showed no significant responses. It is thus proposed that since the autumn phytoplankton in the SIZ exhibited a lack of an iron limitation at the time of sampling, the ambient iron concentrations may have been sufficient to fulfil the cellular requirements. This provides new insights into extended iron replete post-bloom conditions in the typically assumed iron deficient high nutrient–low chlorophyll Southern Ocea

Multifocal Neuroblastoma and Central Hypoventilation in An Infant with Germline ALK F1174I Mutation

Funding Information: This work has been supported by grants from the Swedish Cancer Society (TM 15-794; TM 20-1213; PK 19-566), the Swedish Childhood Cancer Foundation (TM 16-147; TM 17-166; TM 19-139; PK 17-122; SF 15-61, 18-99; DT 12-002, NC12-0026), the Swedish Research Council (TM 521-2014-3031), the Swedish state under the LUA/ALF agreement (TM ALFGBG-447171) and the Swedish Foundation for Strategic Research (TM/PK RB13-0204, www.nnbcr.se). SF was the recipient of a Research Assistant Fellowship (14-64), by the Swedish Childhood Cancer Foundation. Publisher Copyright: © 2022 by the authors.A preterm infant with central hypoventilation was diagnosed with multifocal neuroblastoma. Congenital anomalies of the autonomic nervous system in association with neuroblastoma are commonly associated with germline mutations in PHOX2B. Further, the ALK gene is frequently mutated in both familial and sporadic neuroblastoma. Sanger sequencing of ALK and PHOX2B, SNP microarray of three tumor samples and whole genome sequencing of tumor and blood were performed. Genetic testing revealed a germline ALK F1174I mutation that was present in all tumor samples as well as in normal tissue samples from the patient. Neither of the patient’s parents presented the ALK variant. Array profiling of the three tumor samples showed that two of them had only numerical aberrations, whereas one sample displayed segmental alterations, including a gain at chromosome 2p, resulting in two copies of the ALK-mutated allele. Whole genome sequencing confirmed the presence of the ALK variant and did not detect any aberrations in the coding or promotor region of PHOX2B. This study is to our knowledge the first to report a de novo ALK F1174I germline mutation. This may not only predispose to congenital multifocal neuroblastoma but may also contribute to the respiratory dysfunction seen in this patient.Peer reviewe

11q deletion or ALK activity curbs DLG2 expression to maintain an undifferentiated state in neuroblastoma

High-risk neuroblastomas typically display an undifferentiated or poorly differentiated morphology. It is therefore vital to understand molecular mechanisms that block the differentiation process. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in the maintenance of undifferentiated neural crest-derived progenitors through the repression of DLG2, a candidate tumor suppressor gene in neuroblastoma. DLG2 is expressed in the murine "bridge signature'' that represents the transcriptional transition state when neural crest cells or Schwann cell precursors differentiate to chromaffin cells of the adrenal gland. We show that the restoration of DLG2 expression spontaneously drives neuroblastoma cell differentiation, high-lighting the importance of DLG2 in this process. These findings are supported by genetic analyses of high-risk 11q deletion neuroblastomas, which identified genetic lesions in the DLG2 gene. Our data also suggest that further exploration of other bridge genes may help elucidate the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to neuroblastomas

Företagshemligheter - en värdeskapande strategi

Ingen resumé lämnad

Tre domar – en studie av begränsningen av kvinnors rätt att manifestera sin religion i arbetslivet

I denna artikel granskas och diskuteras anställdas rätt att manifestera sin religion i arbetslivet. Studien bygger på tre domar där kvinnors rätt att bära huvudduk, respektive att vägra medverka i abortvård, ställts mot arbetsgivarens företags- och arbetsledningsrätt. Domarna analyseras utifrån teorin om normativa grundmönster där rättsreglerna sätts i relation till underliggande normer i samhället. I artikeln visas dels på de rättsliga konsekvenserna när kategorin kön tillförs, dels på paradigm i arbetslivet som handlar om assimilering. Arbetsgivare har såväl möjligheter som skyldigheter att arbeta för ett inkluderande arbetsliv. Stöd för detta finns i diskrimineringslagens bestämmelser om aktiva åtgärder

Tre domar : en studie av begränsningen av kvinnors rätt att manifestera sin religion i arbetslivet

I denna artikel granskas och diskuteras anställdas rätt att manifestera sin religion i arbetslivet. Studien bygger på tre domar där kvinnors rätt att bära huvudduk, respektive att vägra medverka i abortvård, ställts mot arbetsgivarens företags- och arbetsledningsrätt. Domarna analyseras utifrån teorin om normativa grundmönster där rättsreglerna sätts i relation till underliggande normer i samhället. I artikeln visas dels på de rättsliga konsekvenserna när kategorin kön tillförs, dels på paradigm i arbetslivet som handlar om assimilering. Arbetsgivare har såväl möjligheter som skyldigheter att arbeta för ett inkluderande arbetsliv. Stöd för detta finns i diskrimineringslagens bestämmelser om aktiva åtgärder