The big-headed turtle (Platysternon megacephalum) from east Asia is the sole living representative of a poorly-studied turtle lineage (Platysternidae). It has no close living relatives, and its ...phylogenetic position within turtles is one of the outstanding controversies in turtle systematics. Platysternon was traditionally considered to be close to snapping turtles (Chelydridae) based on some studies of its morphology and mitochondrial (mt) DNA, however, other studies of morphology and nuclear (nu) DNA do not support that hypothesis.
We sequenced the complete mt genome of Platysternon and the nearly complete mt genomes of two other relevant turtles and compared them to turtle mt genomes from the literature to form the largest molecular dataset used to date to address this issue. The resulting phylogeny robustly rejects the placement of Platysternon with Chelydridae, but instead shows that it is a member of the Testudinoidea, a diverse, nearly globally-distributed group that includes pond turtles and tortoises. We also discovered that Platysternon mtDNA has large-scale gene rearrangements and possesses two, nearly identical, control regions, features that distinguish it from all other studied turtles.
Our study robustly determines the phylogenetic placement of Platysternon and provides a well-resolved outline of major turtle lineages, while demonstrating the significantly greater resolving power of comparing large amounts of mt sequence over that of short fragments. Earlier phylogenies placing Platysternon with chelydrids required a temporal gap in the fossil record that is now unnecessary. The duplicated control regions and gene rearrangements of the Platysternon mtDNA probably resulted from the duplication of part of the genome and then the subsequent loss of redundant genes. Although it is possible that having two control regions may provide some advantage, explaining why the control regions would be maintained while some of the duplicated genes were eroded, examples of this are rare. So far, duplicated control regions have been reported for mt genomes from just 12 clades of metazoans, including Platysternon.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children's Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in ...outcome using multiple cytotoxic agents in a dose-intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin-like growth factor-1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone.
Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m
) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites.
One hundred sixty-eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow-up of 2.9 years, the 3-year event-free survival rate was 16% (95% confidence interval, 7%-25%) with cixutumumab and 18% (95% confidence interval, 2%-35%) with temozolomide.
The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.
Because of the observed increase in incidence of glaucoma among some individuals taking selenium as a dietary supplement, the present study was undertaken to investigate mechanisms of ...selenium-induced changes in homeostasis of human trabecular meshwork (HTM) cells. Specifically, the impact of selenium on matrix metalloproteinases (MMPs), their inhibitors (tissue inhibitors of metalloproteinases; TIMPs), and the second messengers that regulate MMP expression was investigated in an HTM cell culture model.
HTM cell cultures were treated with an organic selenium compound (methyl seleninic acid), and changes in secretion and activity of MMPs and TIMPs were analyzed by Western blot and zymography. Changes in extracellular-signal-related kinases 1 and 2 (ERK1/2) and phospho-ERK1/2 levels were monitored by Western blot analysis of whole-cell lysates prepared from selenium-treated cells. Photographs of cultures over time were used to document selenium-induced changes in cell morphology.
Treatment of HTM cells with selenium for 24 hours at doses ranging from 1 to 10 micro M caused a dose-dependent decrease in the secretion of MMP-2 and TIMP-1. Treatment for 6 hours revealed a significant decrease in MMP-2 and TIMP-1 at the highest dose. MMP-1, -3, and -9 and TIMP-2 were either not detected or their secretion was not consistently influenced by selenium treatment. Selenium treatment caused a significant decrease in ERK1/2 phosphorylation, but no change in overall ERK protein levels. Selenium treatment resulted in dose-dependent, reversible changes in HTM cell-matrix associations.
Selenium-induced changes in MMP-2/TIMP-1 secretion may alter the balance of extracellular matrix turnover in the conventional outflow pathway and cause an increase in intraocular pressure that eventually leads to glaucoma.
Fibrous hamartoma of infancy is a rare soft tissue lesion of infants and young children with characteristic triphasic morphology, which typically occurs in the axilla and less commonly in other ...locations. We reviewed 145 cases of fibrous hamartoma of infancy from our consultation archives. Cases occurred in 106 males and 39 females (mean age—15 months; range—birth to 14 years), and involved both typical sites (eg, axilla/back/upper arm) (n=69) and unusual locations (n=76). Six were congenital. The tumors presented as subcutaneous masses and ranged from 0.4 to 17 cm (mean 3 cm). All displayed triphasic morphology, but varied widely in the relative percentages of fat, fibroblastic fascicles, and primitive mesenchyme. Hyalinized zones with cracking artifact, mimicking giant cell fibroblastoma, were present in a 44 (30%) of cases; however FISH for PDGFB gene rearrangement was negative in five tested cases. In addition to classical fibrous hamartoma of infancy, two lesions contained large sarcomatous-appearing foci with high cellularity, high nuclear grade, and brisk mitotic activity. One occurred in a 10-month-old female as a new mass in a congenital fibrous hamartoma of infancy; the other occurred as a leg mass in a 6-year-old male. ETV6 gene rearrangement was negative in the tumor from the 10-month-old female. Genomic microarray (OncoScan) showed normal molecular karyotype in eight tested cases, whereas the two tumors with sarcomatous features showed a hyperdiploid/near tetraploid molecular karyotype with copy neutral loss of heterozygosity of chromosomes 1p and 11p, and loss of 10p, chromosome 14, and a large portion of chromosome 22q (22q11.23q13.33), respectively. Follow-up (52 patients; range: 1–208 months, median: 8 months) showed only two local recurrences and no metastases. Extensive local disease in the 10-month-old female with sarcomatous-appearing fibrous hamartoma of infancy necessitated forequarter amputation. In summary, our study confirms the classic clinicopathologic features, including the triphasic morphologic appearance of most cases. In contrast to earlier studies, our series illustrates a broader histologic spectrum than previously appreciated, including its close resemblance to giant cell fibroblastoma in one quarter of cases and the rare presence of ‘sarcomatous' areas, the latter providing evidence that these are complex neoplasms rather than hamartomas.
There are few studies in the literature regarding the imaging features of alveolar soft-part sarcoma (ASPS). We performed a comprehensive assessment of the imaging characteristics of this rare tumor ...to determine whether there are features that suggest the diagnosis.
Twenty-two subjects with ASPS underwent pretherapy imaging as part of enrollment in Children's Oncology Group protocol ARST0332 for the treatment of nonrhabdomyosarcoma soft-tissue sarcomas: 16 patients underwent MRI; three, CT; and three, both MRI and CT. Two radiologists retrospectively reviewed the imaging studies by consensus and recorded tumor location, size, contour, internal architecture, signal characteristics, presence of flow voids, and enhancement patterns.
The 12 females and 10 males in the study group ranged in age from 8 to 23 years 7 months (mean, 15 years 8 months). The most common anatomic site was the lower extremity (12/22, 55%) followed by the upper extremity (4/22, 18%). The maximal tumor diameter ranged from 2.3 to 20.0 cm (median, 5.9 cm). All tumors imaged with MRI had flow voids (19/19, 100%), and 19 (19/22, 86%) had large peripheral vessels, lobulated margins, and nodular internal architecture. Unenhanced T1-weighted MRI was available for 18 tumors: 14 (14/18, 78%) appeared slightly hyperintense to muscle. Of the 16 tumors imaged with contrast material, 11 (11/16, 69%) showed intense enhancement and five (5/16, 31%), moderate enhancement. Six tumors (6/16, 38%) had a thick enhancing peripheral rim with a nonenhancing center consistent with necrosis.
The imaging features of ASPS include flow voids, large peripheral vessels, internal nodularity, and lobulated margins. Contrast administration produces intense to moderate enhancement, sometimes with a thick enhancing peripheral rim around central necrosis. Extremity tumors with these imaging features in a child or young adult should suggest the diagnosis of ASPS.
Intergroup Rhabdomyosarcoma Study Group (IRSG) studies III and IV showed improved failure-free survival (FFS) rates with vincristine, dactinomycin, and cyclophosphamide (VAC; total cumulative ...cyclophosphamide dose, 26.4 g/m(2)) compared with vincristine and dactinomycin (VA) for patients with subset-one low-risk embryonal rhabdomyosarcoma (ERMS; stage 1/2 group I/II ERMS or stage 1 group III orbit ERMS). The objective of Children's Oncology Group ARST0331 was to reduce the length of therapy without compromising FFS for this subset of low-risk patients by using VA in combination with lower-dose cyclophosphamide (total cumulative dose, 4.8 g/m(2)) plus radiotherapy (RT).
This noninferiority prospective clinical trial enrolled newly diagnosed patients with subset-one clinical features. Therapy included four cycles of VAC followed by four cycles of VA over 22 weeks. Patients with microscopic or gross residual disease at study entry received RT.
With a median follow-up of 4.3 years, we observed 35 failures among 271 eligible patients versus 48.4 expected failures, calculated using a fixed outcome based on the FFS expected for similar patients treated on the IRSG D9602 protocol. The estimated 3-year FFS rate was 89% (95% CI, 85% to 92%), and the overall survival rate was 98% (95% CI, 95% to 99%). Patients with paratesticular tumors had the most favorable outcome. Three-year cumulative incidence rates for any local, regional, or distant failures were 7.6%, 1.5%, and 3.4%, respectively.
Shorter-duration therapy that included lower-dose cyclophosphamide and RT did not compromise FFS for patients with subset-one low-risk ERMS.
ABSTRACT
Sphingosine 1‐phosphate (S1P) is a bio‐active lipid that can function both extracellularly and intracellularly to mediate a variety of cellular processes. Using lipid affinity matrices and a ...radiolabeled lipid binding assay, we reveal that S1P directly interacts with the transcription factor peroxisome proliferator‐activated receptor (PPAR) γ. Herein, we show that S1P treatment of human endothelial cells (ECs) activated a luciferase‐tagged PPAR‐γ‐specific gene reporter by ~12‐fold, independent of the S1P receptors. More specifically, in silico docking, gene reporter, and binding assays revealed that His323 of the PPAR‐γ ligand binding domain is important for binding to S1P. PPAR‐γ functions when associated with coregulatory proteins, and herein we identify that peroxisome proliferator‐activated receptor‐γ coactivator 1 (PGC1)β binds to PPAR‐γ in ECs and their progenitors (nonadherent endothelial forming cells) and that the formation of this PPAR‐γ:PGC1β complex is increased in response to S1P. ECs treated with S1P selectively regulated known PPAR‐γ target genes with PGC1β and plasminogen‐activated inhibitor‐1 being increased, no change to adipocyte fatty acid binding protein 2 and suppression of CD36. S1P‐induced in vitro tube formation was significantly attenuated in the presence of the PPAR‐γ antagonist GW9662, and in vivo application of GW9662 also reduced vascular development in Matrigel plugs. Interestingly, activation of PPAR‐γ by the synthetic ligand troglitazone also reduced tube formation in vitro and in vivo. To support this, Sphk1‐/‐ Sphk2+/‐ mice, with low circulating S1P levels, demonstrated a similar reduction in vascular development. Taken together, our data reveal that the transcription factor, PPAR‐γ, is a bona fide intracellular target for S1P and thus suggest that the SlP:PPAR‐γ:PGC1β complex may be a useful target to manipulate neovascularization.—Parham, K. A., Zebol, J. R., Tooley, K. L., Sun, W. Y., Moldenhauer, L. M., Cockshell, M. P., Gliddon, B. L., Moretti, P. A., Tigyi, G., Pitson, S. M., Bonder, C. S. Sphingosine 1‐phosphate is a ligand for peroxisome proliferator‐activated receptor‐γ that regulates neoangiogenesis. FASEB J. 29, 3638‐3653 (2015). www.fasebj.org
•LCN2 is robustly upregulated in the central nervous system during acute and chronic inflammation.•Chronic, but not acute, central LCN2 treatment alters hippocampal cell composition.•Decreased mature ...neurons, but increased newborn neurons, Microgliosis, Immune cell invasion.•Cellular composition alterations in the hippocampus occur through MC4R-independent pathways.•Mice treated with chronic LCN2 display impaired spatial recognition memory.
Lipocalin 2 (LCN2) is a pleiotropic molecule that is induced in the central nervous system (CNS) in several acute and chronic pathologies. The acute induction of LCN2 evolved as a beneficial process, aimed at combating bacterial infection through the sequestration of iron from pathogens, while the role of LCN2 during chronic, non-infectious disease remains unclear, and recent studies suggest that LCN2 is neurotoxic. However, whether LCN2 is sufficient to induce behavioral and cognitive alterations remains unclear. In this paper, we sought to address the role of cerebral LCN2 on cognition in both acute and chronic settings. We demonstrate that LCN2 is robustly induced in the CNS during both acute and chronic inflammatory conditions, including LPS-based sepsis and cancer cachexia. In vivo, LPS challenge results in a global induction of LCN2 in the central nervous system, while cancer cachexia results in a distribution specific to the vasculature. Similar to these in vivo observations, in vitro modeling demonstrated that both glia and cerebral endothelium produce and secrete LCN2 when challenged with LPS, while only cerebral endothelium secrete LCN2 when challenged with cancer-conditioned medium. Chronic, but not short-term, cerebral LCN2 exposure resulted in reduced hippocampal neuron staining intensity, an increase in newborn neurons, microglial activation, and increased CNS immune cell infiltration, while gene set analyses suggested these effects were mediated through melanocortin-4 receptor independent mechanisms. RNA sequencing analyses of primary hippocampal neurons revealed a distinct transcriptome associated with prolonged LCN2 exposure, and ontology analysis was suggestive of altered neurite growth and abnormal spatial learning. Indeed, LCN2-treated hippocampal neurons display blunted neurite processes, and mice exposed to prolonged cerebral LCN2 levels experienced a reduction in spatial reference memory as indicated by Y-maze assessment. These findings implicate LCN2 as a pathologic mediator of cognitive decline in the setting of chronic disease.
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