Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, ...suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.
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•ATRTs are comprised of three epigenetically distinct subgroups: TYR, SHH, and MYC•H3K27Ac enhancer landscapes reveal ATRT subgroup-specific regulatory networks•Regulatory networks lead to identification of potential therapeutic targets•Epigenetic profiles point at distinct cellular origins of ATRT subgroups
SMARCB1 is the sole highly recurrently mutated gene in atypical teratoid/rhabdoid tumors (ATRTs). Johann et al. show that ATRTs are composed of three epigenetic subgroups that have different clinical characteristics, and identify subgroup-specific regulatory networks that suggest potential therapeutic targets.
Here, we present results from sediments collected in the Argentine Basin, a non‐steady state depositional marine system characterized by abundant oxidized iron within methane‐rich layers due to ...sediment reworking followed by rapid deposition. Our comprehensive inorganic data set shows that iron reduction in these sulfate and sulfide‐depleted sediments is best explained by a microbially mediated process—implicating anaerobic oxidation of methane coupled to iron reduction (Fe‐AOM) as the most likely major mechanism. Although important in many modern marine environments, iron‐driven AOM may not consume similar amounts of methane compared with sulfate‐dependent AOM. Nevertheless, it may have broad impact on the deep biosphere and dominate both iron and methane cycling in sulfate‐lean marine settings. Fe‐AOM might have been particularly relevant in the Archean ocean, >2.5 billion years ago, known for its production and accumulation of iron oxides (in iron formations) in a biosphere likely replete with methane but low in sulfate. Methane at that time was a critical greenhouse gas capable of sustaining a habitable climate under relatively low solar luminosity, and relationships to iron cycling may have impacted if not dominated methane loss from the biosphere.
Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy ...is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic
NF1
inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was
FGFR1
mutation, which conferred an additional growth advantage in multiple complementary experimental murine
Nf1
models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts.
Context.
Isotopologue line intensity ratios of circumstellar molecules have been widely used to trace the photospheric elemental isotopic ratios of evolved stars. However, depending on the molecular ...species and the physical conditions of the environment, the isotopologue ratio in the circumstellar envelope (CSE) may deviate considerably from the stellar atmospheric value.
Aims.
In this paper, we aim to examine how the
12
CO/
13
CO and H
12
CN/H
13
CN abundance ratios vary radially due to chemical reactions in the outflows of asymptotic giant branch (AGB) stars and the effect of excitation and optical depth on the resulting line intensity ratios. We study both carbon-rich (C-type) and oxygen-rich (O-type) CSEs.
Methods.
We performed chemical modeling to derive radial abundance distributions of our selected species in the CSEs over a wide range of mass-loss rates (10
−8
<
Ṁ
< 10
−4
M
⊙
yr
−1
). We used these as input in a non-local thermodynamic equilibrium radiative transfer code to derive the line intensities of several ground-state rotational transitions. We also test the influence of stellar parameters, physical conditions in the outflows, the intensity of the interstellar radiation field, and the importance of considering the chemical networks in our model results.
Results.
We quantified deviations from the atmospheric value for typical outflows. We find that the circumstellar value of
12
CO/
13
CO can deviate from its atmospheric value by up to 25–94% and 6–60% for C- and O-type CSEs, respectively, in radial ranges that depend on the mass-loss rate. We show that variations of the intensity of the interstellar radiation field and the gas kinetic temperature can significantly influence the CO isotopologue abundance ratio in the outer CSEs of both C-type and O-type. On the contrary, the H
12
CN/H
13
CN abundance ratio is stable throughout the CSEs for all tested mass-loss rates. The radiative transfer modeling shows that the integrated line intensity ratio
I
12
CO
/
I
13
CO
of different rotational transitions varies significantly for stars with mass-loss rates in the range from 10
−7
to 10
−6
M
⊙
yr
−1
due to combined chemical and excitation effects. In contrast, the excitation conditions for the HCN isotopologues are the same for both isotopologues.
Conclusions.
We demonstrate the importance of using the isotopologue abundance profiles from detailed chemical models as inputs to radiative transfer models in the interpretation of isotopologue observations. Previous studies of circumstellar CO isotopologue ratios are based on multi-transition data for individual sources and it is difficult to estimate the errors in the reported values due to assumptions that are not entirely correct according to this study. If anything, previous studies may have overestimated the circumstellar
12
CO/
13
CO abundance ratio. The use of the HCN molecule as a tracer of C isotope ratios is affected by fewer complicating problems, but we note that the corrections for high optical depths are very large in the case of high-mass-loss-rate C-type CSEs; and in O-type CSEs the H
13
CN lines may be too weak to detect.
DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1–3, intermediate A and B, and malignant. ...Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of
NF2
inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of
DMD
were found to be enriched in MCs with
NF2
mutations, and
DMD
was among the most differentially upregulated genes in
NF2
mutant compared to
NF2
wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super enhancer near the
HOXD
gene cluster in this MC, which, together with general upregulation of
HOX
genes in the malignant MC, indicates a role of
HOX
genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging HRR as a novel therapeutic target.
Polypyrimidine tract-binding protein (PTB) is an RNA-binding protein with multiple functions in the regulation of RNA processing and IRES-mediated translation. We report here overexpression of PTB in ...a majority of epithelial ovarian tumors revealed by immunoblotting and tissue microarray (TMA) staining. By western blotting, we found that PTB was overexpressed in 17 out of 19 ovarian tumor specimens compared to their matched-normal tissues. By TMA staining, we found PTB expression in 38 out of 44 ovarian cancer cases but only in two out of nine normal adjacent tissues. PTB is also overexpressed in SV40 large T-antigen immortalized ovarian epithelial cells compared to normal human ovarian epithelial cells. Using doxycycline-inducible small interfering RNA technology, we found that knockdown of PTB expression in the ovarian tumor cell line A2780 substantially impaired tumor cell proliferation, anchorage-independent growth and in vitro invasiveness. These results suggest that overexpression of PTB is an important component of the multistep process of tumorigenesis, and might be required for the development and maintenance of epithelial ovarian tumors. Moreover, because of its novel role in tumor cell growth and invasiveness, shown here for the first time, PTB may be a novel therapeutic target in the treatment of ovarian cancer.
Background
Hypogonadism is a worldwide problem among men causing sexual, physical and mental problems. Testosterone therapy is the first‐choice treatment for male hypogonadism, with several side ...effects, that is, subfertility. Clomiphene citrate (CC) is an alternative off‐label therapy for a certain group of hypogonadal males, especially for those with an active or future child wish. There is scarce literature in usage of CC for men with hypogonadism. The aim of this retrospective study was to evaluate the effectiveness and safety of CC for hypogonadal males.
Methods
In this single‐centre study, men treated with CC for hypogonadism were evaluated retrospectively. Primary outcome was hormonal evaluation including total testosterone (TT), free testosterone (FT), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Secondary outcomes were hypogonadal symptoms, metabolic and lipid parameters, haemoglobin (Hb), haematocrit (Ht), prostate specific antigen (PSA), side effects, the effect of a trial without medication and potential predictors for biochemical and clinical response.
Results
In total, 153 hypogonadal men were treated with CC. Mean TT, FT, LH and FSH increased during treatment. TT increased from 9 to 16 nmol/L, with a biochemical increase in 89% of the patients. In patients who continued CC treatment, an increased level of TT persisted after 8 years of treatment. With CC treatment, 74% of the patients experienced hypogonadal symptom improvement. LH at the lower normal range before CC treatment was predictive for better TT response. During CC therapy, few side effects were reported and no clinical important changes in PSA, Hb and Ht were found.
Conclusion
Clomiphene citrate is an effective therapy on short and long term, improving both clinical symptoms and biochemical markers of male hypogonadism with few side effects and good safety aspects.
This retrospective study shows the good short and long‐term outcomes of clomiphene citrate on testosterone in hypogonadal males with good safety aspects.
RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with ...metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points.
Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored.
At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months 95% confidence interval (CI) 15.1–26.7 with everolimus-sunitinib and 22.2 months (95% CI 16.0–29.8) with sunitinib-everolimus hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9–1.6. Median OS was 22.4 months (95% CI 18.6–33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8–33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9–1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences.
Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals.
ClinicalTrials.gov identifier, NCT00903175
The purpose of this study was to examine the acute effects of static stretching on peak torque (PT), the joint angle at PT, mean power output (MP), electromyographic (EMG) amplitude, and ...mechanomyographic (MMG) amplitude of the vastus lateralis (VL) and rectus femoris (RF) muscles during maximal, voluntary concentric isokinetic leg extensions at 60 and 240 degrees x s(-1) of the stretched and unstretched limbs. Twenty-one volunteers mean age (SD) 21.5 (1.3) years performed maximal, voluntary concentric isokinetic leg extensions for the dominant and non-dominant limbs at 60 and 240 degrees x s(-1). Surface EMG (muVrms) and MMG (mVrms) signals were recorded from the VL and RF muscles during the isokinetic tests. PT (Nm), the joint angle at PT, and MP (W) were calculated by a dynamometer. Following the initial isokinetic tests, the dominant leg extensors were stretched using four static stretching exercises. After the stretching, the isokinetic tests were repeated. PT decreased (P< or =0.05) from pre- to post-stretching for the stretched limb at 60 and 240 degrees x s(-1) and for the unstretched limb at 60 degrees x s(-1). EMG amplitude of the VL and RF also decreased (P< or =0.05) from pre- to post-stretching for the stretched and unstretched limbs. There were no stretching-induced changes (P>0.05) for the joint angle at PT, MP, or MMG amplitude. These findings indicated stretching-induced decreases in force production and muscle activation. The decreases in PT and EMG amplitude for the unstretched limb suggested that the stretching-induced decreases may be due to a central nervous system inhibitory mechanism.
Our previous study revealed that two splicing factors, polypyrimidine tract-binding protein (PTB) and SRp20, were upregulated in epithelial ovarian cancer (EOC) and knockdown of PTB expression ...inhibited ovarian tumor cell growth and transformation properties. In this report, we show that knockdown of SRp20 expression in ovarian cancer cells also causes substantial inhibition of tumor cell growth and colony formation in soft agar and the extent of such inhibition appeared to correlate with the extent of suppression of SRp20. Massive knockdown of SRp20 expression triggered remarkable apoptosis in these cells. These results suggest that overexpression of SRp20 is required for ovarian tumor cell growth and survival. Immunohistochemical staining for PTB and SRp20 of two specialized tissue microarrays, one containing benign ovarian tumors, borderline/low malignant potential (LMP) ovarian tumors as well as invasive EOC and the other containing invasive EOC ranging from stage I to stage IV disease, reveals that PTB and SRp20 are both expressed differentially between benign tumors and invasive EOC, and between borderline/LMP tumors and invasive EOC. There were more all-negative or mixed staining cases (at least two evaluable section cores per case) in benign tumors than in invasive EOC, whereas there were more all-positive staining cases in invasive EOC than in the other two disease classifications. Among invasive EOC, the majority of cases were stained all positive for both PTB and SRp20, and there were no significant differences in average staining or frequency of positive cancer cells between any of the tumor stages. Therefore, the expression of PTB and SRp20 is associated with malignancy of ovarian tumors but not with stage of invasive EOC.
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