Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of ...PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (
DICER1
,
DROSHA
, and
DGCR8
) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic
MYC-miR-17/92-RB1
pathway were observed in the RB and MYC sub-group, respectively, characterized by
RB1
loss with gain of
miR-17/92
, and recurrent gain or amplification of
MYC
. PB sub-groups exhibited distinct clinical features: group 1–3 arose in older children (median ages 5.2–14.0 years) and had intermediate to excellent survival (5-year OS of 68.0–100%), while Group RB and MYC PB patients were much younger (median age 1.3–1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.
Mononuclear iron(III) species with end-on and side-on peroxide have been proposed or identified in the catalytic cycles of the antitumor drug bleomycin and a variety of enzymes, such as cytochrome ...P450 and Rieske dioxygenases. Only recently have biomimetic analogues of such reactive species been generated and characterized at low temperatures. We report the synthesis and characterization of a series of iron(II) complexes with pentadentate N5 ligands that react with H2O2 to generate transient low-spin FeIII−OOH intermediates. These intermediates have low-spin iron(III) centers exhibiting hydroperoxo-to-iron(III) charge-transfer bands in the 500−600-nm region. Their resonance Raman frequencies, νO - O, near 800 cm-1 are significantly lower than those observed for high-spin counterparts. The hydroperoxo-to-iron(III) charge-transfer transition blue-shifts and the νO - O of the Fe−OOH unit decreases as the N5 ligand becomes more electron donating. Thus, increasing electron density at the low-spin Fe(III) center weakens the O−O bond, in accord with conclusions drawn from published DFT calculations. The parent (N4Py)FeIII(η1-OOH)2+ (1a) ion in this series (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine) can be converted to its conjugate base, which is demonstrated to be a high-spin iron(III) complex with a side-on peroxo ligand, (N4Py)FeIII(η2-O2)+ (1b). A detailed analysis of 1a and 1b by EPR and Mössbauer spectroscopy provides insights into their electronic properties. The orientation of the observed 57Fe A-tensor of 1a can be explained with the frequently employed Griffith model provided the rhombic component of the ligand field, determined by the disposition of the hydroperoxo ligand, is 45° rotated relative to the octahedral field. EXAFS studies of 1a and 1b reveal the first metrical details of the iron−peroxo units in this family of complexes: (N4Py)FeIII(η1-OOH)2+ has an Fe−O bond of 1.76 Å, while (N4Py)FeIII(η2-O2)+ has two Fe−O bonds of 1.93 Å, values which are in very good agreement with results obtained from DFT calculations.
Abstract
Young children with embryonal brain tumors including medulloblastoma (MB), supratentorial primitive neuro-ectodermal tumor, or pineoblastoma have historically been considered high-risk ...patients with poor outcomes despite the use of intensive radiation-sparing treatment. In the ACNS0334 phase III trial, 91 consented children <36 months old with the above diagnoses were randomized to intensive induction chemotherapy with or without methotrexate followed by consolidation with stem cell rescue. Here we present the results of a centralized integrated molecular analysis including global methylation profiling (65/91), and whole exome sequencing of tumor (46/91) and germline (35/91) DNA. Unsupervised clustering analyses of methylation profiles using multiple orthogonal methods against a reference dataset of 1200 pediatric brain tumors, revealed known and new molecular entities. For tumors diagnosed as MB on central pathology review, 7.3% (3/41) had a non-MB molecular diagnosis (2 embryonal tumor with multiple rosettes/ETMR, 1 group MYC pineoblastoma), with the remainder as MB Group SHH (11/41), Group3 (25/41), and Group4 (2/41). Among histologic non-MBs, 3/24 (12.5%) were molecular entities not intended for trial inclusion (1 each for ATRT, pleomorphic xanthoastrocytoma, and high-grade glioma). ETMR, historically considered a rare entity, was molecularly identified in a significant proportion (14/65; 21.5%) of samples. Among MB-SHH, we detected deleterious PTCH1 mutations in 6/9 tumors but none among 5 germline samples tested; a germline SUFU frameshift mutation with tumor LOH was also observed in MB-SHH. Correlation of these and other molecular features to the parallel clinical analysis will yield important markers of risk stratification and predictors of treatment response.
Summary Loss-of-heterozygosity (LOH) analysis of archival tumor tissue can aid in determining the clinical significance of BRCA variants. Here we describe an approach for assessing LOH in ...formalin-fixed, paraffin-embedded (FFPE) tissues using variant-specific probes and droplet digital polymerase chain reaction (ddPCR). We evaluated LOH in 2 related breast cancer patients harboring a rare missense BRCA2 variant of unknown clinical significance (c.6966G>T; M2322I). Conventional PCR followed by Sanger sequencing suggested a change in allelic abundance in the FFPE specimens. However, we found no evidence of LOH as determined by the allelic ratio (wild type–variant) for BRCA2 in both patients’ archival tumor specimens and adjacent normal control tissues using ddPCR. In summary, these experiments demonstrate the utility of ddPCR to quickly and accurately assess LOH in archival FFPE tumor tissue.
Pineoblastoma (PB) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB ...to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular subgroups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each subgroup. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss of function alterations in miRNA biogenesis genes (
DICER1
,
DROSHA
, and
DGCR8
) in 62 and 100% of group 1 and 2 tumors respectively. Recurrent alterations of the oncogenic
MYC-miR-17/92-RB1
pathway were observed in the RB and MYC subgroup, respectively characterized by
RB1
loss with gain of
miR-17/92
, and recurrent gain or amplification of
MYC
. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age <3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibit substantial molecular heterogeneity with sub-group associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.
Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no ...longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction-induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelter in complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and TERT corrected in human HCC. Finally, SIRT1-silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy.
We present ground-based and Swift observations of iPTF16fnl, a likely tidal disruption event (TDE) discovered by the intermediate Palomar Transient Factory (iPTF) survey at 66.6 Mpc. The light curve ...of the object peaked at an absolute mag . The maximum bolometric luminosity (from optical and UV) was erg s−1, an order of magnitude fainter than any other optical TDE discovered so far. The luminosity in the first 60 days is consistent with an exponential decay, with , where t0 = 57631.0 (MJD) and days. The X-ray shows a marginal detection at erg s−1 (Swift X-ray Telescope). No radio counterpart was detected down to 3 , providing upper limits for monochromatic radio luminosities of erg s−1 and erg s−1 (Very Large Array, 6.1 and 22 GHz). The blackbody temperature, obtained from combined Swift UV and optical photometry, shows a constant value of 19,000 K. The transient spectrum at peak is characterized by broad He ii and H emission lines, with FWHMs of about 14,000 km s−1 and 10,000 km s−1, respectively. He i lines are also detected at λλ 5875 and 6678. The spectrum of the host is dominated by strong Balmer absorption lines, which are consistent with a post-starburst (E+A) galaxy with an age of ∼650 Myr and solar metallicity. The characteristics of iPTF16fnl make it an outlier on both luminosity and decay timescales, as compared to other optically selected TDEs. The discovery of such a faint optical event suggests a higher rate of tidal disruptions, as low-luminosity events may have gone unnoticed in previous searches.
Summary Background The scale-up of tobacco control, especially after the adoption of the Framework Convention for Tobacco Control, is a major public health success story. Nonetheless, smoking remains ...a leading risk for early death and disability worldwide, and therefore continues to require sustained political commitment. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) offers a robust platform through which global, regional, and national progress toward achieving smoking-related targets can be assessed. Methods We synthesised 2818 data sources with spatiotemporal Gaussian process regression and produced estimates of daily smoking prevalence by sex, age group, and year for 195 countries and territories from 1990 to 2015. We analysed 38 risk-outcome pairs to generate estimates of smoking-attributable mortality and disease burden, as measured by disability-adjusted life-years (DALYs). We then performed a cohort analysis of smoking prevalence by birth-year cohort to better understand temporal age patterns in smoking. We also did a decomposition analysis, in which we parsed out changes in all-cause smoking-attributable DALYs due to changes in population growth, population ageing, smoking prevalence, and risk-deleted DALY rates. Finally, we explored results by level of development using the Socio-demographic Index (SDI). Findings Worldwide, the age-standardised prevalence of daily smoking was 25·0% (95% uncertainty interval UI 24·2–25·7) for men and 5·4% (5·1–5·7) for women, representing 28·4% (25·8–31·1) and 34·4% (29·4–38·6) reductions, respectively, since 1990. A greater percentage of countries and territories achieved significant annualised rates of decline in smoking prevalence from 1990 to 2005 than in between 2005 and 2015; however, only four countries had significant annualised increases in smoking prevalence between 2005 and 2015 (Congo Brazzaville and Azerbaijan for men and Kuwait and Timor-Leste for women). In 2015, 11·5% of global deaths (6·4 million 95% UI 5·7–7·0 million) were attributable to smoking worldwide, of which 52·2% took place in four countries (China, India, the USA, and Russia). Smoking was ranked among the five leading risk factors by DALYs in 109 countries and territories in 2015, rising from 88 geographies in 1990. In terms of birth cohorts, male smoking prevalence followed similar age patterns across levels of SDI, whereas much more heterogeneity was found in age patterns for female smokers by level of development. While smoking prevalence and risk-deleted DALY rates mostly decreased by sex and SDI quintile, population growth, population ageing, or a combination of both, drove rises in overall smoking-attributable DALYs in low-SDI to middle-SDI geographies between 2005 and 2015. Interpretation The pace of progress in reducing smoking prevalence has been heterogeneous across geographies, development status, and sex, and as highlighted by more recent trends, maintaining past rates of decline should not be taken for granted, especially in women and in low-SDI to middle-SDI countries. Beyond the effect of the tobacco industry and societal mores, a crucial challenge facing tobacco control initiatives is that demographic forces are poised to heighten smoking's global toll, unless progress in preventing initiation and promoting cessation can be substantially accelerated. Greater success in tobacco control is possible but requires effective, comprehensive, and adequately implemented and enforced policies, which might in turn require global and national levels of political commitment beyond what has been achieved during the past 25 years. Funding Bill & Melinda Gates Foundation and Bloomberg Philanthropies.
Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group ...trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT.
Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for
status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored.
Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (
< .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients.
The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.
PDF
