Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). It is characterized by the t(15;17)(q22;q11.2) chromosomal translocation that creates the promyelocytic ...leukemia-retinoic acid receptor α (PML-RARA) fusion oncogene. Although this fusion oncogene is known to initiate APL in mice, other cooperating mutations, as yet ill defined, are important for disease pathogenesis. To identify these, we used a mouse model of APL, whereby PML-RARA expressed in myeloid cells leads to a myeloproliferative disease that ultimately evolves into APL. Sequencing of a mouse APL genome revealed 3 somatic, nonsynonymous mutations relevant to APL pathogenesis, of which 1 (Jak1 V657F) was found to be recurrent in other affected mice. This mutation was identical to the JAK1 V658F mutation previously found in human APL and acute lymphoblastic leukemia samples. Further analysis showed that JAK1 V658F cooperated in vivo with PML-RARA, causing a rapidly fatal leukemia in mice. We also discovered a somatic 150-kb deletion involving the lysine (K)-specific demethylase 6A (Kdm6a, also known as Utx) gene, in the mouse APL genome. Similar deletions were observed in 3 out of 14 additional mouse APL samples and 1 out of 150 human AML samples. In conclusion, whole genome sequencing of mouse cancer genomes can provide an unbiased and comprehensive approach for discovering functionally relevant mutations that are also present in human leukemias.
We announce the discovery of KELT-23Ab, a hot Jupiter transiting the relatively bright (V = 10.3) star BD+66 911 (TYC 4187-996-1), and characterize the system using follow-up photometry and ...spectroscopy. A global fit to the system yields host-star properties of K, , , , (cgs), and . KELT-23Ab is a hot Jupiter with a mass of , radius of , and density of g cm−3. Intense insolation flux from the star has likely caused KELT-23Ab to become inflated. The time of inferior conjunction is and the orbital period is days. There is strong evidence that KELT-23A is a member of a long-period binary star system with a less luminous companion, and due to tidal interactions, the planet is likely to spiral into its host within roughly a gigayear. This system has one of the highest positive ecliptic latitudes of all transiting planet hosts known to date, placing it near the Transiting Planet Survey Satellite and James Webb Space Telescope continuous viewing zones. Thus we expect it to be an excellent candidate for long-term monitoring and follow up with these facilities.
Abstract
Policy- and decision-makers require assessments of status and trends for marine species, habitats, and ecosystems to understand if human activities in the marine environment are sustainable, ...particularly in the face of global change. Central to many assessments are statistical and dynamical models of populations, communities, ecosystems, and their socioeconomic systems and management frameworks. The establishment of a national system that could facilitate the development of such model-based assessments has been identified as a priority for addressing management challenges for Australia’s marine environment. Given that most assessments require cross-scale information, individual models cannot capture all of the spatial, temporal, biological, and socioeconomic scales that are typically needed. Coupling or integrating models across scales and domains can expand the scope for developing comprehensive and internally consistent, system-level assessments, including higher-level feedbacks in social–ecological systems. In this article, we summarize: (i) integrated modelling for marine systems currently being undertaken in Australia, (ii) methods used for integration and comparison of models, and (iii) improvements to facilitate further integration, particularly with respect to standards and specifications. We consider future needs for integrated modelling of marine social–ecological systems in Australia and provide a set of recommendations for priority focus areas in the development of a national approach to integrated modelling. These recommendations draw on—and have broader relevance for—international efforts around integrated modelling to inform decision-making for marine systems.
The purpose of this study was to evaluate the effect of obesity and obesity-associated factors on the outcomes of patients with cervical cancer. Outcomes were evaluated in 591 patients with FIGO Ib ...to IV cervical cancer treated uniformly with definitive radiation. Patients were stratified into 3 groups based upon pretreatment Body Mass Index (BMI): A ≤ 18.5; B 18.6 - 34.9; and C ≥ 35. The 5-year freedom from failure rates were 58, 59, and 73% for BMI groups A, B, and C (p = 0.01). Overall survival rates were 50, 59, and 68%, respectively (p = 0.02). High expression of phosphorylated AKT (pAKT) was associated with poor outcomes only in non-obese patients. Obese patients with PI3K pathway mutant tumors had a trend toward favorable outcomes, while a similar effect was not observed in non-obese patients. Compared to similar tumors from non-obese hosts,
and
mutant tumors from obese patients failed to express high levels of phosphorylated AKT and its downstream targets. These results show that patients with obesity at the time of diagnosis of cervical cancer exhibit improved outcomes after radiation. PI3K/AKT pathway mutations are common in obese patients, but are not associated with activation of AKT signaling.
Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), ...normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.
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► Normal HSPCs contain random background mutations that increase with aging ► AML genomes contain hundreds of mutations, but very few are recurrent ► Comparison of M1 and M3 AML genomes identifies initiating versus cooperating mutations ► Most AML mutations are probably background events in HSPCs, “captured” by cloning
Comparison of the genomes of two groups of patients, each with a different form of AML, allows the resolution of potential driver and cooperating mutations in each disease and reveals that the genetic history of all AML cases is marked by random, benign mutations acquired by normal HSPCs as a function of age.
1 Department of Biochemistry, 7 Department of Pathology, and 8 Division of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 2 Department of Biochemistry ...and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan; 3 Geenebaum Cancer Center, 4 Department of Biochemistry and Molecular Biology, 5 Graduate Program in Life Science, and 6 Department of Pathology, University of Maryland, Baltimore, Maryland; and 9 Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, District of Columbia
Submitted 7 May 2009
; accepted in final form 10 June 2009
Matriptase, a transmembrane serine protease, is broadly expressed by, and crucial for the integrity of, the epithelium. Matriptase is synthesized as a zymogen and undergoes autoactivation to become an active protease that is immediately inhibited by, and forms complexes with, hepatocyte growth factor activator inhibitor (HAI-1). To investigate where matriptase is activated and how it is secreted in vivo, we determined the expression and activation status of matriptase in seminal fluid and urine and the distribution and subcellular localization of the protease in the prostate and kidney. The in vivo studies revealed that while the latent matriptase is localized at the basolateral surface of the ductal epithelial cells of both organs, only matriptase-HAI-1 complexes and not latent matriptase are detected in the body fluids, suggesting that activation, inhibition, and transcytosis of matriptase would have to occur for the secretion of matriptase. These complicated processes involved in the in vivo secretion were also observed in polarized Caco-2 intestinal epithelial cells. The cells target latent matriptase to the basolateral plasma membrane where activation, inhibition, and secretion of matriptase appear to take place. However, a proportion of matriptase-HAI-1 complexes, but not the latent matriptase, appears to undergo transcytosis to the apical plasma membrane for secretion. When epithelial cells lose their polarity, they secrete both latent and activated matriptase. Although most epithelial cells retain very low levels of matriptase-HAI-1 complex by rapidly secreting the complex, gastric chief cells may activate matriptase and store matriptase-HAI-1 complexes in the pepsinogen-secretory granules, suggesting an intracellular activation and regulated secretion in these cells. Taken together, while zymogen activation and closely coupled HAI-1-mediated inhibition are common features for matriptase regulation, the cellular location of matriptase activation and inhibition, and the secretory route for matriptase-HAI-1 complex may vary along with the functional divergence of different epithelial cells.
hepatocyte growth factor activator inhibitor-1; secretion; protease
Address for reprint requests and other correspondence: C.-Y. Lin, Greenebaum Cancer Center, Dept. of Biochemistry and Molecular Biology, Univ. of Maryland Baltimore, BRB 10-027, 655 W. Baltimore St., Baltimore, MD 21201 (e-mail: cylin{at}som.umaryland.edu )
During mammalian ovary formation, the production of ovarian follicles is accompanied by an enormous loss of germ cells. It is not known how this loss is regulated. We have investigated the role of ...the Trk tyrosine kinase receptors, primarily TrkB, in this process. The ovaries of TrkB â/â and TrkC â/â mice with a mixed (129Sv à C57BL/6) genetic background were examined shortly after birth. Around 50% of TrkB â/â mice had grossly abnormal ovaries that contained greatly reduced numbers of follicles. No defects were found in the ovaries of TrkC â/â mice. Congenic TrkB â/â mice were generated on 129Sv and C57BL/6 backgrounds: whereas the former had a mixed ovarian phenotype similar to that of the original colony of mice, the ovaries of all offspring of the C57BL/6 congenic line contained reduced numbers of follicles. RT-PCR showed that mRNA encoding TrkB and its two ligands, neurotrophin 4 (NT4) and brain-derived neurotrophic factor (BDNF), were present throughout the period of follicle formation in the mouse. In situ hybridisation showed that TrkB was expressed primarily in the germ cells before and after follicle formation. Mouse neonatal and fetal ovaries and human fetal ovaries were cultured in the presence of K252a, a potent inhibitor of all Trk receptors. In mice, K252a inhibited the survival of germ cells in newly formed (primordial) follicles. This effect was rescued by the addition of basic fibroblast growth factor (bFGF) to the culture medium. Combined addition of both BDNF and NT4 blocking antibodies lowered germ-cell survival, indicating that these TrkB ligands are required in this process. The results indicate that signalling through TrkB is an important component of the mechanism that regulates the early survival of female germ cells.
To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of ...neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute encephalitis syndrome (AES) in children poses a significant public health challenge in India. This study aims to explore the utility of host inflammatory mediators and neurofilament (NfL) ...levels in distinguishing etiologies, assessing disease severity, and predicting outcomes in AES. We assessed 12 mediators in serum (n = 58) and 11 in cerebrospinal fluid (CSF) (n = 42) from 62 children with AES due to scrub typhus, viral etiologies, and COVID‐associated multisystem inflammatory syndrome (MIS‐C) in Southern India. Additionally, NfL levels in serum (n = 20) and CSF (n = 18) were examined. Clinical data, including Glasgow coma scale (GCS) and Liverpool outcome scores, were recorded. Examining serum and CSF markers in the three AES etiology groups revealed notable distinctions, with scrub typhus differing significantly from viral and MIS‐C causes. Viral causes had elevated serum CCL11 and CCL2 compared with scrub typhus, while MIS‐C cases showed higher HGF levels than scrub typhus. However, CSF analysis showed a distinct pattern with the scrub typhus group exhibiting elevated levels of IL‐1RA, IL‐1β, and TNF compared with MIS‐C, and lower CCL2 levels compared with the viral group. Modeling the characteristic features, we identified that age ≥3 years with serum CCL11 < 180 pg/mL effectively distinguished scrub typhus from other AES causes. Elevated serum CCL11, HGF, and IL‐6:IL‐10 ratio were associated with poor outcomes (p = 0.038, 0.005, 0.02). Positive CSF and serum NfL correlation, and negative GCS and serum NfL correlation were observed. Median NfL levels were higher in children with abnormal admission GCS and poor outcomes. Measuring immune mediators and brain injury markers in AES provides valuable diagnostic insights, with the potential to facilitate rapid diagnosis and prognosis. The correlation between CSF and serum NfL, along with distinctive serum cytokine profiles across various etiologies, indicates the adequacy of blood samples alone for assessment and monitoring. The association of elevated levels of CCL11, HGF, and an increased IL‐6:IL‐10 ratio with adverse outcomes suggests promising avenues for therapeutic exploration, warranting further investigation.
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