Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel–Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.
Neuroendocrine tumors (NETs) are rare neoplasms originating from neuroendocrine cells most commonly located in the endocrine glands but also in the gastrointestinal and bronchopulmonary systems (Fig. 1) (1). NETs usually display slow proliferation but have a high rate of advanced stage at presentation (2, 3). Neuropeptide hypersecretion is a hallmark of these diseases and often results in distinct hormonal syndromes. These syndromes are associated with both increased morbidity and mortality (2, 4). The median survival of patients with well differentiated NETs is about 10 years, contributing to the relatively high prevalence of these diseases (5, 6).
Overview of genes with recurrent mutations in NETs and their distribution accordingly to anatomical location.
NET is one of the most heritable groups of neoplasms that feature in at least ten genetic syndromes. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. In this review we will present relevant genetic information regarding these diagnostic entities. We will also summarize data from tumor sequencing studies that provided comprehensive maps of the genomic landscape of NETs. Finally we comment on the current and future potential of these data as tools for the development of biomarkers as well as novel druggable targets. Below we present syndromes and additional susceptibility genes with increased risk of NET development (Table 1). The present paper reviews genetic profiles, by means of early and late mutations, of relevance for tumorigenesis in NETs.
Genetic syndromes with NET manifestation. Overview of genetic syndromes that involve NETs; penetrance of NETs at the specified location is presented in parenthesis; figures on penetrance are presented when available.
a Penetrance in MEN2 is specific to the particular mutation.
Multiple endocrine neoplasia type 1 (MEN1; OMIM 131100) is one of the first described autosomal dominantly inherited complex endocrine syndromes (7). MEN1 has a high penetrance, over 90% by age 40, and is present in about three per 100 000 individuals. Gene carriers most frequently develop tumors in the parathyroid glands (95%), the anterior pituitary (20–40%), and in the endocrine cells of the pancreas/duodenum (40–80%) (8). Any of these can be the presenting lesion, and typically clinically detectable in the young adult, although rare cases of childhood tumors are reported. By definition MEN1 is present if two of these classical target tissues are affected by tumors, and familial MEN1 includes at least one relative with a corresponding tumor. Apart from the above-mentioned organs, MEN1 carriers frequently develop NETs of the foregut, e.g. bronchial, thymic, and gastric ECLomas. Adrenocortical lesions, mostly non-secreting, hyperplasias or adenomas but also rare cases of adrenocortical carcinomas are also present in MEN1 patients. The most lethal of the MEN1 lesions are the pancreatic and the thymic NETs which frequently develop into metastatic disease. Several non-endocrine tumors are also overrepresented in MEN1 patients, such as facial angiofibromas, collagenomas, lipomas and meningeomas. The typical clinical picture of the disease is highly variable between family members and dependent of the affected organs and the pattern of hypersecreted hormones in each case.
In 1988 the MEN1 gene was linked to chromosome 11q13 and suggested to be a suppressor (9). The gene was finally identified by positional cloning, and heterozygous germline inactivating MEN1 mutations was revealed in 70% of typical index cases (10). The proportion of MEN1 patients with a causative MEN1 mutation was later estimated to 75–95% (11). By now more than 1000 mutations have been recognized. The vast majority causes truncation of the protein. The most likely cases to reveal a germline MEN1 mutation are probands developing lesions at young age and show multiple tumors per organ. There is no convincing genotype–phenotype correlation identified so far. Furthermore if a mutation cannot be found it does not exclude MEN1 and recently alternative genes giving rise to syndromes resembling MEN1 have been suggested, e.g. germline CDKN1B (p27kip) mutations resulting in MEN4 (12). It have also been postulated that common genetic variants within CDKN1B could act as disease modifiers in MEN1, possibly contributing to the observed clinical heterogeneity (13).
Classical MEN1 tumorigenesis depends on a second MEN1 hit, by means of a somatic mutation eliminating also the WT allele. But some NETs in MEN1, such as thymic and duodenal NETs, do not to necessary require a complete inactivation of the gene (14). Somatic homozygous inactivation of MEN1 is also frequently seen in sporadic tumors of the MEN1 target organs.
The MEN1 protein, named menin, is ubiquitously expressed and preferentially located in the nucleus (10). It has been suggested to be a scaffold protein with more than 40 interacting proteins and thus are involved in a large number of biological functions, such as chromatin modification, DNA repair, transcription, cell division, protein degradation, motility and adhesion (15). Several Men1 knock-out mouse models mimicking the human syndrome are available.
Multiple endocrine neoplasias type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC) are autosomal dominantly inherited disorders characterized by development of multiple endocrine MTC, pheochromocytoma (PCC) and parathyroid adenomas (reviewed in Wells et al. (16)). MEN2 subtype A (OMIM 171400) accounts for about 80% of cases with an almost complete penetrance for MTC, while PCC and parathyroid adenoma are seen in about 50 and 30% of patients (17). MEN2B (Omim 162300) includes more aggressive MTC, dysmorphic marfanoid features but no parathyroid adenoma (18).
MEN2 and FMTC are caused by gain of function mutations in the rearranged during transfection (RET) protooncogene, localized on chromosome 10, which encodes a receptor tyrosine kinase (19, 20, 21). Gain of function mutations in RET result in autonomous activation that transduces activating signals through the RAS/MAPK and PI3K/AKT pathways (22). A majority of MEN2 and FMTC cases reveal constitutional mutations in the cysteine-rich extracellular domains (exons 10–11) of the RET gene (23), while disease causing variants within RET non-cysteine regions (exons 13–16) are less common and the related phenotype is characterized by pronounced heterogeneity (24). Patients with constitutional RET mutations show strong genotype–phenotype correlations, e.g. codon 634 transitions linked to MEN2A and codon 918 mutations linked to MEN2B. It is critical to recognize the specific RET mutation in order to optimize patient and family management, particularly for the timing of prophylactic thyroidectomy and to provide information on the risk of developing PCC and parathyroid adenoma (25, 26).
FMTC (OMIM 155240) is characterized exclusively by MTC. It has been suggested that FMTC show less aggressive disease characteristics than MTC occurring in the context of MEN2A and B (16, 27).
Multiple endocrine neoplasia type 4 (MEN4; OMIM 610755) is a rare syndrome that is thought to predispose development of NETs, mainly parathyroid and pituitary adenomas. The trait is inherited through germline mutations in CDKN1B encoding p27kip (12). MEN4 seems to occur in an autosomal dominant fashion and is linked to loss of function mutations in the cell cycle regulator CDKN1B (12). Future studies have to be performed to confirm the phenotype and penetrance of CDKN1B mutations.
Neurofibromatosis type 1 (NF1; OMIM 162200) is an autosomal dominant syndrome that is characterized by multiple endocrinopathies and nervous system manifestations (28). The most common features are fibromatous skin tumors, lichen eye nodules, optic gliomas and café-au-lait spots (29). Endocrinopathies are less common and include PCCs and duodenal NETs (30). Neurofibromatosis type 1 is caused by loss of function mutations in NF1 that has been linked to deregulation of both rat sarcoma viral oncogene homolog (RAS) proteins and the ERK/MAPK signaling pathway (31, 32).
The von Hippel–Lindau syndrome (VHL; OMIM 193300) syndrome has an incidence of ∼1/36 000 individuals (33) and is an autosomal dominant disease. VHL is characterized by increased risk of tumors and cysts; retinal and CNS hemangioblastomas, PCC, paragangliomas (PGLs), renal clear cell carcinomas, renal cysts, pancreatic NETs, pancreatic cysts and endolymphatic sac tumors.
The syndrome is caused by inactivating mutations in the VHL tumor suppressor gene, located in 3p25 that is involved in the oxygen-sensing pathway through regulation of hypoxia-inducible factors (34). Truncation of VHL results in decreased ubiquitination of HIF transcription factors resulting in increased expression of target genes such as VEGFA etc. VHL is subclassified into type 1 (truncating mutations) and type 2 (missense mutations) that differ in clinical presentation (35). Subtype 1 presents without PCC whereas type 2 have a high penetrance of PCC. Subtype 2 may be further subclassified into type 2A without renal cell carcinoma or pancreatic cysts that may be present in subtype 2B.
There are at least 12 genes that have proved to confer susceptibility to PCCs and/or PGLs: SDHA (36), SDHB (37), SDHC (38), SDHD (39), SDHAF2 (40), FH (41), VHL (42), EPAS1 (43), NF1 (32), RET (20), TMEM127 (44) and MAX (45). The classic genetic syndromes MEN2, NF1 and VHL have been presented above. In the following section we will give an overview to more recently described diagnoses that show pronounced heterogeneity both in term of the affected organs, disease penetrance and mode of inheritance.
Familial PGL syndromes types 1–5 are transmitted in an autosomal dominant manner. These syndromes are caused by the loss of function mutations in SDHD (PGL 1), SDHAF2 (PGL 2), SDHC (PGL 3), SDHB (PGL 4) and SDHA (PGL 5). SDHx genes (SDHA, SDHB, SDHC and SDHD) encode succinate dehydrogenase subunits that are catalyzing reactions in tricarboxylic acid cycle and in the respiratory electron transfer chain. Due to the disruption of the tricarboxylic acid cycle the associated PGL harbor unique metabolic profiles with accumulation of oncometabolites (46). Although familial PGL syndromes share pathogenic mechanisms, with disruption of the succinate dehydrogenase complex, the phenotype varies between the different subtypes (47). The molecular rationale for this heterogeneity remains to be identified. Paternal transmission has been shown to occur in PGL 1 and 2.
Familial PGL type 1 (OMIM 168000) have an almost complete penetrance for parasympathetic tumors in the head–neck region (48, 49). Furthermore, unilateral PCC and/or sympathetic PGLs are seen in about 25% of patients respectively (50, 51).
Familial PGL type 2 (OMIM 601650) has so far only been detected in a few European families (40, 52, 53, 54), and all reported patients have presented with parasympathetic lesions.
Familial PGL type 3 (605373) is also a rare condition that is mainly manifested by parasympathetic tumors (55, 56, 57).
Familial PGL type 4 (OMIM 115310) is associated with significant morbidity and increased mortality due to the substantial risk of development of malignant sympathetic PGLs (51, 58, 59). PCC and parasympathetic PGL also occur. In addition, patients with PGL 4 have an increased risk of developing gastrointestinal stromal tumors (GIST) as well as renal cell carcinoma (50).
Familial PGL type 5 (OMIM 614165) is associated with PCC, PGL as well as GIST. Concomitant presentation of two or more of these three tumor types seems to be exceedingly rare (36, 60, 61).
Patients with familial PCC and PGL of the TMEM127 subtype (OMIM 613403) have an estimated penetrance of PCC of 30% whereas abdominal PGL are less frequent (44, 62, 63, 64). No other phenotypes have been described. This disorder presents in patients with loss of function mutations in the Transmembrane protein 127 gene that is linked to dysinhibition of the mammalian target of rapamycin (mTOR) pathway.
Myc-associated factor X (MAX) associated familial PCC and PGL (OMIM 154950) is an autosomal dominant disorder with a suggested paternal mode of transmission (45, 65). These patients show susceptibility to PCCs and PGLs with unknown penetrance. No other phenotypes have been described. This syndrome is caused by loss of function mutations in MAX that results in deregulation the MYC–MAX–MXD1 pathway (45).
Fumarate hydratase (FH) associated PCC and PGL (OMIM 136850) is an autosomal dominant syndrome previously known to result in susceptibility to leimyomatosis and renal call cancer (OMIM 150800 (66)). PCC and PGL was recently recognized as a feature of this syndrome and the penetrance is currently unknown (41, 67, 68). The syndrome is caused by function mutations in FH that results in reduced enzymatic activity with fumarate accumulation.
A recent study described germline mutations in MDH2 as a cause of PGL (69). Although this finding needs to be confirmed, it is indeed remarkable that MDH2 is the third Krebs cycle gene suggested to be involved in PGL tumorigenesis (69).
Disruption of oxygen sensing is also a recurrent disease mechanism in NETs. The recently recognized polycytemia and PGL syndrome was shown to occur as a result gain of function mutations in EPAS1 that resulted in a pseudohypoxic state through reduction in HIF2α degradation mediated by disturbed VHL binding (43, 70, 71, 72). The mode of inheritance for the polycytemia and PGL syndrome (OMIM 603349) is currently unknown due to near exclusive presentation in mosaicism. These patients are prone to develop PGL, PCC, polycytemia and somatostatinoma (72). A recent study also suggested ocular manifestations in patients with polycytemia and PGL syndrome (73). A majority of patients with mosaic mutations have had female gender and the underlying mechanism for this phenomenon is unknown (72).
Tuberous sclerosis complex subtypes 1 and 2 (OMIM 191100 and 613254) are autosomal dominant syndromes that occur in 1:6000–10 000 individuals (74, 75, 76). These patients show multiorgan manifestations; mainly hamartomas but also angiomyolipomas, renal cell carcinoma and pulmonary lymphangioleiomyomatosis (reviewed by Curatolo et al. (77)). Pancreatic NET is a less frequent manifestation (78). These syndromes are due to the loss of function mutations in TSC1 and TSC2 that encode proteins forming the tuberin–hamartin complex that is essential for mTOR signaling (79). Somatic mutations in TSC2 occur frequently in pancreatic NETs (80).
Hyperparathyroidism-jaw tumor syndrome (OMIM 145001) is an autosomal dominant syndrome caused by truncating mutations in the HRPT2 located on 1q31.2 (81). It is characterized by adenomatous or malignant lesions of the parathyroids, jaw tumors, as well as renal and uterine tumors (82, 83).
Compared with other tumor types the genetic landscape of NETs is characterized by relatively few mutations and chromosomal aberrations per tumor (Fig. 2). So far, around 24 genes have been associated with neuroendocrine tumorigenesis (Table 2). These genes seem to interconnect to important pathways involved in cell metabolism, chromatin modification and growth control (Fig. 3).
Overview of mutational burden in NETs merged from raw data in (80, 85, 86, 87, 98, 99, 100, 104, 117, 120, 121, 122, 128, 136, 137). Each dot represents a unique tumor, and the line shows the median number of mutations of each category. PT, parathyroid.
List of genes involved in neuroendocrine tumorigenesis. Overview of genes involved in NET tumorigenesis. ALT, alternative lengthening of telomeres.
Simplified overview of genes and pathways involved in NET tumorigenesis.
Constitutional mutations in CDC73 (81), MEN1 (84), RET (20) and possibly CDKN1B (12) and CASR (83) cause susceptibility to parathyroid adenoma. Two exome sequencing studies investigated the genomic landscape of parathyroid adenomas and discovered somatic MEN1 mutations in 35% of cases (85, 86). A third study investigated the exomes of parathyroid carcinomas identified recurrent mutations in the PRUNE2 gene (87). The median number of somatic amino acid substituting mutations per adenoma was eight (range 2–100) (86). Parathyroid carcinomas harbored more mutations (synonymous average 51, range 3–176) that showed an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) like mutational signature (87). APOBEC associated genomic instability is a result of cytosine-to-uracil deamination that is catalyzed by APOBEC3A-H enzymes and have been shown to occur in multiple different types of carcinomas (88).
Constitutional mutations in MEN1 (84), VHL (42), NF1 (32), EPAS1 (somatostatinoma) (43), as well as TSC1 and 2 (74, 75) cause susceptibility to pancreatic NETs. CDKN1B have also been suggested as a susceptibility locus, but limited numbers of cases have been presented (12). In sporadic pancreatic NETs ATRX, DAXX, MEN1, TP53, ATM and mTOR pathway related genes are commonly mutated in a somatic fashion (80, 89, 90, 91). Pancreatic NETs harboring somatic mutations in ATRX and DAXX have been associated with chromosomal instability and reduced survival (92). It has been suggested that ATRX and DAXX mutations are not involved in the initial phase of tumorigenesis. Instead these mutations are thought to be late events that result in malignant transformation of PNETs (92, 93). The proposed pathogenic mechanism of ATRX and DAXX deficiency is the activation of the alternative lengthening of telomeres phenotype (94, 95). This phenotype has been associated with genome rearrangements, defects in the G2/M checkpoint and altered double-strand break repair (95). It have also been suggested that ATRX/DAXX mutations lead to differential epigenetic deregulation (96). The mean number of amino acid substituting somatic mutations in non-functioning pancreatic NETs were 16 (80). The degree of chromosomal aberrations is more variable and ranges from no somatic copy number alterations to genome-wide aneuploidy (92, 97).
Insulin producing pancreatic NETs with manifest hypoglycemic symptoms, i.e. insulinomas, have been identified with recurrent somatic mutations in YY1. This gene encodes a nuclear transcription factor and the described recurrent mutation Thr372Arg has been shown to result in neomorphic effects and altered transcription (98, 99, 100). Insulinomas exhibit a low mutational burden and the average amino acid substituting mutations were four per tumor (98, 99, 100). High chromosomal instability has been recognized in a subset of insulinomas especially in those with malignant features (101).
Although limited studies have been presented, evidence indicates that the genetics of duodenal and gastric NETs overlap with the profile observed in pancreatic NETs (90, 102).
Germline mutations in RET cause MEN 2 and FMTC; both syndromes showing high penetrance of MTC (20). MTC from MEN2 patients rarely show any other somatic driver mutations (103). Investigating the genomic landscape of sporadic MTCs revealed mutually exclusive oncogenic mutations in RET and RAS subtypes K and H in 75 and 15% respectively (104, 105, 106). Furthermore there were an average of 18 amino acid substituting somatic mutations per MTC (104). ALK gene fusions were recently described in two out of 98 investigated cases suggesting that ALK inhibition might further be evaluated for treatment of these rare tumors (107, 108).
Theory of evolution, with relevant driver genes, in NET tumorigenesis. The 15 genes involved in pheochromocytoma and PGL tumorigenesis are: SDHx, SDHAF2, MDH2, VHL, EPAS1, NF1, RET, HRAS, TMEM127, MAX, KIF1B and KMT2D.
This section describes the genomic findings of well differentiated NETs derived from the broncopulmonary system. These have classically been denoted typical and atypical pulmonary carcinoids based on morphological criteria (126). Pulmonary carcinoids occur in about 5% of MEN1 patients (127). One study examining genome-wide mutation status in 44 sporadic pulmonary carcinoids identified three genes with recurrent mutations: MEN1, PSIP1 and ARID1A (128). Network analysis of genes with somatic mutations extended the number of cases with relevant mutations, 40% had covalent histone modifiers and 22% subunits of the SWI/SNF complex (22%) (128). The occurrence of somatic MEN1 mutations in sporadic pulmonary carcinoids have previously been highlighted (129). There were the averages of 13 protein-altering mutations per sample (128). Differential expression of miRNAs in typical vs atypical lung carcinoids has also been reported (130).
NET of the thymus is a part of MEN1 syndrome with a penetrance of <10% (8). CGH analysis found recurrent copy number alterations with the most commonly disturbance identified being gain of 8q24 (MYC locus) (131). Mutational screening of tumor tissue has been performed on a per case-basis with the finding of a few somatic MEN1 mutations (132).
Small intestinal NETs (SI-NETs) have also been described to occur with familial aggregation in a small fraction of patients (133, 134). Despite substantial efforts no definitive genetic basis for this phenomenon has been described. A recent study used linkage analysis and exome sequencing that revealed IPMK germline mutations in a single family (135). Although experimental investigations seem to indicate a pathogenic effect of the IPMK mutation a validation effort that included 32 additional families did not reveal the presence of any additional mutations (135). Thus IPMK inactivation is not likely to be a significant cause of familial SI-NET. The genomic landscape of SI-NETs has been investigated with exome coverage in close to 100 tumor samples (136, 137). Recurrent mutations were only identified in the CDKN1B gene with a mutation prevalence of 9% of SI-NET patients (136, 137, 138). Instead, the most frequent genomic alteration is hemizygous deletions affecting chromosome 18q (133, 136, 137, 139). Recent data have shown that SI-NETs can be sub-classified based on tumor methylome into three distinct clusters (140, 141). Sub classification of SI-NETs based on gene expression may also provide relevant information (142).
As clinicians seek to select treatments based on genetic biomarkers, knowledge of spatial and temporal heterogeneity could be important and should be researched further. Indeed genetic heterogeneity within and between paired tumors has been described in most NET types. Consistent with the theoretical assumption that MEN1 patients experience parallel development of independent NET clones, studies using loss of heterozygosity (LOH) LOH markers were able to show that paired tumors from MEN1 patients have unique genetic compositions (143, 144). In contrast, X-chromosome inactivation studies of sporadic parathyroid adenomas, gastrinomas, gastric-NETs and MTCs indicate that these tumors develop in a monoclonal fashion (145, 146, 147, 148). Multiple intestinal tumor lesions have been observed in about 20% of SI-NET patients (149). Whether these are the consequences of independent tumor formation or metastatic spread remain to be settled (144, 145). Recent studies highlighted that a subset of SI-NETs show pronounced genetic heterogeneity within and between tumor lesions (136, 138). Korpershoek et al. (150) determined, by using LOH markers, that there is genetic heterogeneity within different areas of selected PCCs and PGLs. Furthermore they recognized that adrenal medullary hyperplasia in MEN2 patients is in fact a precursor lesion for PPGL (151). Widespread genetic heterogeneity within these tumors as well as and between paired lesions has been recently shown (152). Of particular notice was the observed differences between paired primary and metastatic tumor lesions as well as indication of parallel evolution of different metastatic clones (152).
Precision medicine, where the unique properties of patients and tumors are used to tailor diagnostic and therapeutic procedures is now the standard of care of selected cancer types. For instance in carcinomas of the lung and gastrointestinal system knowledge of tumor mutation status is used to predict the response of treatment and detect the emergence of resistance during treatment with kinase signaling inhibitors (153, 154). The concept of precision medicine has also been useful in the management of patients with NETs, mainly for identification of those with genetic syndromes, enabling genetic counseling followed by appropriate diagnostic measures. However, knowledge of tumor mutation status is not yet used on a routine basis in NETs. Ongoing research is currently investigating whether specific RET mutations could predict the success of treatment with receptor kinase inhibitors (NCT01945762) in MTC. Another hypothesis that needs to be tested is that mutations in genes involved in mTOR signaling could be used as biomarkers of rapalogue response (155, 156).
Recent times also saw the publication of experimental findings in NETs that could be important for the development of future therapies: both combination therapy with FAK and mTOR inhibitors (157) as well as inhibition of B-catenin in MEN1 deficient pancreatic NETs (158). Immunotherapy is also an emerging branch in cancer treatment where the knowledge of tumor genetics and biology has proved to be important for prediction. Through determination of the degree of genomic instability and the neo-antigen immunoreactivity the success of PD-1 and CTLA-4 blockade may be estimated (159, 160). On the experimental level mapping the unique somatic mutations present in a particular tumor can also be used to design personalized tumor vaccination protocols (161). Furthermore, genetic instability could be targeted in ATRX or DAXX mutated tumors as they harbor the unique alternative lengthening of telomeres phenotype. Recent experimental data suggest that such tumors are sensitive to ATR inhibition (162).
However hypotheses based on extrapolation of data from basic NET research needs to be thoroughly tested in a clinical setting. There is an on-going debate whether currently available NET models are representative for human NET disease, supported by the discrepancies of the genomic landscape between NETs and commonly used cell lines (163, 164). Interpretation of basic science data must therefore be made with caution.
In order to screen for genetic disturbances in the established NET genes in a cost effective manner, reliable protocols for novel deep sequencing techniques should be implemented (165, 166). These techniques could also facilitate improvement of diagnostic yield of patients with suspicion of heritable disease. It has also been proposed that deep sequencing can improve the sensitivity in the detection of somatic mutations, especially in scenarios with a low tumor cell fraction (167). Current strategies to analyze tumor genomes are limited by the need of sufficient amount of good quality tumor tissue. In the future peripheral blood samples (liquid biopsies) containing either circulating tumor cells or circulating cell free DNA might instead be used for recognition of the genomic landscape of the individual tumors (168, 169).
Our research is supported by Lions Cancerforskningsfond Uppsala and Swedish Cancer Foundation. Joakim Crona holds a research position funded by Akademiska Sjukhuset.
We thank Professor Peter Stålberg for his valuable suggestions and comments.
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ROGERSVILLE — When new Hawkins County Director of Schools Matt Hixson addressed every teacher and administrator during two assemblies in early January, he said his immediate goal would be getting to know the system.
He took over on Jan. 30.
His short-term goals were to spend time at each school, walk each campus with the administrative team, visit classrooms, ask what's working and what's not and if there are sufficient resources to tackle what needs improvement.
Hixson, who previously served as assistant director of the San Jacinto, California, school system, also planned on meeting with each school board member to discuss what's going well in their district and what needs improvement.
A little more than a month later, Hixson met with the Times News to talk about his observations and the direction he'd like to help take Hawkins County Schools.
How much progress have you made in your goal of visiting with every school, administrator and school board member?
I'm still meeting folks. I've met with each board member individually, and my next course of action is to follow up with each of the principals, directors and supervisors individually, just to get their take on the strengths of the district as a whole, strengths of their department, strengths of their school site, and note any challenges or areas of deficit they see now that we can focus on heading into next year.
There were a lot of positive results on last year's state report card, but the blaring negative was scoring at Level 1 overall. That's a huge elephant in the room you'll have to deal with.
You're absolutely right. I think there's two ways to look at student achievement data. One is, how many kids are reaching that proficiency target — meeting or exceeding state standards? And then there's another way of looking at it. Where we get the kids at the start of the year, and how much growth they've shown throughout the year. Both sets of data are equally important. No district is ever going to get to the point where you've got 80-90 percent "exceeding" (standards). You may get close to that in "meeting" (standards) which is everybody's target, but a lot of students bring in things that need to be worked on, so I feel the goal first and foremost is to see where they're at, diagnose them early on, at the start of the school year, and then chart them on a course for continued growth throughout the year. If we can make up some of that ground each year, by the time we have them three or four years, down the road hopefully they stay with us long enough to let that play out, and all of a sudden they're meeting or exceeding standards.
What are some of your biggest hindrances to success?
We're seeing a lot more emotional needs with our kids coming in, mental health needs with our kids coming in at early ages. Kindergarten and first grade have been impacted by that this year, not only here in Hawkins but the district that I came from. We had a lot more younger students bringing in a lot more non-educational related needs.
Did your previous district have a high poverty level like Hawkins County?
Yes. We were Title 1 across the board. We were 100 percent free and reduced lunch.
It seems like there are more troubled children now than any other time I can remember in my lifetime.
I think you're absolutely right. We are actually working with our Special Ed Department and others at the state level to determine what this is being caused by, and we're thinking with the drug use that has played out the past several years, we're starting to see the kids being impacted unfortunately. We've got a big enough job just focusing on academics. Now we're faced with how do we weave in some of the prerequisite skill sets that, when we were in school, that most kids came to school with? The models of behavior. The expectations at home. Boundaries. We're not seeing that across the board, so we're having to reteach that. Hopefully we're getting them in preschool and kindergarten, and we can start to be proactive early on.
And then hope everything you build at school doesn't get torn down at home.
That's the struggle. In the future, you'll see a lot of our resources aimed at helping parents out too. A lot of our parents are young. A lot of our parents, this is their first time around with a child in school. Part of our job, if at all possible, is to team with other agencies to see if we can get that education across the board, not only for the kids, but in some cases for the parents. I think the work ethic is something we don't always see exemplified at home.
What other challenges have you observed so far that you plan on addressing?
If I really had to narrow it down to one thing now, I think "preparedness" is the catchphrase of the day. We educate and we graduate. That's in our mission statement. But I think we also need to look at how we prepare our kids for real world work and life situations.
How does CTE (career/technical education) fit into your plan?
In education we typically push for every kid to graduate and go to a four-year university. That's the model of success for an educational system. But I think we're doing ourselves a disservice if we're not supporting kids who want to learn a trade, who want to go into the military, who want to go to community college and figure things out first. I'm not taking away from tracking kids toward a four-year university if they're academically ready and socially ready for that challenge. But we should be placing equal emphasis on other alternatives such as our CTE programs. I really want to build on that as long at the board supports that decision.
Have you had a chance to look over Hawkins County's CTE program, and if so, what do you think of it?
I love it. I was talking with (CTE Supervisor) Wes Smith over the past few days, and he's got good plans on continuing and expanding our partnerships with local businesses to get kids out there learning real life skills, build upon their strengths and interests and provide our workforce here some suitable young adults who are ready for the workforce. We've got another TCAT meeting where we're looking to expand partnerships and internships with the Phipps Bend Industrial Park. There are several industries there asking for some students who might be able to take their academic classes in the morning and then head over to a plant and learn those job-related skills in the afternoons. If we can do that along with our dual enrollment programs, that's valuable because they can get a taste of college or work experience while they're still in high school.
What other observations have you made in your first month and a half on the job?
I'm a big proponent in school leaders setting the tone at their individual schools. What we typically do in education from the Central Office is set out a one-size-fits-all goal. We should set the boundaries here at Central Office of what we want to see improved, like a 3 percent growth goal in English Language arts or 3 percent growth goal for math or science growth. I really feel my role here is to facilitate the overall direction of the school district, but then allow the principals and teachers to get to know their kids and their needs individually and to tailor those goals further specifically for those kids' needs.
Is that why you're out meeting with principals right now?
Yes. Identifying strengths and weaknesses at every school and to build rapport. I don't want to be a director who catches school sites off guard when I'm there. I want to be there regularly. I want to be visible. I want it to be second hat that I'm there walking around looking at instruction.


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You are here: Best Essay » Free Essays » Julius Caesar essays » What if Julius Caesar survived his assassination?
Because of his leadership style that was characterized by exemplary traits and strengths, survival of Caesar would mean a more enduring Rome founded on strong models of governance and an adequate military process within the country. Had he to follow such autonomies, Caesar would have leveraged Rome in a historic overview supported by his well-monitored state of jurisdiction. Julius Caesar, an excellent politician and army general, lived from 100 BC to 44 BC and was ruler in Rome from 46 to 44 BC. Despite the fact that Caesar ruled for a brief period, he gave Rome new hope and an entire family of emperors. Caesar had an important role to play in the reorganization of the Republic of Rome into the Roman Empire. Born in an upper-class family, Caesar was brought up during bleak times when Rome was unable to manage its power and size (Harris 11). In addition, the upper class was widely discredited, and the once-present order had disappeared to be replaced by chaos. Military dictatorship was the sole clear option.
Caesar would have further employed his former and historical populist strategies of incorporating other important and well-knowledgeable icons on his state leadership thus devolving powers across many people. This would consequently imply that the running of the state would not have solely rested on his hands but in a devolved power distribution. Traditionally, Caesar employed populist strategies as a political icon. Having real power, Julius collaborated with two major persons, Marcus Licinius Crassus and Gnaeus Pompey Magnus toward the close of the 60s and the early 50s BC. Pompey was a battle hero who had previously been badly treated by the Rome Senate. On the other hand, Crassus was a very rich person (Sandner 18). The two individuals were foes, but Caesar managed to bring them together. Therefore, the three men developed the influential first triumvirate. This alliance dominated the Roman political scene for a number of years. If this would have been his future legacy, Rome would have rested on a peaceful and more constitutionally rationale place.
With his zeal on reform program, he could have made Rome a better place to live in by changing the impending traditional models and policies to yet new ones that addressed the needs of the people in a more adaptable manner. His first program, the triumvirate, assumed power in 59 BC after the election of Caesar as consul. The reform program of the triumvirate was endorsed after which Caesar got himself nominated governor in charge of Gaul and Illyricum. Power within Rome was attained via military invasion. Through this method, the general acquired riches from the conquered, a devoted army, as well as prestige and popularity at home. Therefore, the Gaul and Illyricum governorship permitted Caesar to assume the conqueror and general statuses he very much wanted to have.
Julius Caesar started a stunning war of invasion in central Europe. In a sequence of moderately brilliant drives, Caesar added a substantial amount of land to the Roman kingdom within northern Belgium, France, and, southern Great Britain (Baugh 39). He vanquished the Celts within such territories. If Caesar were to follow pursuit to such program implementation, he could have led to more equitable resource distribution for his people and therefore a better country to live in.
He could also have harnessed great strengths chiefly as exemplified in the way he related with his military troops. For example, he allotted land to them as a sign of honoring their struggle that would have led to even stringer and peaceful nation without any external attack. As consul, Julius Caesar wished to recompense Pompey's troops by allotting them community land. Such a move was unpopular, and hence, in order to implement it, Caesar planned for a protest and employed the accompanying melee to implement his wishes. Gaul accorded Julius some power base to conscript troops as well as carry out military drives that were meant to build his name as well as earn himself a fortune (Berlin 26).
Employing his military skills further during his course of living would have meant a more revamped military energy for his troop hence greater levels of safety for his country from external attacks. For instance, Julius Caesar employed his skills in military tactics as well as the discipline and military training of the Roman army to subdue and conquer the other part of Gaul all the way to the Rhine River. This expanded the Roman Empire into the North Sea. During 55 BC, Caesar carried out the initial roman attack of Britain as well. Such accomplishments granted Caesar unrivaled military, threatening to obscure the power wielded by Pompey. The future of his military success required such skills, which were well-endowed in his capacity
With his ideal capacity of statesmanship and writing he could have hallmarked the history of his leadership yet to greater heights by speaking for his people and writing important and persuading commentaries on his leadership. Caesar was among the most famous generals and statesmen history has ever known. His abilities as a speaker were exceptional. Caesar was a talented writer as well.
His character as a ruthless leader was perhaps the most admissible one that would have waged his nation on bounds of political and resource equality as well as fighting for the rights of the weak. For example, when fighting with overseas foes, Julius Caesar exhibited ruthlessness, i.e., surrounding rebels within the present-day Dordogne, Julius waited up to the time their water supply was exhausted after which he severed the hands of every survivor. This was a good example of what he could have done for his people even in the future.
With his insight for his country, he could have brought widely expanded horizons of changes through growth and development of his country. For instance, Julius Caesar diverted his concentration back home. The triumvirate was under extreme pressure. Pompey became increasingly envious of the success of Caesar whereas Pompey was still hated by Crassus. Following the death of Crassus at war, Caesar and Pompey drifted apart, finally finding themselves on opposite sides. This was facilitated by political reorganizations within Rome because Pompey had sided with the Senate. However, Caesar was by this time very successful. On the other hand, Caesar had numerous foes, and hence, his life and his position were threatened. However, his love for Rome ignited him with the reservation of working even harder toward its success.
Julius recorded some initial victories; in 46 BC, he was Rome's dictator for 10 years, an unmatched leader in the Roman world. Caeser was accorded imperium over the empire. He was therefore essentially above the constitution and the law. After one year spent in getting rid of his foes, Caesar went back home. Bighearted in victory, Caesar exhibited kindness toward his beaten foes, according all of them amnesties and also inviting a number of them to his government. He started extensive transformations in the Roman society. Caesar greatly decentralized the red tape of the nation and was therefore declared dictator in perpetuity.
The imperator title of Julius Caesar was yet another hallmark of his future leadership. He led through generosity and courage and put into consideration all the importance officers in the government. This was an ideal aspect for the success of Rome. For example, following his appointment by the Senate as lifetime dictator, in 44 BC, Caesar was accorded the imperator title. Caesar quickly assumed every one of the significant officers within the regime. The word emperor word is derived from this title. Caesar's courage and generosity had greatly popularized him among his troops. However, his arrogance and power infuriated many people. Despite the fact that Caesar rejected being publicly crowned, telling his fans that he was not king but Caesar, the general feeling was that he intended to reinstate the kingdom. His future leadership would thus have put Rome into a remarkable advantage where observation of the rule of law was implicit (Baugh 50).
Additionally, his nature of governance was recognized as remarkable only by the few. This implied that putting his state of governance in such a context, all the structures would have run as expected as no conflict within the internal layout of the same. For example, Caesar reorganized the regime in numerous ways. However, such reorganizing was functionally worthless because Caesar had absolute power. Such absolute power (lifetime imperium) was very much like some monarchy; it was essentially a monarchy. The Roman people, taking pride in their Republican custom, deeply hated Caesar's power.
His dictatorial regime would have been one that would provide social ties for future growth and success of his country. However, Caesar's foes collaborated with several of his fans who had been fed up with his dictatorial regime. On 15th March 44 BC, Caesar was assassinated within the Roman Senate on the Ides of March. At the time of his assassination, Caesar was entering the Senate in his customary method, without protection or bodyguards. The aftermath of Caesar's assassination was that the Roman Republic came to an end. The Roman lower and middle classes, who were die-hard fans of Caesar, were angry that a little clique of noblemen had murdered their icon (Harris 23). Despite the fact that the rule of Caesar was not remarkable, his triumph within the Civil War restored a nation, governed by the Senate and the consuls with a kingdom, ruled by emperors as well as their family heirs. Caesar's assassinators were under the command of Marcus Junius Brutus. The assassinators hoped that the ordinary operation of the nation would resume and that the nation would mysteriously reconcile itself. However, an additional civil war broke out. This very brutal war lasted for 13 years. When such war ended, the Roman Republic had been shattered to an extent that it by no means again appears in history. This was ultimately resulted in the setting up of an enduring autocracy by Gaius Octavian, Julius' adopted heir. Octavian came to be known as the emperor Augustus (Sandner 170).

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Die Liste der Naturdenkmale in Lauchringen nennt die verordneten Naturdenkmale (ND) der im baden-württembergischen Landkreis Waldshut liegenden Gemeinde Lauchringen. In Lauchringen gibt es insgesamt zwei als Naturdenkmal geschützte Objekte, davon ein flächenhaftes Naturdenkmal (FND) und ein Einzelgebilde-Naturdenkmal (END).

Stand: 1. November 2016.

Flächenhafte Naturdenkmale (FND)

Einzelgebilde (END)

Weblinks
 Schutzgebietsverzeichnis der Landesanstalt für Umwelt, Messungen und Naturschutz Baden-Württemberg
 Übersichtstabelle: FND, END

Naturdenkmale
Lauchringen

redpajama_set_name: RedPajamaWikipedia


text:
Q: value in jquery.min.js selectors I'm using jquery and I have a question.
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What does the selectors = {cacheLength: mean in jquery.min.js?
and also is it possible to change the value of cacheLength?

A: Unless you are working on developing the jQuery library itself, you should not be editing the jQuery file.

redpajama_set_name: RedPajamaStackExchange


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Scientists have created a face mask that can detect common respiratory viruses, including influenza and the coronavirus, in the air in droplets or aerosols. The highly sensitive mask, presented September 19 in the journal Matter, can alert the wearers via their mobile devices within 10 minutes if targeted pathogens are present in the surrounding air.
"Previous research has shown face mask wearing can reduce the risk of spreading and contracting the disease. So, we wanted to create a mask that can detect the presence of virus in the air and alert the wearer," says Yin Fang, the study's corresponding author and a material scientist at Shanghai Tongji University.
Respiratory pathogens that cause COVID-19 and H1N1 influenza spread through small droplets and aerosols released by infected people when they talk, cough, and sneeze. These virus-containing molecules, especially tiny aerosols, can remain suspended in the air for a long time.
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Fang and his colleagues tested the mask in an enclosed chamber by spraying the viral surface protein containing trace-level liquid and aerosols on the mask. The sensor responded to as little as 0.3 microliters of liquid containing viral proteins, about 70 to 560 times less than the volume of liquid produced in one sneeze and much less than the volume produced by coughing or talking, Fang says.
The team designed a small sensor with aptamers, which are a type of synthetic molecule that can identify unique proteins of pathogens like antibodies. In their proof-of-concept design, the team modified the multi-channel sensor with three types of aptamers, which can simultaneously recognize surface proteins on SARS-CoV-2, H5N1, and H1N1.
Once the aptamers bind to the target proteins in the air, the ion-gated transistor connected will amplify the signal and alert the wearers via their phones. An ion-gated transistor is a novel type of device that is highly sensitive, and thus the mask can detect even trace levels of pathogens in the air within 10 minutes.
"Our mask would work really well in spaces with poor ventilation, such as elevators or enclosed rooms, where the risk of getting infected is high," Fang says. In the future, if a new respiratory virus emerges, they can easily update the sensor's design for detecting the novel pathogens, he adds.
Next, the team hopes to shorten the detection time and further increase the sensitivity of the sensor by optimizing the design of the polymers and transistors. They are also working on wearable devices for a variety of health conditions including cancers and cardiovascular diseases.
"Currently, doctors have been relying heavily on their experiences in diagnosing and treating diseases. But with richer data collected by wearable devices, disease diagnosis and treatment can become more precise," Fang says.
IMAGE CREDIT: Matter/Wang et al.
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