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Genes 2014, 5(2), 444-459; doi:10.3390/genes5020444
Published: 28 May 2014
Abstract: Traditionally, tumors are classified by histopathological criteria, i.e., based on their specific morphological appearances. Consequently, current therapeutic decisions in oncology are strongly influenced by histology rather than underlying molecular or genomic aberrations. The increase of information on molecular changes however, enabled by the Human Genome Project and the International Cancer Genome Consortium as well as the manifold advances in molecular biology and high-throughput sequencing techniques, inaugurated the integration of genomic information into disease classification. Furthermore, in some cases it became evident that former classifications needed major revision and adaption. Such adaptations are often required by understanding the pathogenesis of a disease from a specific molecular alteration, using this molecular driver for targeted and highly effective therapies. Altogether, reclassifications should lead to higher information content of the underlying diagnoses, reflecting their molecular pathogenesis and resulting in optimized and individual therapeutic decisions. The objective of this article is to summarize some particularly important examples of genome-based classification approaches and associated therapeutic concepts. In addition to reviewing disease specific markers, we focus on potentially therapeutic or predictive markers and the relevance of molecular diagnostics in disease monitoring.
1. Approaches to a Genome-Based Tumor Classification
1.1. The 2008 WHO Classification of Hematological Malignancies
The 2008 WHO classification of chronic myeloid malignancies is at present the most evolved approach to a taxonomy considering defined molecular aberrations [1]. The malignancies that are included are now classified into five categories:
- (1)
Acute myeloid leukemia (AML) and related precursor neoplasms;
- (2)
Myelodysplastic syndromes (MDS);
- (3)
Myeloproliferative neoplasms (MPN);
- (4)
Myelodysplastic/Myeloproliferative neoplasms (MDS/MPN);
- (5)
Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1.
The integration of histology and genetics is particularly visible in the category of myeloproliferative neoplasms (MPN). Classification of specific entities into MPN is dependent on presence or absence of BCR-ABL1, the disease-causing translocation in CML [2]. The first description of the associated karyotype t(9;22)(q34;q11), according to an abnormally short chromosome 22, was published as early as 1960 and is widely known as the Philadelphia (Ph) chromosome [3]. Due to the high specificity of BCR-ABL1, its detection is mandatory for diagnosis of CML and is further underscored by the influence on therapy with the small molecule tyrosine kinase inhibitor (TKI) Imatinib [4]. Nevertheless, the remarkable journey, from the genomic aberration to the specific therapy, required approximately forty years and started long before the elucidation of the human genome (Figure 1).
Further myeloproliferative neoplasms are characterized by the absence of BCR-ABL1, including the three Ph-negative classic MPNs—polycythemia vera (PV), essential thrombocythemia (ET) and progressive myelofibrosis (PMF). Despite the absence of BCR-ABL1, it has consecutively been shown that these MPNs are themselves also characterized by additional recurrent aberrations [5,6] (Figure 1).
The JAK2 V617F mutation is detectable in approximately 95% of all PV patients and 50% of both ET and PMF patients [7,8,9]. It is further detected in patients with refractory anemia with ring sideroblasts and thrombocytosis (RARS-T), but in less than 5% of patients with acute myeloid leukemia (AML) or myeloid dysplastic syndrome (MDS) and not in solid tumors [10,11]. Although, the diagnostic process is initially dominated by peripheral blood cell count and serum erythropoetin (EPO) levels, JAK2 V617F or less common JAK2 Exon 12 mutations [12] confirm the diagnosis of a suspected PV without the need of a bone marrow biopsy [13]. Beside the two most important genetic aberrations in the diagnostic algorithm of MPNs, namely BCR-ABL1 and JAK2 V617F, several other potentially helpful recurrent aberrations are known. These include the presence of recurrent mutations in CALR exon 9 [14] and MPL codon 515 [15], essentially occurring in JAK2 V617F negative cases (Figure 2).
Another important example of the integration of molecular aberrations in the 2008 WHO classification of hematological malignancies is the newly introduced group of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1. This reclassification highlights the consideration of the targetable alterations FIP1L1-PDGFRA or PDGFRB-rearrangements and those harboring FGFR1-rearrangements, indicating response or resistance to Imatinib [2,16].
1.2. Lung Cancer as a Paradigm: Advances in the Molecular Characterization of Solid Malignancies
The ongoing comprehensive characterizations of solid tumors, such as those conducted by The Cancer Genome Atlas (TCGA) will significantly impact upcoming tumor classifications. This also includes lung cancer, the leading cause of cancer death worldwide [17] and an example for substantial advances by genome-based therapy approaches [18]. In general, NSCLC is subclassified into adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Future classifications need to characterize clinically relevant subtypes, instead of the traditional distinction of non-small cell lung cancers (NSCLC) and small-cell lung cancer (SSLC). Concepts for a reclassification of lung adenocarcinoma were suggested, particularly with respect to reclassify large cell carcinoma based on genomic aberrations into adenocarcinoma, squamous cell carcinoma and large cell neuroendocrine carcinoma, respectively. Recommendations for (immuno)histological diagnostic work-up, and also for determining specific molecular aberrations in lung adenocarcinoma subtypes have been published [19].
Major rationales for changes in adenocarcinoma histologic variants are that the invasive mucinous type shows frequent mutations in KRAS and hardly any in EGFR, whereas non-mucinous adenocarcinoma of predominant lepidic subtype is characterized by frequent mutations in EGFR and fewer in KRAS [20]. In this context, it is worth noting and described in more detail below, that clinical studies with the TKIs Gefitinib and Erlotinib showed significantly improved survival in patients suffering from lung adenocarcinoma harboring mutations in the kinase domain of EGFR [21,22]. Besides the mutations in EGFR and KRAS, the targetable translocation EML4-ALK recurrently occurs in lung adenocarcinoma [23] and is most frequent in tumours with mucinous signet-ring appearance. Clinical trials using the tyrosine kinase inhibitors Crizotinib and Ceritinib have now shown improved progression-free survival in those patients [24,25].
In contrast, squamous cell carcinoma of the lung is commonly associated with mutations in the NFE2L2/KEAP-axis [26] and often harbors targetable alterations of FGFR1 [27] and in fewer cases mutations in DDR2. Interestingly, DDR2-transformed cell lines maintain SRC phosphorylation and are sensitive to Dasatinib [28], proved by the response in squamous cell lung cancer patients [29].
Beyond the combined loss of RB1 and TP53 in neuroendocrine pulmonary tumors [30], it was shown that low- and intermediate-grade pulmonary cacinoids harbor recurrent mutations in chromatin remodeling complexes [31], whereas the high-grade neuroendocrine tumor, small cell lung cancer, is associated with sequential changes, including the deletion of PTEN [32].
Additionally, we assessed cancer genome alterations linked to histomorphological and immunohistochemical features, considering high therapeutic relevance and improved patient outcome [33] (Figure 3). By this approach, we devised a genomic-based prediction model of lung cancer subtypes. This model shows that the majority of large cell cancers could be reassigned to adenocarcinoma, squamous cell carcinoma or small-cell lung cancer. By the combined analysis of immunohistochemical, genomic and clinical features it becomes further evident that personalized approaches significantly improve the outcome of patients with advanced lung cancer and other solid cancers.
Beyond the principally well-characterized situation in lung cancer, we already know of highly recurrent genomic alterations in many other solid malignancies. Prostate cancer is the most common cancer in men and is characterized by fewer mutations in typical cancer genes, when compared to other solid cancers [34,35,36]. However, genomic alterations in androgen signaling, the rearrangement of ETS transcription factors, especially the fusion of TMPRSS2-ERG [37], as well as the deletion of PTEN [38] are known to be highly recurrent in primary cancers [39], early-onset cancers [40] and castration-resistant prostate cancers [41]. Beside the outstanding therapeutic role of androgen deprivation, recent efforts investigate a mechanistic rationale of PARP inhibition in ETS-rearranged prostate cancers [42].
1.3. EWS and the Importance of Translocations in the Diagnostic Workup of Mesenchymal Malignancies
Tumors ascribed to the family of Ewing's sarcomas or primitive neuroectodermal tumors (PNET) are the second most common bone tumors in children, but can also arise from any other tissue. The recent molecular understanding of these aggressive tumors has greatly advanced new therapeutic approaches. However, whereas chemotherapy improved the survival rate from 10% to 70%–80% in localized disease, the survival of patients with distant metastases is still poor [43]. The WHO classification of Ewing sarcoma (ES) as a single entity is underlined by its cytogenetic signature t(11;12)(q24;q12), according to the translocation EWSR1-FLI1 in approximately 85% of patients. Although, EWSR1 translocations can be found in many other mesenchymal tumors, almost all of the remaining ES cases are characterized by further ES-specific EWSR1 translocations [44,45]. This also includes the second most common cytogenetic aberration t(21;22)(q22;q12), corresponding to EWSR1-ERG [46] (Table 1).
Intriguingly, the well-characterized molecular situation of ES is in contrast to the fact that the cell of origin of the small round cell appearing tumor is not known. A further complication of the histological diagnosis is caused by atypical ES, including large/epithelioid/clear/spindle cell ES, vascular-like ES, adamantinoma-like ES, ES with neuroectodermal features, synovial sarcoma-like PNET and sclerosing PNET [47]. Beyond this difficult histopathological classification, sarcomas may be genetically classified from a near-diploid karyotpe to a more complex genomic instability. The first is characterized by highly recurrent translocations, the latter by numerical and structural abnormalities affecting multiple chromosomes [48]. In the case of small round cell appearing sarcoma, recently, new subtypes were defined by recurrent translocations of BCOR-CCNB3 [49] and CIC-DUX4 [50].
Furthermore, we already know several diagnostically relevant genomic rearrangements in soft tissue malignancies [51]. The recurrently occurring reciprocal translocation t(X;18) is characteristic of synovial sarcoma, and leads to the potentially therapeutic relevant SSX-S18 protein [52]. The translocation FUS-CHOP is detected in myxoid liposarcoma [53] and recurrent amplifications of the E3-Ubiqutitin ligase MDM2, as well as CDK4, in well differentiated and dedifferentiated liposarcoma [54,55]. Interestingly, ongoing efforts investigate the reactivation of p53 by MDM2-p53 interaction inhibitors [56].
|Table 1. Fusion partners of EWSR1-rearrangements in different soft tissue tumors. Overlapping rearrangements in different histopathological entities are in bold. Adapted from [44,45].
|Histological type
|Ewing's Sarcoma
|Angiomatoid fibrous histiocytoma
|Clear cell sarcoma
|Malignant gastrointestinal neuroectodermal tumor
|Myoepithelial tumor of soft tissue and bone
|Extraskeletal myxoid chondrosarcoma
|Myxoid liposarcoma
1.4. Cancer of Unknown Primary Origin (CUP)
Carcinoma of an unknown primary origin (CUP) is descriptive of a metastatic cancer without an identifiable primary tumor site. CUP accounts for 3%–5% of all cancer diagnoses and is usually characterized by an aggressive metastatic growth and a challenging clinical presentation. In theory, CUP could be considered as a unique biological entity, or in the opposite view, as a group of different entities. The classification of CUP is essentially based on the prognostic outcome, thereby distinguishing favorable and unfavorable carcinomas [57,58,59] (Table 2).
|Table 2. Classification of cancers of unknown primary origin.
|Clinically favorable CUP
|Clinically unfavorable CUP
|Extragonadal germ-cell cancer
|Metastatic adenocarcinoma
|Peritoneal papillary adenocarcinoma
|Non papillary malignant ascites
|Adenocarcinoma in axillary lymph nodes
|Multiple cerebral metastases
|Cervical squamous-cell carcinoma
|Squamous-cell carcinoma of the abdominopelvic cavity
|Neuroendocrine carcinoma
|Lytic bone metastases
|Blastic bone metastases and PSA elevation
This classification predominantly depends on the morphological and immunohistochemical appearance. At present, the specimen is investigated by the use of specific antibodies (investigated epitopes in parentheses):
- (1)
Identification of the cancer type:
Carcinoma CK AE1/3), mesothelioma (Calretinin, BerEP4), sarcoma (Vimentin), lymphoma (LCA), melanoma (HMB-45, MITF, S100);
- (2)
Identification of the subtype:
Adenocarcinoma CK7, CK20), squamous cell carcinoma (CK5/6, p40, p63), hepatocellular carcinoma (Hepar1), renal cell carcinoma (RCC, PAX8, CA9), urothelial carcinoma (GATA3, S100P, Uroplakin), thyroid cancer (hTG, TTF1), neuroendocrine cancer (CD56, Synaptophysin, ChromoA), germ-cell tumor (PLAP);
- (3)
Identification of the origin:
Lung TTF1, NapsinA), colorectal cancer (CDX2, CK20), breast (ER, PR), pancreas (CDX2, CK7, CK20), ovary (Ca125, ER, WT1), prostate (PSA, PSAP, AR).
However, only 30% of all cases studied can be assigned to a primary tumor and even fewer benefit from a change in therapy regimen. Over the last decade, the molecular characterization by gene-expression profiling in various tumor types has led to the development of several gene signature assays with identification rates of a putative tissue of origin in up to 90% of cases. Furthermore, it was shown that CUP can be treated along actionable genomic alterations and recent whole exome sequencing revealed the existence of known recurrent mutations [60]. These include therapeutically relevant mutations in PIK3CA, MET, FGFR3, IDH1 as well as several others and it has been already demonstrated that targeted therapies can significantly influence a more favorable outcome in CUP patients [61]. As another variation on this theme, a drug-sensitizing genome alteration in one tumor type may not confer drug susceptibility in another histology, as has been observed in the case of BRAF mutations that confer MEK and BRAF dependency in melanomas [62,63] but not in colorectal carcinomas resulting from EGFR activation [64]. These interactions highlight the need for classifications integrating cancer genome alterations, but also histomorphological and immunohistochemical features.
2. Monitoring of Malignancies
Molecular monitoring of CML is the most advanced routinely used surveillance strategy and reflects the need for standardization and quality controls of diagnostic tests. A main objective is the identification of patients, which have a worse response or resistance to therapy with tyrosine kinase inhibitors. The quantification of BCR-ABL1 transcripts in peripheral blood is thereby of outstanding value in the early phase after initial drug administration, corresponding to the molecular response rate (MMR) upon TKI therapy [65,66,67]. The MMR is calculated in relation to a control gene (e.g., BCR or ABL1) and was standardized between laboratories using the international scale (IS) [68]. Essentially, the WHO has undertaken extensive efforts to simplify and standardize the assay by providing reference reagents. The importance of such efforts is reflected by a comparable poor overall survival of patients with an early MMR >10%, in turn leading to universally valid changes in the associated NCCN and ELN guidelines [66].
Despite significant progress in therapy of lung adenocarcinoma, all patients with EGFR mutations and ALK or ROS1 translocations receiving specific tyrosine kinase inhibitors will ultimately experience relapse. Recent work highlights the potential of noninvasive detection and monitoring of resistance mutations in free circulating plasma DNA of lung cancer patients. The most prominent example is the known resistance mechanisms mediated by T790M in EGFR [69]. Beside the potential of directly targeting cancers harboring T790M by new tyrosine kinase inhibitors [70], it is important to note that T790M cells proliferate more slowly, thereby enabling resensitizing of tumors to primarily used TKIs after temporary withdrawal of the drug. Since it is difficult in clinical practice to undertake repeat biopsies at multiple metastatic sites, noninvasive targeted sequencing techniques may further enable additional therapeutic strategies [71]. It thereby becomes evident that new diagnostic techniques will not only lead to major influences in treatment and monitoring guidelines, but will influence therapeutic guidelines and also the classification of tumors. Especially, the opportunity of non-invasive testing seems to be an attractive and emerging field in diagnostic and therapeutic concepts, as further delineated by testing for TMPRSS2-ERG in the case of suspicion of prostate cancer [72].
3. Clinical Success of Targeted Therapeutic Approaches Based on Molecular Biomarkers
As depicted above, BCR-ABL1 is the driving lesion in CML, leading to the development of the first small molecule TKI, Imatinib [4,73]. Several multicenter studies confirmed that the overall survival of advanced-stage cancer patients in a chronic disease phase climbed from approximately 50% before 2002 up to approximately 90% after introduction of Imatinib in 2002 [74]. The success of the targeted approach in CML patients is further underscored by ongoing studies investigating the discontinuation of Imatinib [75] and the groundbreaking question of a potential cure [76]. Despite these promising developments, several further therapeutic possibilities for second line therapies are underway. These include the use of second generation TKIs in case of therapeutic failure or intolerance, e.g., Dasatinib, Nilotinib, Bosutinib and Ponatinib, the latter particularly used in case of a secondary resistance by T315I mutation [75] (Figure 1).
The most common melanoma mutation in BRAF exon 15, the activating mutation V600E, leads to response rates of more than 50% of all patients treated with the specific TKI Vemurafenib. Further, therapy with Vemurafenib is associated with a relative reduction in death of 63% when compared to standard therapeutic regime with Dacarbazine [62]. In contrast to the activating biology of BRAF V600E, ongoing clinical trials investigate the potency of Dasatinib in tumors harboring inactivating BRAF exon 11 mutations (NCT01514864 clinicaltrials.gov).
3.3. EGFR-Family and KRAS Mutational Status
Genetic aberrations in members of the EGFR-family are well known for targeted therapies, including HER2- and EGFR-targeted inhibition of downstream signaling cascades. HER2/ERBB2 is primary known as being amplified and activated in breast cancer causing high recurrence rates and increased mortality in approximately 15% of all patients [77]. Patients with amplification of HER2/ERBB2 treated with the monoclonal antibody Trastuzumab in combination with chemotherapy showed improved outcome in several studies [78]. Beyond Trastuzumab several ongoing studies are investigating further drug therapies targeting the HER2-axis. These include the combined inhibition of HER2/HER3-heterodimerization and activation by Trastuzumab/Pertuzumab [79] and the use of the covalent immunoconjugate Trastuzumab-Emtansine (T-DM1) [80] (Figure 4). Moreover, several trials evaluate the therapeutic significance of small molecule inhibition in HER2-positive breast cancer, e.g., Lapatinib, Afatinib, Pazopanib and Neratinib [81].
Comparable to the situation in HER2-amplified breast cancer, substantial progress has been made by the introduction of EGFR-targeted therapies in the treatment of lung cancer and colorectal cancer. These efforts become evident by comparing the median overall survival of lung adenocarcinoma patients under standard therapeutic regimes of approximately 12 months with approximately 2 years under EGFR-targeted therapy with Erlotinib or Gefitinib in EGFR-mutated cancers [82]. As depicted above, further efforts are made to overcome primary and secondary therapeutic resistance by next generation TKIs [70]. Similar positive achievements were made for treatment of metastatic colorectal cancer (mCRC) by an improvement of survival from 12 months with fluoruracil monotherapy up to approximately 2 years with EGFR/VEGFR-targeted therapy combined with chemotherapy [83].
Beyond that, it recently became evident that we need to predict therapeutic response to cetuximab/panitumumab in mCRC not only by KRAS mutational status, but also by NRAS mutational status [84], highlighting the increasing importance of mutations in downstream or interacting pathways. As depicted above, it becomes also clear that combined approaches, like the inhibition of the EGFR/BRAF-axis in BRAF V600E mutated colorectal cancers [64], could be used to overcome primary resistance in histological subtypes.
4. Conclusions
The purpose of integrating pathogenetic and molecular information into disease classification systems, exemplified by the 2008 WHO classification of hematological malignancies, reflects the high clinical relevance for predicting therapy outcome and prognosis. The human genome project and emerging technologies in the last decade have led to fundamental pathogenetic breakthroughs, which substantially improved the translation into clinical practice and individual therapeutic possibilities. Altogether, this data underlines the significant influence of cancer genomics and the substantial increase in genomic information on the process of defining tumor entities and effective and selective treatment approaches.
Author Contributions
Wrote the paper: MK and RB.
Conflicts of Interest
MK declares no conflict of interest. RB is serving on Scientific Advisory Boards and has received lecture honoraria from AstraZeneca, Qiagen, Roche, Lilly, MerckSerono, Pfizer and is a co-founder and co-owner of Targos Molecular Pathology, Inc. RB received grant support from the Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe and the Bundesministerium für Bildung und Forschung (BMBF).
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© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).


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William Turc attorney reviews
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I'm proud of a fellow member from Wisconsin suggesting rules like these haha
Lol the messed up part is we're only down 7...for now.
Jesus we need help
We need Thompson.
I thought our special teams wouldnt be flagged as often now that Campbell is gone but apparently thats not the case!
Did we bring in the replacement refs for our practices or what! We seriously have a flag on every other play!
I should have clarified that. For the remainder of the year, I believe Mett should start.
I feel like Mett played good enough to warrant the starting spot. While I admit I only watched about 3 quarters of the game, I noticed that we had...
This is the first time I've been excited for Titans football since week 2! Hopefully the mettsiah will take us to the promise land!
The thing is, today was supposed to be a glorious day. We started off extremely well and outside of Locker hurting his hand we were on fire....
honestly we win the game today if it wasnt for the horrible timed penalties.
Yeah that was a rough one. Our WR's actually showed up today so thats always a positive. Too bad our defense / QB couldn't keep it together.
This mobile site is terrible! Bring back tapatalk support!
Also I wonder if Locker starts again in the second half?
Lol so much for our defense getting riled up
So what happens if locker lights it up this week?
Hunter has been a total let down as well. He was supposed to be the man this year!!
I can see Jake and the offense settling in a little more. I feel like we'll open it up more so against Dallas since their offense has way more...
I'm just happy we beat a solid AFC opponent.
Hunter :/


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When did we get so stupid?
Find a Conversation
|Sat, 01-22-2011 - 4:13pm
Thought I would kick this new folder off with something that a couple of friends and I have been discussing this week. We are all in our 50s, with kids between 24 & 35 and grandkids under 4. We also worked full time while raising these kids during a time where a father was considered wonderful if he helped in the home.
During the last few weeks, we have all experienced the same reaction from our kids when we foolishly offered advice regarding their kids or lives. In my case, my grandson started running a temperature without cold symptoms for 2 days. Then the runny nose & coughing started. The temp was up & down for 5 days. I suggested seeing a doctor, reaction was it's a waste of time Mom as it's just the flu. We were to baby-sit overnight. No problem but I said that they had to take my grandson to the walk in clinic before dropping him off with us. They reluctantly complied & the poor kid had severe infections in both ears. My DD feels awful now but said she asked him several times if his ears hurt & he said no. Apparently, I ran to the dr too much with my kids which is interesting in that I don't remember ever being there & not having the dr confirm that they needed tests, drugs, etc.. Plus we didn't get to take time off work to deal with family issues. You had to take a vacation day or lie & call in sick yourself. In our province, an employer must give you up to 10 days per year to deal with family illness & most companies pay you for it.
Similar thing happened to my girlfriend, her little grandson had been coughing for weeks & her daughter did take him to the dr but was told his lungs were clear but he didn't get better & her DD said it was a waste of time to take him back. 3 wks later my girlfriend demanded that her daughter take him back to the dr because he was getting worse and turns out this little one had pneumonia.
My other girlfriend cautioned her son about quitting his job before he confirmed that he had a firm offer for another job. He had the verbal but nothing in writing. He knew better & quit. Unfortunately, the company results weren't as good as forecasted & they are now in a hiring freeze. So he didn't get a formal offer & he is without a job, no benefits & his wife only working part time.
These are a few examples of how wonderful kids can still create frustration for us as parents even when they are "grown kids". Anyone else get frustrated with their frown kids & wish you could still send them to their room? Any other examples of how little we know & how much they know?
Have a good day, Dee.
|Sat, 01-22-2011 - 9:54pm
I seem to be in-between bouts of stupidity LOL probably because I don't have any grandchildren yet. When my kids were teens I didn't know anything but when they hit their 20s I started getting smarter. I'm enjoying the lull as I will surely lose all of my wisdom again.
I do know what you are talking about Dee, I saw it firsthand with my niece. On Christmas night 2009 she and her dh and 2 little girls were here for dinner, along with my SIL her mom. SIL picked up the 2yo by the wrist and immediately 2yo started screaming. SIL and I checked out 2yo and nothing appeared to be broken or dislocated so we advised distracting the child to get her calmed down and see if it would pass. Niece and her dh wouldn't hear of it, they had to rush her to the ER. On Christmas night. When they finally returned 5 hours later (having missed dinner I will add) the diagnosis was that nothing was wrong with her arm. SIL and I can't figure out how we managed to raise our kids to adulthood since we know nothing about assessing injuries in children!
|Sat, 01-22-2011 - 10:47pm
Yes, I remember that in between stage, well. I actually thought I had gained back some of my brain power lost during the teen years! My dd did ask for my opinion on her house purchase, her job situation & her relationship with her SO. But I'm dumb when it comes to raising kids. Go figure! Somehow though, I had my grandson when he got sick during his 1st 18 mths, he survived & never needed I dr. I used to think DD was able to sense when he was getting sick & then ask me to babysit. My DD seemed to forget those occasions. lol


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The City of Fairfax Commission on the Arts presents this FREE performance as song and dance man Mr. Skip, members of Sior-Og, and Irish dancers come together to celebrate St. Patrick's Day!
Mr. Skip, our favorite Children's Song and Dance man, makes the week start with a smile as we celebrate St. Patrick's Day! Wear your green, bring your little ones, and come ready to sing, move, and celebrate!
WETA looks back at the people and events of the 1980s — the disorderly decade that saw Washington's emergence as a true global capital.See all broadcast times →
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Garrett Peck, author of "Capital Beer: A Heady History of Brewing in Washington, D.C." discusses the history of brewing in the nation's capital.Watch video →
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Arlington, Virginia's Fire Chief James Schwartz recalls the county fire department's milestones.Watch video →
WETA Channel 26 hit the Washington airwaves on October 2, 1961, when station manager George Baker introduced viewers to WETA's inaugural broadcast, The New Era.Watch first broadcast →


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Product news: design studio Kawamura-Ganjavian is now producing a smaller version of its squishy headpiece for napping on the go for children (+ slideshow). More »
Tag: products
Ostrich Pillow Junior by
Makers With Agendas by
Julien De Smedt and William Ravn
Architect Julien De Smedt has launched Makers With Agendas, a new design brand with products ranging from solutions to natural disasters and humanitarian crises to coat hooks and tea sets (+ slideshow + interview). More »
Pogo connectors
by Jon Patterson
These magnetic headphone jacks by New York designer Jon Patterson split in two when tugged to prevent damaging devices when wires get snagged (+ movie). More »
Parasite Production
by Samuel Treindl
London Design Festival 2013: German designer Samuel Treindl has made a clock, lamp and other products from shapes cut out of existing furniture (+ slideshow). More »
The Alchemist's Dressing
Table by Lauren Davies
Royal College of Art graduate Lauren Davies has designed a range of copper, maple and glass tools to make scented oils, creams and cosmetics at home (+ slideshow). More »
A utensil is not just a utensil
by James Stoklund
An elasticated egg cup, a fork that bends to pick up food and a glass tumbler with a cheeky bottom all feature in a collection of utensils by Royal College of Art graduate James Stoklund (+ slideshow). More »
Handle Pendants
by Josie Morris
Product news: Northumbria University graduate Josie Morris has created a range of copper-spun pendant lamps with chunky handles. More »
Corniches by Ronan and
Erwan Bouroullec for Vitra
Product news: French designers Ronan and Erwan Bouroullec have added three new colours to their Corniches shelves for Vitra. More »
Bulb Fiction pendant lamp
by KiBiSi
Product news: Copenhagen design firm KiBiSi designed this low-energy pendant lamp by scaling up the shape of a classic light bulb. More »
Gala chandelier by
Rich Brilliant Willing
Product news: these chandeliers by American lighting designers Rich Brilliant Willing feature glowing blobs of glass that dangle from aluminium rods. More »
Food Huggers by Adrienne McNicholas
and Michelle Ivankovic
Industrial designers Adrienne McNicholas and Michelle Ivankovic have launched a range of silicone caps designed to preserve leftover fruit and vegetables (+ slideshow). More »
Dyslexic Objects win New Designer
of the Year Award 2013
BioElectric by
Jeongwon Ji
Royal College of Art graduate Jeongwon Ji has made her own bioplastic from crab shells. More »
OUYA by Fuseproject
Designer Yves Behar of San Francisco studio Fuseproject has launched his OUYA open-source game console. More »
Reflet by
Claire Lavabre
French designer Claire Lavabre has made a mirror that only works when it's placed in front of a dark shape painted on the wall. More »
Hairbrush by Jack Beveridge
and Lizzie Reid
Designers Jack Beveridge and Lizzie Reid have adapted the flocking process to make a hairbrush that's coated in human hair. More »
Plug + Play by
Neil Merry
This kit by Royal College of Art graduate Neil Merry allows musicians to control sound and lighting effects at their gigs by slinging the microphone around or waggling their instruments about (+ movie). More »
Fan TV by
Industrial designer Yves Behar of Fuseproject has unveiled a television set-top box that includes a remote control with no buttons (+ slideshow). More »
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Reebok Men's St. Patrick's Day Boston Bruins Zdeno Chara #33 Kelly Green T-Shirt
$25.97 $30.00*
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Product Information:
Display your love o' the Irish and rep your favorite Bruins player in this Reebok® St. Patrick's Day Zdeno Chara tee. A screen-printed Bruins logo adorns the front along with a clover to show your Bruins fandom and add Irish flair. Chara and 33 are printed on the back to rep your favorite player. Gear up for the holiday and take your fandom top shelf in this Reebok® Men's St. Patrick's Day Boston Bruins Zdeno Chara T-Shirt.
- Boston Bruins Zdeno Chara 33 Saint Patrick's Day Kelly Green Tee
- High quality screen-printed Boston Bruins logo decks the front to support your boys
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- Reebok® logo on the back above the numbers for brand awareness
- NHL® shield on the front and NHLPA® logo on the back for authenticity
- Regular fit and crew neck for lasting comfort
- Officially licensed by the NHL®
- Fabric: 100% cotton
- Reebok
Country of Origin: ImportedWeb ID: 31973156


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Accent your great disguise with our bushy Mustache and Eyebrow Set. With these big black eyebrows and handlebar mustache you're sure to fool everyone you know! Our Mustache & Eyebrow Set comes in black and the eyebrows measure approximately 3 1/2" across and the mustache 6 3/4" across. One size fits most. Please order in increments of 1 set. We cannot accept returns for facial hair unless it is unopened and sealed in its original packaging.
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Don't sweat the small stuff this New Year's Eve—planning for a party becomes a piece of cake with the help of New Year's Party Kits!
10 Ways to Decorate Your Office or Classroom this Holiday Season
Add Christmas decorations to your office, cubicle or classroom to bring some festivity into the work place this holiday season! Get inspiration from some of these decorating ideas.
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Invite friends and family over for a Hanukkah celebration! Decorate the party space in blue, white and silver and serve traditional foods while making memories.


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Welcome to Cert Kits
Our high-efficiency reflective Mylar thermal blanket reflects up to 90% of body heat. It unfolds to a generous 84" x 52" from a sealed packet measuring only 4.25" x 4.25" x .5" and weighing under 2 oz.
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7 Tips to Prepare for Your Appointment
The key to a successful appointment is communication. To get the most out of your visit, prepare ahead of time so you can lead the conversation with your doctor. These 7 tips will get you ready
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Item #13467
The perfect gift for the constant golfer, this Custom Golf Shoe Bag includes a breathable, zipped mesh side and an easy-grip handle. Customize at no additional cost; embroider with a single block initial or monogram in red thread. In the monogram, the middle initial (which should be the last name) will appear larger. Dual golf club and tee design.
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RushHour by sjgarcia - over 4 years ago
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Showing you how to find your favorite energy-saving tips and advice.
With fall right around the corner, we are relaunching our EnergySaver.gov website with fresh updates that will help you and your family save money by saving energy.
Although today's home appliances are designed to be far more energy efficient than those made in the decades past, there's always room for improvement.
Ernie's musings about pet ownership and its effects on a healthy and energy-efficient lifestyle.
Are you prepared for a blackout? What have you done to prepare?
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Having a household disaster plan is important if a natural disaster or blackout strikes your area.
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One woman's quest to reduce her energy bill, train into good habits and set goals toward energy savings - and her life.
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Plane makes emergency landing on Texas highway
The pilot of a single-engine plane made an emergency landing on a highway ramp in Arlington, Texas, and it was all caught on camera.
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The pilot of a single-engine plane made an emergency landing on a highway ramp in Arlington, Texas, and it was all caught on camera.
Plans to ramp up patrols along the Texas-Mexico border at a potential cost of $1.3 million a week are getting new attention in the Capitol.
Strict enforcement of a previously obscure state regulation is threatening the no-kill movement across Texas and could result in animal shel…
Infants dying in their sleep while sharing a bed with an adult or older child is on the rise in Texas.
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South Texas sheriff's officials say a body found this month in brush near the border apparently was an 11-year-old unaccompanied immigrant f…
Schools from Round Rock, Bastrop, Leander and Austin rank among the state's most expensive.
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| Source: The Harvard Crimson
Students could choose among a more exotic set of offerings than the usual brunch fare of Veritaffles and omelettes Sunday afternoon at Harvard University Dining Services' annual festive brunch,...
| Source: The Oregonian
More than half of Oregon eighth-graders skip breakfast at least one day a week and 29 percent of them skip it more often than they eat it, a new survey found.
Skidmore College, in Saratoga Springs, N.Y., hosted an American Culinary Federation (ACF) sanctioned competition in January.
| Source: The Press Democrat
Have you ever sat in a hospital bed craving pizza for breakfast, or maybe pancakes and fresh fruit for dinner?
| Source: The Herald News
New state law will require large institutions to recycle food waste.
| Source: The Daily Voice
The Phelps Memorial Hospital Center menu for patients is getting closer to resembling room service than hospital food.
| Source: The Post and Courier
The tortellini taste test was part of Charleston County School District's effort to give school menus a healthy overhaul for the 2014-15 school year...
| Source: The Maine Campus
Last week, UMaine Dining began serving students, and guests, outside the Bear's Den Café & Pub in a new, restaurant-style extension of the dining facility.
| Source: Houston Press
One of the most pressing issues concerning childhood obesity deals specifically with the lunches and snacks that are served to students in schools.
| Source: KUMV-TV
The six month, $1.1 million renovation starts on Monday and the last remodel was done in 1981. And the Capitol Grounds facilities director says the changes are needed.
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Three Takes On offers several different versions of the same classic dish. This month spinach, vegan and an interesting Latin take on lasagna.
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Mondelēz International Foodservice
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Kraft Foodservice
Consumers today are getting smart about their health, and your patrons expect to see healthy choices alongside the not-so-healthy ones. As they wise-up, it's important for you—and for your business—to stay abreast of the latest trends to keep them satisfied and coming back for more.


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Delhi thrashed Karnataka by 10 wickets to reach the semifinals of the Vijay Merchant Trophy (under-16) cricket tournament on the fourth and final day of their quarterfinal match at the St. Stephen's College ground here on Saturday.
Sumit Mathur claimed five wickets and Sidhant Sharma bagged four to help Delhi restrict Karnataka, which resumed at 119 for five, to 191 runs in the second innings and pave the way for the home team's win.
In another match, Madhya Pradesh got past Tamil Nadu on the basis of first innings lead after the match ended in a draw.
The scores: Karnataka 185 and 191 in 95.2 overs (Ankith Udupa 85, Sumit Mathur five for 64, Sidhant Sharma four for 36) lost to Delhi 353 and 24 for no loss in 9.3 overs.
Madhya Pradesh 331 & 118 for five in 70 overs (Arjun Patel 31 n.o., Shreyas Pandit 25, R. Sai Kishore three for 41) drew with Tamil Nadu 285 in 151.2 overs (K. Vishal Vaidhya 78, Daryl S. Ferrario 66, Washington Sundar 44, G.V. Vignesh 40, Kshitij Somkunwar six for 73); Madhya Pradesh entered the semifinals on the basis of first innings lead. — Principal Correspondent


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Ocho Rios House Rental Photos and Description
5 spacious air-conditioned bedrooms, 5th bedroom is for kids with 4 fun bunk bed
div class=\villalist\' Villa Lido is a wonderful and spacious villa which has direct access to a white sandy beach in your own backyard.Guests will certainly enjoy their vacation in Jamaica in this wonderful and luxurious waterfront home. This is home which has been completely refurbished in 2002 now reveals a very fresh home but still retains the warm character of the original home and décor.This beautiful property is situated on 4 ½ lovely beach front acres and is a two storey villa which features polished hard wood floors, four poster beds, oriental rugs and many original Jamaican art pieces which the owner has collected with care.The main floor has a comfortable living area with large double doors which open to a spacious, covered veranda. This wonderful veranda overlooks the pool and white sandy beach and the blues of the Caribbean Sea in your back yard. The formal dining room inside also has a wonderful ocean view. There are two bedroom located on the main floor and a children's room with bunk beds, trundle beds, computer, and lots of games and toys for children.Upstairs, there are two very private and spacious suites are well appointed, one with king bed and the other with two queen beds. Both bedrooms open up onto a covered ocean front balcony. All bedrooms are air-conditioned for your comfort and all have ensuite bathrooms and TV's. The staff here needs special mention as Roy, the head of household has been with this Villa for over 40 years. Hylton who is the gardener and butler has also been working here for 18 years and they will make sure that your holiday is carefree. Anything you need from shopping assistance, sight seeing knowledge or if you would like a taxi, they will certainly help you out in all situations. Their local knowledge is great and they are happy to share with you. Very popular member of staff, Indian, assists with all watersports activities. object width=\'720\' height=\'530\' data=\'virtual_tours/JAMAICA%202010/Villa%20Lido/vsl.swf\' type=\'application/x-shockwave-flash\' param name=\'data\' value=\'virtual_tours/JAMAICA%202010/Villa%20Lido/vsl.swf\' / param name=\'quality\' value=\'high\' / param name=\'src\' value=\'virtual_tours/JAMAICA%202010/Villa%20Lido/vsl.swf\' / Bedroom ConfigurationMaster Bedroom located upstairs has a king bed, en-suite bathroom, air conditioning, flat screen TV, ceiling fan and telephone, and opens to a verandah overlooking the pool and beach. Safe in master bedroom.Bedroom 2 located upstairs has a kingsize bed, en-suite bathroom, air conditioning, flat screen TV, ceiling fan and telephone, and opens to a verandah overlooking the pool and beach. Bedroom 3 downstairs, has a kingsize bed, en-suite bathroom, air conditioning, flat screen TV and ceiling fan. The room opens to a poolside terrace. Bedroom 4 downstairs, has 2 double beds, en-suite bathroom, air conditioning and ceiling fan. The room opens to a poolside terrace. Bedroom 5 the kid's room has 2 bunk beds and trundles , one queen size pull out sofa, air conditioning, ceiling fan and adjoining bathroom. This room also has a television, computer with internet access and a fax machine. The maximum occupancy is 12 however it would have to be 8 adults and 4 kids. The villa is fully staffed with cook, housekeeper, bulter and gardener/caretaker. There is also a night security guard. Professional staff of 5 will pamper you at Villa Lido, beachfront with own tennis court and watersport activities. img src=\'images/prp112/DSC08832-x.jpg\' alt=\'\' width=\'580\' height=\'400\' / • There is ample bedding and living rooms in Villa Lido, for the bedroom configuration:Upstairs:• Master bedroom 1: King bed, ensuite bathroom• Master bedroom 2: King bed, ensuite bathroomDownstairs:• Bedroom 3 : 2 double bedrooms, ensuite bathroom• Bedroom 4: Kingsize bed, ensuite bathroom• Bedroom 5: Large room with 2 trundle beds• 2 Trundle beds• 2 bunk beds/ trundle• One queen sofa• Sleeps a total of 7 persons in the bedroom• Every bedroom has its own Satellite TV• There is also another TV in the living room• DVD playersStaff on property includes:• Madge the Cook• Roy the butler• Indian – extra butler/ watersports• Gary –Gardener• Sharon- housekeeper• SecuritySISTER VILLAS IN THIS MAMMEE BAY/ OCHO RIOS AREA a href=\'http://www.jamaicantreasures.com/prp962.php\' VILLA PARADISO - 7 bedrooms a href=\'http://www.jamaicantreasures.com/prp962.php\' a href=\'http://www.jamaicantreasures.com/prp626.php\' KIMA - 3 BEDROOMS a href=\'http://www.jamaicantreasures.com/prp626.php\' a href=\'http://www.jamaicantreasures.com/prp633.php\' TERRA NOVA- 4 BEDROOMS a href=\'http://www.jamaicantreasures.com/prp801.php\' L'HORIZON VILLA - 7 BEDROOMS a href=\'http://www.jamaicantreasures.com/prp801.php\' a href=\'http://www.jamaicantreasures.com/prp276.php\' MIRAMAR - 9 BEDROOMS a href=\'http://www.jamaicantreasures.com/prp276.php\' a href=\'http://www.jamaicantreasures.com/prp925.php\' STONE HARBOUR- 4 BEDROOMS a href=\'http://www.jamaicantreasures.com/prp925.php\' a href=\'http://www.jamaicantreasures.com/prp035.php\' FOUR WINDS- 5 BEDROOMS a href=\'http://www.jamaicantreasures.com/prp035.php\' a href=\'http://www.jamaicantreasures.com/prp922.php\' MALATAI - 6 BEDROOMS a href=\'http://www.jamaicantreasures.com/prp922.php\' a href=\'http://www.jamaicantreasures.com/prp112.php\' VILLA LIDO - 5 BEDROOMS img longdesc=\'http://www.jamaicantreasures.com\' src=\'images/mammee_bay_beach/DSC_0458.jpg\' alt=\'Jamaica beach Ocho Rios Villas\' width=\'640\' height=\'420\' / Clear blue ocean, white sandy beach - Mammee Bay Beach Club img longdesc=\'http://www.jamaicantreasures.com\' src=\'images/mammee_bay_beach/DSC_0438.jpg\' alt=\'Mammee Bay Beach Club Jamaica\' width=\'640\' height=\'420\' / Beach, Bar and Grill open frorm 11am to 11pmFantastic menu, great for lunch of dinners! img longdesc=\'http://www.jamaicantreasures.com\' src=\'images/mammee_bay_beach/DSC_0457.jpg\' alt=\'lobster in Jamaica\' width=\'640\' height=\'420\' / Choose your own lobster and cook to order on the spot at the Beach, Bar and Grill! img longdesc=\'http://www.jamaicantreasures.com\' src=\'images/mammee_bay_beach/DSC_0435.jpg\' alt=\'Mammee Bay Beach Club, Ocho Rios\' width=\'640\' height=\'420\' / 3 minutes drive to the Mammee Bay Beach Club from your Villa for another white sandy beach!


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Android · Breaking · HTC · Mobile · Sprint
HTC EVO 4G: America's First 4G Phone Launches
The big word on the block for months now has been WiMAX (aka 4G), and the HTC EVO 4G. Both are one, and one is both. The EVO 4G, a 1Ghz Snapdragon-running, 8 megapixel 720p HD shooting, and with 4.3-inch WVGA multitouch LCD is the pinnacle of smartphones (at the moment). With a price of $199, and the ability to use both 3G and 4G bands, 2 way video calling, and personal Wi-Fi hotspot features up to 8 users, the EVO 4G is crazy. As is its plan pricing (read: not by much, for all the features you get). Also, sales are limited of 5 per customer, so get out of this article quick, and hit the "source" link, which is a glimpse into the future of phones.
Source: Sprint


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View Entire Collection
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By Journal
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Faith Community Nursing
Future of Nursing Initiative
These days, nearly everyone faces sporadic or chronic staffing challenges. Read these creative tips and you'll be better prepared to cope.
Examine your assignments and categorize nursing activities as high, medium, or low priority. Start with the high-priority activities. These include critical assessments and interventions, such as tracheal suctioning. Next, tackle medium-priority duties, such as teaching patients. Many low-priority activities can be delegated to unlicensed assistive personnel (UAPs), family members, or volunteers.
After receiving report, determine the care your patients will need. Gather equipment and supplies before entering a patient's room. Give support personnel a list of any missing items and ask that they get them right away.
Make a rule that no one can sit until everyone can sit. If you finish your work before others, pitch in. Teamwork creates bonds between co-workers, makes difficult situations tolerable, and enhances patient safety.
Know what you can and can't delegate to UAPs according to regulations governing nursing practice in your state and facility job descriptions.
Engage other personnel, not just nurses, to distribute the workload more evenly. The unit clerk, for example, can help you communicate with others.
Communicate clearly so that everyone knows the plan for surviving the staff shortage. Safeguard the feelings and dignity of all team members. Assess your own communication style: Do you ever speak in a demeaning or condescending way when you're harried? Supporting each other and being kind smooths the way for everyone.
Inform your nurse-manager when staffing is inadequate. He may be able to call in staff, offer overtime or incentive pay, reallocate staff, or employ staff from an agency. He may also help fend off time-consuming special requests.
When family or significant others are visiting, ask them in a friendly way if they want to help, without mentioning the staff shortage. If they're amenable, offer suggestions such as assisting with meals. Be sure to thank them.
During each shift, try to take a break from the caregiver role, even if only briefly. If you can't leave the unit, take a moment for yourself in the break room. To stave off burnout, eat a balanced diet and get enough rest and exercise.
Attitude is everything. If you go into a challenging situation with a positive, can-do attitude, you can achieve great results. In contrast, a negative outlook can bring down the morale and performance of the entire team. Positive self-talk is an important first step. Tell yourself and then the team that you can survive and even thrive in challenging situations. Reframe the staffing shortage to generate camaraderie and a sense of mastery over apparent obstacles. In time, positive thinking and creative problem solving will become habits for the entire staff.
Laskowski-Jones L, Toulson K. Top 10 tips for coping with short staffing. Nursing2005. 34(12):61, December 2004.
Squires A. Documenting short-staffing: A delicate balance. Nursing2004. 34(9):24, September 2004.
For life-long learning and continuing professional development, come to Lippincott's NursingCenter.
Caring for...Patients of different religions
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How The Election Will Be Remembered In 1,000 Years
The History of Tomorrow is a documentary series made in the distant future. In 1,000 years historians will learn about us from the media and pop culture of today.
This post was created by a user and has not been vetted or endorsed by BuzzFeed's editorial staff. BuzzFeed Community is a place where anyone can post awesome lists and creations. Learn more or post your buzz!


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The Astonishing Story of The Holy Prophet Muhammed (PBUH)
Ahmadiyya Muslim Community USA, Silicon Valley Chapter
Sunday, October 19, 2014 from 3:30 PM to 6:30 PM (PDT)
Fremont, CA
Who's Going
San Francisco, California
London, United Kingdom
Florence, Italy
Event Details
Ahmadiyya Muslim Community will be presenting a multi-media presentation in an effort to show the true character of Prophet Muhammad (PBUH) and highlighting the pure and pristine teachings of Islam. Prophet Muhammad (PBUH) has inspired billions of human beings over the past 1400 years and has brought about a spiritual revolution. The presentation will be a guided tour to present to you the man behind the name Muhammad (PBUH) and to offer you glimpses of why 1.7 billion Muslims today and many more throughout the last 1400 years hold such special love and reverence for him.
Ahmadiyya Muslim Community invites you to come join us and take a journey through the life of one of an individual who found God while living among ungodly people and who spread moral enlightenment in a society that lived in dark ages.
"If we could view Muhammad as we do any other important historical figure we would surely consider him to be one of the greatest geniueses the world has known. To create a literary masterpiece, to found a major religion and a new world power are not ordinary achievements."
-Karen Armstrong (Muhammad: A Biography of the Prophet)
When & Where
Smith Center at Ohlone College
43600 Mission Blvd
Sunday, October 19, 2014 from 3:30 PM to 6:30 PM (PDT)
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Ahmadiyya Muslim Community USA, Silicon Valley Chapter
The Ahmadiyya Muslim Community is a dynamic, fast growing international revival movement within Islam. Founded in 1889, the Ahmadiyya Muslim Community spans over 190 countries with membership exceeding tens of millions. The Ahmadiyya Muslim Community USA, established in 1921, is the first American-Muslim organization. Its journal, The Muslim Sunrise, is among the earliest and longest running American-Muslim periodicals.


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