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Context.--There has been a paradigm shift in the understanding of molecular pathogenesis of lung cancer. A number of oncogenic drivers have been identified in non-small cell lung carcinoma, such as the epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) gene rearrangement. Because of the clinical presentation at an advanced stage of disease in non-small cell lung carcinoma patients, the use of minimally invasive techniques is preferred to obtain a tumor sample for diagnosis. These techniques include image-guided biopsies and fine-needle aspirations, and frequently the cytology specimen may be the only tissue sample available for the diagnosis and molecular testing for these patients. Objective.--To review the current literature and evaluate the role of cytology specimens in lung cancer mutation testing. We reviewed the types of specimens received in the laboratory, specimen processing, the effect of preanalytic factors on downstream molecular studies, and the commonly used molecular techniques for biomarker testing in lung cancer. Data Sources.--PubMed and Google search engines were used to review the published literature on the topic. Conclusions.--Mutation testing is feasible on a variety of cytologic specimen types and preparations. However, a thorough understanding of the cytology workflow for the processing of samples and appropriate background knowledge of the molecular tests are necessary for triaging, and optimum use of these specimens is necessary to guide patient management. doi: 10.5858/arpa.2017-0444-RA, Molecular profiling of lung cancer has identified multiple driver mutations occurring in several oncogenes that have led to an increasing number of US Food and Drug Administration (FDA)-approved targeted therapies [...]

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYCamplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis., Lung cancer is the most common cause of global cancer-related mortality, leading to over a million deaths each year and adenocarcinoma is its most common histological type. Smoking is the [...]

Recent clinical and experimental studies are redefining the cellular and molecular bases of pulmonary arterial hypertension (PAH). The genetic abnormalities first identified in association with the idiopathic form of PAH--together with a vast increase in our understanding of cell signaling, cell transformation, and cell-cell interactions; gene expression; micro RNA processing; and mitochondrial and ion channel function--have helped explain the abnormal response of vascular cells to injury. Experimental and clinical studies now converge on the intersection and interactions between a genetic predisposition involving the BMPR2 signaling pathway and an impaired metabolic and chronic inflammatory state in the vessel wall. These deranged processes culminate in an exuberant proliferative response that occludes the pulmonary arterial (PA) lumen and obliterates the most distal intraacinar vessels. Here, we describe emerging therapies based on preclinical studies that address these converging pathways., Pathological features of PAH Pulmonary arterial hypertension (PAH) is diagnosed by an elevation in mean pulmonary arterial (PA) pressure above 25 mmHg at rest or 30 mmHg with exercise. Patients [...]

The spread of avian H5N1 influenza viruses around the globe has become a worldwide public health concern. To evaluate the pathogenic potential of reassortant viruses between currently cocirculating avian H5N1 and human H3N2 influenza viruses, we generated all the 254 combinations of reassortant viruses between A/chicken/South Kalimantan/UT6028/06 (SK06, H5N1) and A/ Tokyo/Ut-Sk-1/07 (Tok07, H3N2) influenza viruses by reverse genetics. We found that the presence of Tok07 PB2 protein in the ribonucleoprotein (RNP) complex allowed efficient viral RNA transcription in a minigenome assay and that RNP activity played an essential role in the viability and replicative ability of the reassortant viruses. When the pathogenicity of 75 reassortant H5 viruses was tested in mice, 22 were more pathogenic than the parental SK06 virus, and three were extremely virulent. Strikingly, all 22 of these viruses obtained their PB2 segment from Tok07 virus. Further analysis showed that Tok07 PB1 alone lacked the ability to enhance the pathogenicity of the reassortant viruses but could do so by cooperating with Tok07 PB2. Our data demonstrate that reassortment between an avian H5N1 virus with low pathogenicity in mice and a human virus could result in highly pathogenic viruses and that the human virus PB2 segment functions in the background of an avian H5N1 virus, enhancing its virulence. Our findings highlight the importance of surveillance programs to monitor the emergence of human H5 reassortant viruses, especially those containing a PB2 segment of human origin. influenza reassortants | pathogenicity | pandemic www.pnas.org/cgi/doi/10.1073/pnas.0912807107

Neuropathology involving TAR DNA binding protein-43 (TDP-43) has been identified in a wide spectrum of neurodegenerative diseases collectively named as TDP-43 proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). To test whether increased expression of wide-type human TDP-43 (hTDP-43) may cause neurotoxicity in vivo, we generated transgenic flies expressing hTDP-43 in various neuronal subpopulations. Expression in the fly eyes of the full-length hTDP-43, but not a mutant lacking its amino-terminal domain, led to progressive loss of ommatidia with remarkable signs of neurodegeneration. Expressing hTDP-43 in mushroom bodies (MBs) resulted in dramatic axon losses and neuronal death. Furthermore, hTDP-43 expression in motor neurons led to axon swelling, reduction in axon branches and bouton numbers, and motor neuron loss together with functional deficits. Thus, our transgenic flies expressing hTDP-43 recapitulate important neuropathological and clinical features of human TDP-43 proteinopathy, providing a powerful animal model for this group of devastating diseases. Our study indicates that simply increasing hTDP-43 expression is sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43 may contribute to the pathogenesis of TDP-43 proteinopathy. amyotrophic lateral sclerosis | animal model | RNA binding protein www.pnas.org/cgi/doi/10.1073/pnas.0913602107

Genetic factors are known to contribute to seizure susceptibility, although the long-term effects of these predisposing factors on neuronal viability, remain unclear. To examine the consequences of genetic factors conferring increased seizure susceptibility, we surveyed a class of Drosophila mutants that exhibit seizures and paralysis following mechanical stimulation. These bang-sensitive seizure mutants exhibit shortened life spans and age-dependent neurodegeneration. Because the increased seizure susceptibility in these mutants likely results from altered metabolism and since the [Na.sup.+]/[K.sup.+] ATPase consumes the majority of ATP in neurons, we examined the effect of ATP[alpha] mutations in combination with bang-sensitive mutations. We found that double mutants exhibit strikingly reduced life spans and age-dependent uncoordination and inactivity. These results emphasize the importance of proper cellular metabolism in maintaining both the activity and viability of neurons.

Human mitochondrial tRNA (hmt-tRNA) mutations are associated with a variety of diseases including mitochondrial myopathies, diabetes, encephalopathies, and deafness. Because the current understanding of the precise molecular mechanisms of these mutations is limited, there is no efficient method to treat their associated mitochondrial diseases. Here, we use a variety of known mutations in hmt-[tRNA.sup.Phe] to investigate the mechanisms that lead to malfunctions. We tested the impact of hmt-[tRNA.sup.Phe] mutations on aminoacylation, structure, and translation elongation-factor binding. The majority of the mutants were pleiotropic, exhibiting defects in aminoacylation, global structure, and elongation-factor binding. One notable exception was the G34A anticodon mutation of hmt-[tRNA.sup.Phe] (mitochondrial DNA mutation G611A), which is associated with MERRF (myoclonic epilepsy with ragged red fibers). In vitro, the G34A mutation decreases aminoacylation activity by 100-fold, but does not affect global folding or recognition by elongation factor. Furthermore, G34A hmt-[tRNA.sup.Phe] does not undergo adenosine-to-inosine (A-to-I) editing, ruling out miscoding as a possible mechanism for mitochondrial malfunction. To improve the aminoacylation state of the mutant tRNA, we modified the tRNA binding domain of the nucleus-encoded human mitochondrial phenylalanyl-tRNA synthetase, which aminoacylates hmt-[tRNA.sup.Phe] with cognate phenylalanine. This variant enzyme displayed significantly improved aminoacylation efficiency for the G34A mutant, suggesting a general strategy to treat certain classes of mitochondrial diseases by modification of the corresponding nuclear gene. aminoacyl-tRNA synthetase | translation | mitochondria

Prion proteins are key molecules in transmissible spongiform encephalopathies (TSEs), but the precise mechanism of the conversion from the cellular form ([PrP.sup.C]) to the scrapie form ([PrP.sup.Sc]) is still unknown. Here we discovered a chemical chaperone to stabilize the [PrP.sup.C] conformation and identified the hot spots to stop the pathogenic conversion. We conducted in silico screening to find compounds that fitted into a 'pocket' created by residues undergoing the conformational rearrangements between the native and the sparsely populated high-energy states ([PrP.sup.*]) and that directly bind to those residues. Forty-four selected compounds were tested in a TSE-infected cell culture model, among which one, 2-pyrrolidin-1-yl-N- [4-[4-(2-pyrrolidin-1-yl-acetylamino)-benzyl]-phenyl]-acetamide, termed GN8, efficiently reduced [PrP.sup.Sc]. Subsequently, administration of GN8 was found to prolong the survival of TSE-infected mice. Heteronuclear NMR and computer simulation showed that the specific binding sites are the A-S2 loop (N159) and the region from helix B (V189, T192, and K194) to B-C loop (E 196), indicating that the intercalation of these distant regions (hot spots) hampers the pathogenic conversion process. Dynamics-based drug discovery strategy, demonstrated here focusing on the hot spots of [PrP.sup.C], will open the way to the development of novel anti-prion drugs. anti-prion compound | binding sites | chemical chaperone | dynamics-based drug discovery | transmissible spongiform encephalopathy

Kinetic PCR (kPCR) is used to monitor the growth of biotrophic pathogens in plants at various times following host infection. The capacity of kPCR to distinguish pathogens in the same sample has wider molecular ecology applications for dynamically monitoring the growth of fungi in their environments or in mixed populations or to measure the efficacy of pest control strategies.

The molecular pathways involved in the pathogenesis of Parkinson's disease (PD) are discussed. The principle molecular pathways underlying the pathogenesis of sporadic and familial forms of PD are represented by mitochondrial dysfunction, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins and impairment of ubiquitin-proteasome system.

Byline: Gabriele Grassi (1), Mario Grassi (2), Anne Kuhn (1), Reinhard Kandolf (1) Abstract: aHammerhead ribozymes provide valuable tools in the field of gene therapy due to their cleavage specificity and the broad range of RNA targets. A major prerequisite for the selection of suitable ribozymes for in vivo application is represented by in vitro determination of ribozyme cleavage kinetic constants. From the experimental cleavage data, kinetic constants are usually calculated under the assumption of rapid conversion of the substrate into the ribozyme-substrate complex. However, this condition is often not satisfied for ribozymes carrying additional RNA stretches, due to cloning strategies or necessary for ribozyme expression in the cell. To overcome this problem, we propose a mathematical model which is able to calculate ribozyme kinetic constants in the case of non-rapid conversion of substrate into ribozyme-substrate complex. In addition, our system gives the opportunity to evaluate the nature of the S conversion into ES through the determination of a model parameter. The validity of the proposed model is restricted to the hypothesis of a ribozyme excess over the substrate at the beginning of the cleavage reaction and to the absence of any mass exchange with the external environment. Author Affiliation: (1) Department of Molecular Pathology, Institute for Pathology, University of Tubingen, Liebermeisterstrasse 8, D-72076, Tubingen, Germany. e-mail: gegrassi@med.uni-tuebingen.de, DE (2) Department of Chemical, Environmental and Raw Materials Engineering -- DICAMP, University of Trieste, Piazzale Europa 1, I-34127 Trieste, Italy, IT Article note: Received: 1 February 2001 / Revised version: 1 September 2001 / Published online: 23 August 2002

Context.--Due to its anticipated curative potential, therapeutic angiogenesis recently became a major preoccupation for the biomedical research community. Most of the related work reported to date employs either biochemical or genetic tools. Objective.--To identify opportunities for application of the current developments in microtechnology and nanotechnology to the field of therapeutic angiogenesis. Data Sources.--Survey of recent English-language literature on microvascular tissue engineering in the context of therapeutic angiogenesis. We include our results regarding the role played by microtopographical cues in the progression of angiogenesis, such as those produced during processing of the extracellular matrix by chronic inflammatory cells. Conclusion.--While notable accomplishments have been identified in the field of tissue engineering of larger vessels, reports on purposeful assembly of microvascular structures with the ability to be transferred in vivo by implantation are still scarce. Under these circumstances, we suggest the development of a new class of implantable biomedical microdevices, that is, "angiogenesis assist devices" (or "angiochips"), and we indicate some of their conceivable applications., Tissue engineering is a very promising and dynamic research field. Its applications currently vary from simple materials used as implants, molded to reproduce the geometry and/or the mechanical properties of [...]

* Objectives.--To review hepatitis C virus (HCV), describe the types of molecular-based tests available for the diagnosis and management of HCV infection, and discuss the appropriate utilization of these tests. Data Sources.--Current information is presented from the published literature, as well as new information where available. Study Selection.--A major cause of posttransfusion and community-acquired non-A, non-B hepatitis worldwide is HCV. Approximately 4 million people in the United States are infected with HCV, resulting in 8000 to 10 000 deaths annually. Because HCV is not readily cultured, in vitro molecular-based tests have been developed for use in the diagnosis and treatment of HCV-infected patients. Molecular tests include qualitative and quantitative nucleic acid amplification tests, branched DNA tests, and HCV genotyping assays. Qualitative HCV nucleic acid amplification tests are used routinely in association with serologic tests to help make a diagnosis of infection with HCV. Quantitative HCV testing and genotyping methods have been found to be valuable tools in the treatment of infected patients. A patient's pretreatment HCV viral load and the rate of virus decline during therapy have been shown to correlate with the likelihood of long-term response to antiviral therapy. Information pertaining to the genotype of HCV infecting patients has been shown to be helpful in making recommendations regarding treatment. Certain genotypes of HCV are much more responsive to therapy, allowing a shorter course of treatment. Conclusions.--Molecular tests are valuable tools for use in the diagnosis and treatment of patients infected with HCV., Hepatitis C virus (HCV) is a major cause of posttransfusion and community-acquired non-A, non-B hepatitis worldwide. Approximately 4 million people in the United States are infected with HCV, resulting in [...]

* The human lymphocyte antigen (HLA) typing community was one of the early groups to adopt molecular testing. This action was borne out of the need to identify the many alleles of the highly polymorphic HLA system. Early paradigms used restriction fragment length polymorphism regimes, but the polymerase chain reaction method of amplification quickly replaced that less-than-discriminating choice. Methods currently in use for HLA typing, with commercial kits available, are sequence-specific oligonucleotide probe (both dot blot and the reverse blot dot), sequence-specific primer amplification, restriction fragment length polymorphism of amplified products, double-stranded sequence conformation polymorphism (with and without reference strand), sequence-based typing, and microarray technologies. More than 1250 alleles are recognized by the World Health Organization and meet their criteria for assignment. These alleles can be identified by molecular methods and represent alleles present at class I and class II loci of the HLA complex. On occasion, ambiguous results still persist, even with the best molecular typing methods. Therefore, it is clear to the HLA typing community that a combination of the above methods may be needed to allow true discrimination of the possible alleles an individual carries in their genetic makeup. It is also clear that a typing laboratory may need to resort to nonmolecular serology to understand the significance and impact of the type generated by the HLA molecular typing laboratory., The human lymphocyte antigen (HLA) system is one of the most polymorphic genetic systems known. More than 1250 alleles are currently identified and dispersed across the classical class I loci [...]

Context.--Linking single nucleotide polymorphisms to disease etiology is expected to result in a substantial increase in the number of genetic tests available and performed at clinical laboratories. Whole blood serves as the most common DNA source for these tests. Because the number of blood samples rises with the number of genetic tests performed, alternative DNA sources will become important. One such alternative source is clotted blood, a byproduct of serum extraction. Efficiently using an already procured blood sample would limit the overall number of samples processed by clinical laboratories. Objective.--To determine if DNA purified from clotted blood can be effectively used for single nucleotide polymorphism genotyping. Design.--DNA was purified from the clotted blood of 15 donors. Single nucleotide polymorphism genotyping for the methylenetetrahydrofolate reductase and factor V Leiden mutations was performed with each DNA sample by 2 independent methods. Results.--High-quality DNA was obtained from each of the 15 individual clotted blood samples as demonstrated by UV spectrophotometric analysis, gel electrophoresis, and polymerase chain reaction amplification. The DNA was used successfully to obtain genotype data from both the methylenetetrahydrofolate reductase and factor V single nucleotide polymorphism assays for all samples tested. Conclusions.--Clotted blood is a clinically abundant sample type that can be used as a source of high-quality DNA for single nucleotide polymorphism genotyping., The identification of thousands of single nucleotide polymorphisms (SNPs) in the human genome has prompted a rise in population-based research studies designed to link gene-specific SNPs to complex disease states, [...]

* Objectives.--To review the advances in clinically useful molecular biological techniques and to identify their applications in clinical practice, as presented at the Tenth Annual William Beaumont Hospital DNA Symposium. Data Sources.--The 11 manuscripts submitted were reviewed and their major findings were compared with literature on the same topic. Study Selection.--Manuscripts address creative thinking techniques applied to DNA discovery, extraction of DNA from clotted blood, the relationship of mitochondrial dysfunction in neurodegenerative disorders, and molecular methods to identify human lymphocyte antigen class I and class II loci. Two other manuscripts review current issues in molecular microbiology, including detection of hepatitis C virus and biological warfare. The last 5 manuscripts describe current issues in molecular cardiovascular disease, including assessing thrombotic risk, genomic analysis, gene therapy, and a device for aiding in cardiac angiogenesis. Data Synthesis.--Novel problem-solving techniques have been used in the past and will be required in the future in DNA discovery. The extraction of DNA from clotted blood demonstrates a potential cost-effective strategy. Cybrids created from mitochondrial DNA-depleted cells and mitochondrial DNA from a platelet donor have been useful in defining the role mitochondria play in neurode-generation. Mitochondrial depletion has been reported as a genetically inherited disorder or after human immunodeficiency virus therapy. Hepatitis C viral detection by qualitative, quantitative, or genotyping techniques is useful clinically. Preparedness for potential biological warfare is a responsibility of all clinical laboratorians. Thrombotic risk in cardiovascular disorders may be assessed by coagulation screening assays and further defined by mutation analysis for specific genes for prothrombin and factor V Leiden. Gene therapy for reducing arteriosclerotic risk has been hindered primarily by complications introduced by the vectors used to introduce the therapeutic genes. Neovascularization in cardiac muscle with occluded vessels represents a promising method for recovery of viable tissue following ischemia. Conclusions.--The sequence of the human genome was reported by 2 groups in February 2001. The postgenomic era will emphasize the use of microarrays and database software for genomic and proteomic screening in the search for useful clinical assays. The number of molecular pathologic techniques and assays will expand as additional disease-associated mutations are defined. Gene therapy and tissue engineering will represent successful therapeutic adjuncts., The cherry blossoms are truly cherry blossoms only while we wait. Kobayashi Issa (1) This issue of the Archives of Pathology & Laboratory Medicine features 11 papers presented at the [...]

Results demonstrate ssrA which encodes stable RNA molecule, tmRNA, is involved in the pathogenesis of Salmonella by serving as an attachment site to the bacterium-specific sequences. Data indicate that ssrA is also required by the phage for its growth.

The propensity of light chains in forming amyloid fibrils is largely influenced by the presence of amino acid residues at particular positions. Experiments have shown that the light chain variable domain (V(sub L)) thermodynamic stability of human lambda6 light chains is affected by substitutions at these positions. Substitution may cause a non-native aggregation and pathologic forming of the protein. These findings prove the correlation between the propensity of molecules and the light chain thermodynamic stability.

The human hepatitis B virus (HBV) HBx protein is a small transcriptional activator that is essential for virus infection. HBx is thought to be involved in viral hepatocarcinogenesis because it promotes tumorigenesis in transgenic mice. HBx activates the RAS-RAF-mitogen-activated protein (MAP) kinase signaling cascade, through which it activates transcription factors AP-1 and NF-kB, and stimulates cell DNA synthesis. We show that HBx stimulates cell cycle progression, shortening the emergence of cells from quiescence (Go) and entry into S phase by at least 12 h, and accelerating transit through checkpoint controls at [G.sub.0]/[G.sub.1] and [G.sub.2]/M. Compared with serum stimulation, HBx was found to strongly increase the rate and level of activation of the cyclin-dependent kineses CDK2 and CDC2, and their respective active association with cyclins E and A or cyclin B. HBx is also shown to override or greatly reduce serum dependence for cell cycle activation. Both HBx and serum were found to require activation of RAS to stimulate cell cycling, but only HBx could shorten checkpoint intervals. HBx therefore stimulates cell proliferation by activating RAS and a second unknown effector, which may be related to its reported ability to induce prolonged activation of JUN or to interact with cellular p53 protein. These data suggest a molecular mechanism by which HBx likely contributes to viral carcinogenesis. By deregulating checkpoint controls, HBx could participate in the selection of cells that are genetically unstable, some of which would accumulate unrepaired transforming mutations.

The underlying wide variety of vesicle-mediated transport steps in the resulting common mechanisms from the convergence of two effective approaches that characterize molecules mediating vesicular trafficking is discussed. This involves the convergence of the genetic dissection of the yeast secretory pathway and the biochemical characterization of synaptic vesicle membrane proteins. The utility of the combination was established.

A draft version of the complete human genome sequence was published early in 2001. This was the culmination of both public and privately funded efforts initiated a decade ago. The [...]

Objective.--To investigate the nature of creative thinking in biomedical science with specific applications to molecular pathologies and DNA technologies. Data Sources.--Accounts of breakthroughs and inventions contained in autobiographies, biographies, interviews, and archival sources. Study Selection.--Discoveries that have altered, or may yet alter, basic textbook accounts of biomedical sciences for which appropriate data sources exist. Data Extraction.--Approximately 1000 data sources were analyzed, both within appropriate sciences and in other creative fields, such as the arts. Data Synthesis.--The current analysis is based on a framework described in our previous book, Sparks of Genius, which outlines a general approach to understanding creative thinking. Conclusions.--Creative thinking in all disciplines depends on a common mental "toolkit" that consists of 13 fundamental tools: observing, imaging, abstracting, pattern recognition, pattern forming, analogizing, body thinking, empathizing, dimensional thinking, modeling, playing, transforming, and synthesizing. Scientists recognize and solve problems by observing data that break the patterns established by theories; exploring a system by creating an abstract model with which they can play; and transforming data into feelings, sounds, and other forms that create surprising analogies to already-understood principles. The result of such personal thinking is knowledge combined with sensation and emotion--feeling and understanding synthesized into complete awareness. We illustrate some of these modes of thinking with reference to recent breakthroughs in DNA-related areas and suggest ways in which the use of "tools for thinking" can increase the probability of making further discoveries in the biomedical sciences., This symposium on "DNA Technology in the Clinical Laboratory" is understandably focused on the physical tools used by medical practitioners to diagnose and treat disease. What gets overlooked here, as [...]

Context.--Lung carcinoma is the result of sequential accumulation of genetic and epigenetic changes. Lung adenocarcinoma is a heterogeneous disease with diverse somatic mutations, and several of them include the so called driver mutations, which may serve as 'druggable' therapeutic targets. Thus, development of personalized approaches for the treatment of non-small cell lung carcinoma (NSCLC) mandates that pathologists make a precise histologic classification inclusive of routine molecular analysis of such tumors. Objective.--To address the molecular mechanisms underlying NSCLC and how this knowledge reflects the multidisciplinary approach in the diagnosis and management of these patients. We will also summarize the current available and investigational personalized therapies for patients with resectable early-stage, unresectable locally advanced, and metastatic NSCLC. Data Sources.--Peer-reviewed published literature and personal experience. Conclusions.--There are multiple mechanisms involved in the pathogenesis of lung cancer, which operate in parallel and involve pathways of activation and inhibition of various cellular events. Further research is essential to characterize the histologic and mutational profiles of lung carcinomas, which will ultimately translate into improved and more personalized therapeutic management of patients with lung cancer. (Arch Pathol Lab Med. 2013;137:481-491; doi: 10.5858/arpa.2012-0287-RA), Lung cancer is the leading cause of cancer-related mortality in both men and women in the United States. It is projected that in 2012, lung cancer will account for 26% [...]

* Context.--Inflammatory bowel disease (IBD) is a longstanding chronic active inflammatory process in the bowel with increased risk for the development of colorectal carcinoma. Several molecular events involved in chronic active inflammatory processes contribute to multistage progression of human cancer development, including reactive oxygen and nitrogen species, aberrant arachidonic acid metabolites and cytokines/growth factors, and immune dysfunction. These molecular events in IBD lead to genetic abnormality and promote aberrant cell proliferation, which further lead to epithelial changes encompassing a broad spectrum from inflammation-induced hyperplasia to dysplasia. Objective.--To review the (1) epidemiologic and molecular pathogenesis of the risk for colorectal cancer in IBD, (2) morphologic characterization, biomarker(s), and classification of dysplastic lesions, and (3) clinical management of dysplastic lesions arising in IBD. Data Sources.--The different IBD-related dysplastic lesions are illustrated by using morphology in conjunction with molecular pathways, and the 'field cancerization' theory and its potential significance are discussed with a review of the literature. Conclusions.--Patients with IBD are at increased risk of developing colorectal cancer. The risk of developing carcinoma is related to the extent/duration/activity of the patient's disease. There is no consensus regarding the extent of carcinoma risk associated with IBD; however, all would agree that patients with IBD represent a group at significant risk for developing carcinoma and as such, warrant adequate surveillance and prevention. With better screening modalities and detection/characterization of dysplastic lesions, IBD-associated serrated lesions, and 'field cancerization,' we will improve our understanding of and approach to risk stratification. (Arch Pathol Lab Med. 2013;137:338-350; doi: 10.5858/arpa.2012-0086-RA), Chronic inflammation is a well-recognized risk factor for human cancer development, and at least one-third of all human cancers have been associated with inflammation, for example, long-standing chronic inflammatory bowel [...]

Pathologists play an essential role in predicting which patients with cancer are likely to develop metastases. Therapies to treat or prevent metastases are currently based on tumor type, tumor grade, [...]

This is an exciting time for pathology. In my 20 years of focusing on digital pathology, it is rewarding to see that the future is coming into being now and [...]