Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine?

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine.     

Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine?

Background

It remains unclear whether retroviruses can encode and express an intragenomic microRNA (miRNA). Some have suggested that processing by the Drosha and Dicer enzymes might preclude the viability of a replicating retroviral RNA genome that contains a cis-embedded miRNA. To date, while many studies have shown that lentiviral vectors containing miRNAs can transduce mammalian cells and express the inserted miRNA efficiently, no study has examined the impact on the replication of a lentivirus such as HIV-1 after the deliberate intragenomic insertion of a bona fide miRNA.

Results

We have constructed several HIV-1 molecular clones, each containing a discrete cellular miRNA positioned in Nef. These retroviral genomes express the inserted miRNA and are generally replication competent in T-cells. The inserted intragenomic miRNA was observed to elicit two different consequences for HIV-1 replication. First, the expression of miRNAs with predicted target sequences in the HIV-1 genome was found to reduce viral replication. Second, in one case, where an inserted miRNA was unusually well-processed by Drosha, this processing event inhibited viral replication.

Conclusion

This is the first study to examine in detail the replication competence of HIV-1 genomes that express cis-embedded miRNAs. The results indicate that a replication competent retroviral genome is not precluded from encoding and expressing a viral miRNA.     

Do aquatic insects disperse metals from contaminated streams to land?

Hydrobiologia - Mining activities often produce large amounts of pollutants that lead to streams affecting aquatic biota. Aquatic insects have a key role in energy transference from streams to...     

Selective chirality — A closer examination

The recent suggestion (Root-Bernstein, 1982) that the homochirality of amino acids and sugars in the current biosphere may have originated as a result of novel organic selector molecules is examined critically. It is concluded that such selector molecules are non-existent as described, and that their postulation is based on chemical and stereochemical misconceptions.     

Improving cardiac regeneration after injury: Are we a step closer?

During regeneration, lost functional tissue can, in general, be replaced by different mechanisms, including proliferation of terminally differentiated cells or through differentiation of resident stem cells. It is a well-accepted dogma that the mammalian heart cannot efficiently regenerate upon injury as a consequence of insufficient oxygen supply. This is in sharp contrast to the hearts of adult zebrafish or newts that are able to replace lost ventricular tissue. Novel data indicate that the young murine heart also has the ability to regenerate within the first week after birth using mechanisms apparently quite similar to those observed in fish. This now provides us with a good starting point to identify the molecular mechanisms that led to the loss of the regenerative capacity of the adult mammalian heart. These future studies will also indicate whether it will be possible to reawaken the regenerative capability of cardiomyocytes in the human heart by treatment with selected pharmaceuticals.     

DNA helicases: one small step for PcrA, one giant leap for RecBC?

One might imagine that the mechanism of helicases would relate to the number of base pairs that are unwound for each ATP that is hydrolysed. Recent studies, however, suggest the situation can be more complicated than this.     

The Casparian strip—one ring to bring cell biology to lignification?

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Docking of chromaffin granules—A necessary step in exocytosis?

Putative docking of secretory vesicles comprising recognition of and attachment to future fusion sites in the plasma membrane has been investigated in chromaffin cells of the bovine adrenal medulla and in rat phaeochromocytoma (PC 12) cells. Upon permeabilization with digitonin, secretion can be stimulated in both cell types by indreasing the free Ca²⁺-concentration to M levels. Secretory activity can be elicited up to 1 hr after starting permeabilization and despite the loss of soluble cytoplasmic components indicating a stable attachment of granules to the plasma membrane awaiting the trigger for fusion. Docked granules can be observed in the electron microscope in permeabilized PC 12 cells which contain a large proportion of their granules aligned underneath the plasma membrane. The population of putatively docked granules in chromaffin cells cannot be as readily discerned due to the dispersal of granules throughout the cytoplasm. Further experiments comparing PC 12 and chromaffin cells suggest that active docking but not transport of granules can still be performed by permeabilized cells in the presence of Ca²⁺: a short (2 min) pulse of Ca²⁺ in PC 12 cells leads to the secretion of almost all releasable hormone over a 15 min observation period whereas, in chromaffin cells, with only a small proportion of granules docked, withdrawal of Ca²⁺ leads to an immediate halt in secretion. Transport of chromaffin granules from the Golgi to the plasma membrane docking sites seems to depend on a mechanism sensitive to permeabilization. This is shown by the difference in the amount of hormone released from the two permeabilized cell types, reflecting the contrast in the proportion of granules docked to the plasma membrane in PC 12 or chromaffin cells. Neither docking nor the docked state are influenced by cytochalasine B or colchicine. The permeabilized cell system is a valuable technique for thein vitro study of interaction between secretory vesicles and their target membrane.     

Rest in the scorpion — a sleep-like state?

Summary Forest-dwelling scorpions (Heterometrus, Pandinus) were continuously observed by time-lapse video recording and their behavior and body position were analyzed. Activity recorded on the tapes was scored into three states: (1) activity, (2) alert immobility, and (3) relaxed immobility. Arousal thresholds were determined by mechanical stimulation. Responsiveness was highest during activity and alert immobility, and significantly lower during relaxed immobility. Heart rate was continuously measured by chronically implanted electrodes and related to the behavioral state. Heart rate was highest during activity, intermediate in alert immobility, and lowest during relaxed immobility. Activity bouts were associated with sudden increases in heart rate. Settling down, however, was associated with a progressive decline in heart rate.The presence of rest regulation was investigated by 12 h rest deprivation by mechanical stimulation. During recovery, after initial activation, alert immobility and relaxed immobility were decreased.It can be concluded that rest in the scorpion is not a homogeneous state. The subdivision into alert and relaxed immobility on the basis of body posture revealed differences in arousal threshold and heart rate between the two states. The compensation of rest after rest deprivation indicates the presence of regulatory mechanisms comparable with those present in mammals and several nonmammalian vertebrate species, thus providing evidence for a sleep-like state in scorpions.Abbreviations SD sleep deprivation - L light - D dark or dim - LD light-dark or dim - H Heterometrus - P Pandinus     

A giant step towards artificial life?

Step by step, the components of an artificial form of cellular life are being assembled by researchers. Lipid vesicles the size of small bacteria can be prepared and under certain conditions are able to grow and divide, then grow again. Polymerase enzymes encapsulated in the vesicles can synthesize RNA from externally added substrates. Most recently, the entire translation apparatus, including ribosomes, has been captured in vesicles. Substantial amounts of proteins were produced, including green fluorescent protein used as a marker for protein synthesis. Can we now assemble a living cell? Not quite yet because no one has produced a polymerase that can be reproduced along with growth of the other molecular components required by life. But we are closer than ever before.     

Accelerated nitrogen inputs — A new problem or a new perspective?

This paper considers whether new problems are arising in forest ecosystems due to increased levels of inorganic N deposition from the atmosphere, or whether there are no new problems, just a change of perception. Deposition of N has indeed increased. Wet deposition rates are reasonably quantified, but the rates of dry deposition to forests are largely unknown. Current transport and deposition models are probably under-estimating N deposition to forests. Consideration of possible effects of enhanced N deposition reveals with varying degrees of certainty that there may be effects due to high N in biomass, high uptake rates, leaching of nitrate and consequent acidification, and an overall increase in N availability. Forest ecosystems are not well-enough understood to set a critical load for N deposition, but enough is known to define some upper limits.     

One step closer to an experimental infection system for Hepatitis B Virus? — the identification of sodium taurocholate cotransporting peptide as a viral receptor

Following the successful cloning of receptor for SARS coronavirus a few years ago, Dr. Wenhui Li and colleagues raised attention again by publishing a possible receptor for hepatitis B virus in eLife. We will briefly review the significance of this finding and the future prospects of hepatitis B research.     

Overdose the addiction—A new strategy to ablate cancer cells

<正>In the field of antitumor drug development,it is common to see paired images of cultured cancer cells:one mocktreated,and the other subjected to a small molecular drug that leads to cell death or growth suppression(Figure 1).One’s common perception is that an inhibitor is at work to inactivate a critical factor or pathway essential for cancer     

Micronucleophagy: A new mechanism to protect against chromosomal instability?

Comment on: Rello-Varona S, et al. Cell Cycle 2012; 11:170–6