The Journey of Cancer Cells to the Brain: Challenges and Opportunities.

Cancer metastases into the brain constitute one of the most severe, but not uncommon, manifestations of cancer progression. Several factors control how cancer cells interact with the brain to establish metastasis. These factors include mediators of signaling pathways participating in migration, infiltration of the blood-brain barrier, interaction with host cells (e.g., neurons, astrocytes), and the immune system. Development of novel therapies offers a glimpse of hope for increasing the diminutive life expectancy currently forecasted for patients suffering from brain metastasis. However, applying these treatment strategies has not been sufficiently effective. Therefore, there is a need for a better understanding of the metastasis process to uncover novel therapeutic targets. In this review, we follow the journey of various cancer cells from their primary location through the diverse processes that they undergo to colonize the brain. These processes include EMT, intravasation, extravasation, and infiltration of the blood-brain barrier, ending up with colonization and angiogenesis. In each phase, we focus on the pathways engaging molecules that potentially could be drug target candidates.

Numerical and Experimental Analysis of a Prototypical Thermoelectric Generator Dedicated to Wood-Fired Heating Stove.

The typical operating range of domestic heating devices includes only heat generation. However, the availability of combined heat and power generation in microscale devices is currently becoming a more and more interesting option. This paper shows the experimental and numerical analysis of the possibility of developing a micro-cogeneration system equipped with a wood-fired heating stove and a prototype of the thermoelectric generator equipped with low-price thermoelectric modules. In the first step, mathematical modeling made it possible to analyze different configurations of the hot side of the thermoelectric generator (computational fluid dynamics was used). Next, experiments have been conducted on the prototypical test rig. The maximum power obtained during the discussed combustion process was 15.9 We when the flue gas temperature was approximately 623 K. Assuming a case, when such value of generated power occurred during the whole main phase, the energy generated would be at a level of approximately 33.1 Whe, while the heat transferred to the water would be approximately 1 078.0 Whth. In addition to the technical aspects, the economic premises of the proposed solution were analyzed. As was shown, an installation of TEG to the existing stove is economically not viable: the Simply Payback Time will be approximately 28.9-66.1 years depending on the analyzed scenario. On the other hand, the SPBT would be significantly shorter, when the installation of the stove with an integrated thermoelectric generator was considered (approximately 5.4 years). However, it should be noted that the introduction of the power generating system to a heat source can provide fully or partially network-independent operation of the hot water and heating systems.

The Positive and Negative Outcome of Morphine and Disulfiram Subacute Co-Administration in Rats in the Absence of Ethanol Challenge.

Recently, a well-known anti-alcohol agent, disulfiram (DSF), has gain much interest, as it was found to be effective in the treatment of cocaine abusers, thus also giving hope for patients addicted to opioids and other illicit drugs. Therefore, this study was aimed to investigate the possible outcome that might occur within the subacute co-administration of both morphine (MRF) and DSF in rats, but in the absence of ethanol challenge. As observed, intraperitoneal DSF dose-dependently enhanced MRF-mediated analgesia with the maximal efficacy at a dose of 100 mg/kg. Furthermore, MRF-induced tolerance and aggressive behavior were significantly reduced by DSF (100 mg/kg, i.p.) in comparison to MRF solely. Nonetheless, significant blood biochemical markers of hepatotoxicity were found (i.e., alteration in the levels of glutathione, blood urea nitrogen, etc.), following a combination of both drugs. Likewise, histological analysis of liver tissue revealed severe changes in the group of DSF + MRF, which includes swelling, cell death, damage to certain vessels, and hemorrhages into the liver parenchyma. Our findings indicate that DSF should be used with extreme caution, especially within the course of subacute concomitant use with MRF, as several possible side effects may take place.

Novel opioid-neurotensin-based hybrid peptide with spinal long-lasting antinociceptive activity and a propensity to delay tolerance development.

The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tolerance development, was assessed in an acute pain model. The PK23 chimera at a dose of 10 nmol/rat produced a potent pain-relieving effect, especially after its intrathecal administration. Compared with intrathecal morphine, this novel compound was found to possess a favourable side effect profile characterized by a reduced scratch reflex, delayed development of analgesic tolerance or an absence of motor impairments when given in the same manner, though some animals died following barrel rotation as a result of its i.c.v. administration (in particular at doses higher than 10 nmol/rat). Nonetheless, these results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management. This highlights the enormous potential of synthetic neurotensin analogues as promising future analgesics.

A novel strategy to escape a poor habitat: red-necked grebes transfer flightless young to other ponds.

Animals confronted with the threat of the death of their offspring may exhibit unusual and risk-prone behaviours. Grebes (Podicipediformes) are water birds which cannot effectively walk, thus unfledged young are assumed to be unable to depart from their natal ponds by land. We provide evidence that red-necked grebes Podiceps grisegena, breeding on ponds with scarce food resources, transferred their flightless young (2-4 weeks old) to other, unconnected ponds by land or air. Although a large proportion of breeding grebes in the study area nested on food-poor fish ponds acting as ecological traps, where they suffered significant brood losses, brood movements to new ponds accounted for only 3.3% of such breeding attempts. The infrequency of this strategy may be explained by the lack of suitable territories in close proximity and the high risk of predation or fatal injury. The means of chick transfer remains unclear; the chicks may have followed or been carried by parents shuffling across the pond levees; alternatively, parents may have carried the young on their backs in flight. Our findings indicate that red-necked grebes assess the current level of resources available for chicks and may adopt novel and risky strategies to escape total brood failure.