Combination treatment optimization using a pan-cancer pathway model

The design of efficient combination therapies is a difficult key challenge in the treatment of complex diseases such as cancers. The large heterogeneity of cancers and the large number of available drugs renders exhaustive in vivo or even in vitro investigation of possible treatments impractical. In recent years, sophisticated mechanistic, ordinary differential equation-based pathways models that can predict treatment responses at a molecular level have been developed. However, surprisingly little effort has been put into leveraging these models to find novel therapies. In this paper we use for the first time, to our knowledge, a large-scale state-of-the-art pan-cancer signaling pathway model to identify candidates for novel combination therapies to treat individual cancer cell lines from various tissues (e.g., minimizing proliferation while keeping dosage low to avoid adverse side effects) and populations of heterogeneous cancer cell lines (e.g., minimizing the maximum or average proliferation across the cell lines while keeping dosage low). We also show how our method can be used to optimize the drug combinations used in sequential treatment plans—that is, optimized sequences of potentially different drug combinations—providing additional benefits. In order to solve the treatment optimization problems, we combine the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) algorithm with a significantly more scalable sampling scheme for truncated Gaussian distributions, based on a Hamiltonian Monte-Carlo method. These optimization techniques are independent of the signaling pathway model, and can thus be adapted to find treatment candidates for other complex diseases than cancers as well, as long as a suitable predictive model is available.     

Oxidative stress in patients undergoing high-dose chemotherapy plus peripheral blood stem cell transplantation

Chemotherapy and radiation therapy are associated with increased formation of reactive oxygen species and depletion of critical plasma and tissue antioxidants. In patients undergoing high-dose chemotherapy, the plasma antioxidant concentration has been shown to decrease. However, these studies in which the oxidative stress status were investigated have a small number of patients and they are heterogeneous. In this study, the changes in certain trace elements together with oxidative stress parameters were investigated in 36 patients who had undergone autologous stem cell transplantation because of solid and hematological malignancies. Blood samples of the patients were examined before the high-dose chemotherapy (baseline), before stem cell transplantation (day -1), and after stem cell transplantation on day 1, 3, and 6. Erythrocyte zinc, silver, and iron levels were measured by atomic absorption spectrophotometry; malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels were measured by UV-vis spectrophotometry. After high-dose chemotherapy, significant increases in the levels of MDA, GSH-Px, and SOD were observed. On the other hand, Cu levels remained the same while the levels of erythrocyte Zn and Fe were increased. Significant correlation was observed among MDA, GSH-Px, and SOD (p<0.05). High-dose chemotherapy gives rise to an increase in the oxidative stress and the reactive oxygen species. Standard parenteral nutrition protocols were found to be insufficient to lower this stress.     

Examination of metal mobilization from a gunshot by scanning acoustic microscopy,scanning electron microscopy,energy-dispersive X-ray spectroscopy,and inductively coupled plasma optical emission spectroscopy: a case report

Background

Projectile foreign bodies are known to cause chronic heavy metal toxicity due to the release of metal into the bloodstream. However, the local effect around the metallic object has not been investigated and the main goal of our study is to examine the influence of the object in close proximity of the object.

Case presentation

A 36-year-old Caucasian woman with one metallic pellet close to her sciatic nerve due to a previous shotgun injury at the gluteal area presented with a diagnosis of recurrent lumbar disk herniation at L4–5 level. A physical examination confirmed chronic neuropathy and she underwent a two-stage surgery. The surgery included removal of the foreign body, followed by discectomy and fusion at the involved level. During the removal of the metallic foreign body, a tissue sample around the pellet and another tissue sample from a remote area were obtained. The samples were analyzed by scanning acoustic microscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. Lead, chromium, copper, cadmium, iron, manganese, selenium, and zinc elements in tissue, blood, and serum specimens were detected by inductively coupled plasma optical emission spectroscopy.

Conclusions

An acoustic impedance map of the tissue closer to the metallic body showed higher values indicating further accumulation of elements. Energy-dispersive X-ray spectroscopy results confirmed scanning acoustic microscopy results by measuring a higher concentration of elements closer to the metallic body. Scanning electron microscopy images showed that original structure was not disturbed far away; however, deformation of the structure existed in the tissue closer to the foreign body. Element analysis showed that element levels within blood and serum were more or less within acceptable ranges; on the other hand, element levels within the tissues showed pronounced differences indicating primarily lead intoxication in the proximity of the metallic body. We can state that residues of metallic foreign bodies of gunshot injuries cause chronic metal infiltration to the surrounding tissue and induce significant damage to nearby neural elements; this is supported by the results of scanning acoustic microscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and inductively coupled plasma optical emission spectroscopy.

     

Operculum ultrastructure in leech cocoons

Clitellate annelids (i.e., oligochaetes including leeches) secrete cocoons as part of their normal reproductive cycle. Typically, the cocoon sheath is passed over the head of the leech and sealed at both ends by opercula (i.e., glue‐like material secreted by the clitellum). Both the fibrous cocoon wall (CW) and opercula are chemically‐related biomaterials that share unusual physiochemical properties, including thermal and chemical resiliency. To explore the underlying morphology of the operculum, we examined cocoons from four leech species (i.e., Myzobdella lugubris, Theromyzon tessulatum, Erpobdella obscura, and Erpobdella punctata) by transmission (TEM) and scanning electron microscopy (SEM). Transmission electron micrographs of all opercula revealed a common, ultrastructural pattern comprising an electron‐dense mosaic of ordered polygons that surrounded interspersed cavities. The long axes of cavities were often oriented directionally, suggesting that operculum material is pliable prior to solidification and distorted as a consequence of cocoon deposition. Concomitantly, the operculum permeates jagged edges of the cocoon sheath sealing the cocoon, which provides a mechanically strong CW/operculum boundary. SEM of leech opercula revealed globular nanoparticles comparable to that observed in bioadhesives from disparate animal phyla (e.g., mussel, barnacle, sea star), suggesting a convergent mechanism of bioadhesion among animals. J. Morphol. 274:940–946, 2013. © 2013 Wiley Periodicals, Inc.     

Traits associated with winter wheat grain yield in Central and West Asia

Improved adaptation of winter wheat(Triticum aestivum L.) to drought and heat may be influenced by days to heading, plant height, biomass, canopy temperature(CT) at grain filling, and rate of senescence. This study shows that,under supplemental irrigation or rainfed conditions, days to heading and plant height together explain up to 68% of grain yield(GY) variation, and these associations were further confirmed in several locations across West and Central Asia.Days to heading can be slightly reduced below that of check line Karahan to further improve GY while avoiding the effect of late frosts. Plant height has been decreased in recent germplasm, but further reductions below that of check line Karahan could still improve GY in a wide range of environments. However, in Iranian sites, taller genotypes showed better adaptation with higher biomass and increased reservesfor grain filling. Canopy temperature and rate senescence were not associated with GY. A normalized difference vegetation index, used to estimate biomass(Feekes stages 4–5), had intermediate heritability across environments and correlated positively with GY under low plant density and should be explored further as a tool for early selection.     

Plasma membranes as heat stress sensors: From lipid-controlled molecular switches to therapeutic applications

The classic heat shock (stress) response (HSR) was originally attributed to protein denaturation. However, heat shock protein (Hsp) induction occurs in many circumstances where no protein denaturation is observed. Recently considerable evidence has been accumulated to the favor of the “Membrane Sensor Hypothesis” which predicts that the level of Hsps can be changed as a result of alterations to the plasma membrane. This is especially pertinent to mild heat shock, such as occurs in fever. In this condition the sensitivity of many transient receptor potential (TRP) channels is particularly notable. Small temperature stresses can modulate TRP gating significantly and this is influenced by lipids. In addition, stress hormones often modify plasma membrane structure and function and thus initiate a cascade of events, which may affect HSR. The major transactivator heat shock factor-1 integrates the signals originating from the plasma membrane and orchestrates the expression of individual heat shock genes. We describe how these observations can be tested at the molecular level, for example, with the use of membrane perturbers and through computational calculations. An important fact which now starts to be addressed is that membranes are not homogeneous nor do all cells react identically. Lipidomics and cell profiling are beginning to address the above two points. Finally, we observe that a deregulated HSR is found in a large number of important diseases where more detailed knowledge of the molecular mechanisms involved may offer timely opportunities for clinical interventions and new, innovative drug treatments. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.     

Virulence plasmid stability in environmentally occurring <Emphasis Type="Italic">Bacillus anthracis</Emphasis> from North East Turkey

The Bacillus anthracis virulence plasmid pXO2, which encodes for a polypeptide capsule, can be lost during long term laboratory storage. To determine if pXO2 is lost in nature we screened B. anthracis isolates obtained from B. anthracis spores from contaminated animal burial sites in Turkey for their ability to express a capsule upon primary culture. A total of 672 B. anthracis colonies were examined of which ten produced a mixed mucoid (capsule +ve)/non-mucoid (capsule ?ve) phenotype and a further one colony yielded non-mucoid colonies upon repeated culture. Screening by PCR using pXO2 specific primers revealed that seven of these isolates had eliminated the plasmid. Of the four colonies which were positive by PCR, one regained the ability to express a capsule upon repeated culture suggesting that the defect was reversible. This is an important observation as capsule expression is a principal marker of virulence and in the absence of PCR serves as a key diagnostic marker. The results of this preliminary study suggest that pXO2 is lost in nature and that further studies are need to determine the mechanisms by which this occurs.     

RBC NOS: regulatory mechanisms and therapeutic aspects

Nitric oxide (NO), one of the most important vascular signaling molecules, is primarily produced by endothelial NO synthase (eNOS). eNOS is tightly regulated by its substrate l-arginine, cofactors and diverse interacting proteins. Interestingly, an NO synthase (NOS) was described within red blood cells (RBC NOS), and it was recently shown to significantly contribute to the intravascular NO pool and to regulate physiologically relevant mechanisms. However, the regulatory mechanisms and clinical implications of RBC NOS are unknown. The aim of this review is to highlight intracellular RBC NOS interactions and the role of RBC NOS in RBC homeostasis. Furthermore, macro- and microvascular diseases affected by RBC-derived NO are discussed.