Mobilizing Toxins for Cancer Treatment: Historical Perspectives and Current Strategies.

The level of complexity in a disease like cancer presents a number of challenges for effective treatment development, which require significant innovation to overcome [...]

Targeting gastrointestinal cancers with chimeric antigen receptor (CAR)-T cell therapy

The immune system is capable of remarkably potent and specific efficacy against infectious diseases. For decades, investigators sought to leverage those characteristics to create immune-based therapies (immunotherapy) that might be far more effective and less toxic than conventional chemotherapy and radiation therapy for cancer. Those studies revealed many factors and mechanisms underlying the success or failure of cancer immunotherapy, leading to synthetic biology approaches, including CAR-T cell therapy. In this approach, patient T cells are genetically modified to express a chimeric antigen receptor (CAR) that converts T cells of any specificity into tumor-specific T cells that can be expanded to large numbers and readministered to the patient to eliminate cancer cells, including bulky metastatic disease. This approach has been most successful against hematologic cancers, resulting in five FDA approvals to date. Here, we discuss some of the most promising attempts to apply this technology to cancers of the gastrointestinal tract

Dry land tree management for improved household livelihoods: Farmer managed natural regeneration in Niger

Farmer Managed Natural Regeneration (FMNR), a set of practices farmers use to foster the growth of indigenous trees on agricultural land, has drawn substantial attention as a contributing factor to a trend of increasing vegetation greenness in the Republic of Niger. This paper identifies drivers of FMNR adoption and assesses its impacts on rural households in the Region of Maradi, Niger, an area covering 42,000 square kilometers. The results show that 26% of households practice a form of FMNR involving both pruning and protecting woody vegetation. Adoption is strongly linked to soil type, market access, and the education level of the head of household. FMNR raises household income and increases crop diversity, household migration rates, and the density and diversity of trees on farmland. It is estimated that FMNR raises the annual gross income of the region by between 17 and 21 million USD and has contributed an additional 900,000 to 1,000,000 trees to the local environment. These findings support the value of continued promotion of FMNR as an inexpensive means of enhancing rural livelihoods and an attractive alternative to reforestation efforts relying on tree planting

GUCY2C lysosomotropic endocytosis delivers immunotoxin therapy to metastatic colorectal cancer.

The emergence of targeted cancer therapy has been limited by the paucity of determinants which are tumor-specific and generally associated with disease, and have cell dynamics which effectively deploy cytotoxic payloads. Guanylyl cyclase C (GUCY2C) may be ideal for targeting because it is normally expressed only in insulated barrier compartments, including intestine and brain, but over-expressed by systemic metastatic colorectal tumors. Here, we reveal that GUCY2C rapidly internalizes from the cell surface to lysosomes in intestinal and colorectal cancer cells. Endocytosis is independent of ligand binding and receptor activation, and is mediated by clathrin. This mechanism suggests a design for immunotoxins comprising a GUCY2C-directed monoclonal antibody conjugated through a reducible disulfide linkage to ricin A chain, which is activated to a potent cytotoxin in lysosomes. Indeed, this immunotoxin specifically killed GUCY2C-expressing colorectal cancer cells in a lysosomal- and clathrin-dependent fashion. Moreover, this immunotoxin reduced pulmonary tumors \u3e80% (

Habitat Use by Middle Mississippi River Pallid Sturgeon

Little is known about the habitat preferences and needs of pallid sturgeon Scaphirhynchus albus, which was federally listed as endangered in 1990. To learn more about habitat use and selection by pallid sturgeon, sonic transmitters were surgically implanted in 27 individuals from the middle Mississippi River. Study fish were located 184 times (1–23 times/individual) from November 1995 to December 1999. Of the seven macrohabitats identified, pallid sturgeon were found most often in main-channel habitats (39% of all relocations) and main-channel border habitats (26%); the between-wing-dam habitats were used less often (14%). Strauss’s linear selectivity index (Li) values indicated that study fish exhibited positive selection for the main-channel border, downstream island tips, between-wing-dam, and wing-dam-tip habitats; they showed negative selection for main-channel, downstream of wing dams, and upstream of wing dam habitats. Comparison of Li values for four temperature ranges and three daily mean discharge ranges revealed little change in habitat selection due to temperature or discharge. Habitat use patterns also were similar across seasons and discharge regimes, except during spring months when between-wingdam habitats saw greater use and main-channel and main-channel border habitat use declined. These changes may have been a response to high river stages associated with spring flooding, which may create favorable feeding areas in the between-wing-dam habitats. Enhancement and restoration of habitat diversity, particularly downstream island tip and between-wing-dam habitats, may be necessary for the recovery of pallid sturgeon in the middle Mississippi River

Asymptotic analysis for the generalized langevin equation

Various qualitative properties of solutions to the generalized Langevin equation (GLE) in a periodic or a confining potential are studied in this paper. We consider a class of quasi-Markovian GLEs, similar to the model that was introduced in \cite{EPR99}. Geometric ergodicity, a homogenization theorem (invariance principle), short time asymptotics and the white noise limit are studied. Our proofs are based on a careful analysis of a hypoelliptic operator which is the generator of an auxiliary Markov process. Systematic use of the recently developed theory of hypocoercivity \cite{Vil04HPI} is made.Comment: 27 pages, no figures. Submitted to Nonlinearity

Geometric integrator for Langevin systems with quaternion-based rotational degrees of freedom and hydrodynamic interactions

We introduce new Langevin-type equations describing the rotational and translational motion of rigid bodies interacting through conservative and non-conservative forces, and hydrodynamic coupling. In the absence of non-conservative forces the Langevin-type equations sample from the canonical ensemble. The rotational degrees of freedom are described using quaternions, the lengths of which are exactly preserved by the stochastic dynamics. For the proposed Langevin-type equations, we construct a weak 2nd order geometric integrator which preserves the main geometric features of the continuous dynamics. The integrator uses Verlet-type splitting for the deterministic part of Langevin equations appropriately combined with an exactly integrated Ornstein-Uhlenbeck process. Numerical experiments are presented to illustrate both the new Langevin model and the numerical method for it, as well as to demonstrate how inertia and the coupling of rotational and translational motion can introduce qualitatively distinct behaviours

Energy representation for out-of-equilibrium Brownian-like systems: steady states and fluctuation relations

Stochastic dynamics in the energy representation is employed as a method to study non-equilibrium Brownian-like systems. It is shown that the equation of motion for the energy of such systems can be taken in the form of the Langevin equation with multiplicative noise. Properties of the steady states are examined by solving the Fokker-Planck equation for the energy distribution functions. The generalized integral fluctuation theorem is deduced for the systems characterized by the shifted probability flux operator. There are a number of entropy and fluctuation relations such as the Hatano-Sasa identity and the Jarzynski's equality that follow from this theorem.Comment: revtex4-1, 18 pages, extended discussion, references adde

Statin Therapy Alters Lipid Storage in Diabetic Skeletal Muscle

While statins significantly reduce cholesterol levels and thereby reduce the risk of cardiovascular disease, the development of myopathy with statin use is a significant clinical side-effect. Recent guidelines recommend increasing inclusion criteria for statin treatment in diabetic individuals; however, the impact of statins on skeletal muscle health in those with diabetes (who already suffer from impairments in muscle health) is ill-defined. Here we investigate the effects of Fluvastatin treatment on muscle health in wild-type and streptozotocin (STZ)-induced diabetic mice. Wild-type and STZ-diabetic mice received diet enriched with 600 mg/kg Fluvastatin or control chow for 24 days. Muscle morphology, intra and extracellular lipid levels, and lipid transporter content was investigated. Our findings indicate that short-term Fluvastatin administration induced a myopathy that was not exacerbated by the presence of STZ-induced diabetes. Fluvastatin significantly increased ectopic lipid deposition within the muscle of STZ-diabetic animals, findings that were not seen with diabetes or statin treatment alone. Consistent with this observation, only Fluvastatin-treated diabetic mice downregulated protein expression of lipid transporters FAT/CD36 and FABPpm in their skeletal muscle. No differences in FAT/CD36 or FABPpm mRNA content were observed. Altered lipid compartmentalization resultant of a downregulation in lipid transporter content in STZ-induced diabetic skeletal muscle was apparent in the current investigation. Given the association between ectopic lipid deposition in skeletal muscle and the development of insulin-resistance, our findings highlight the necessity for more thorough investigations into the impact of statins in humans with diabetes