Emvododstat, a Potent Dihydroorotate Dehydrogenase Inhibitor, Is Effective in Preclinical Models of Acute Myeloid Leukemia.

Blocking the pyrimidine nucleotide de novo synthesis pathway by inhibiting dihydroorotate dehydrogenase (DHODH) results in the cell cycle arrest and/or differentiation of rapidly proliferating cells including activated lymphocytes, cancer cells, or virally infected cells. Emvododstat (PTC299) is an orally bioavailable small molecule that inhibits DHODH. We evaluated the potential for emvododstat to inhibit the progression of acute myeloid leukemia (AML) using several in vitro and in vivo models of the disease. Broad potent activity was demonstrated against multiple AML cell lines, AML blasts cultured ex vivo from patient blood samples, and AML tumor models including patient-derived xenograft models. Emvododstat induced differentiation, cytotoxicity, or both in primary AML patient blasts cultured ex vivo with 8 of 10 samples showing sensitivity. AML cells with diverse driver mutations were sensitive, suggesting the potential of emvododstat for broad therapeutic application. AML cell lines that are not sensitive to emvododstat are likely to be more reliant on the salvage pathway than on de novo synthesis of pyrimidine nucleotides. Pharmacokinetic experiments in rhesus monkeys demonstrated that emvododstat levels rose rapidly after oral administration, peaking about 2 hours post-dosing. This was associated with an increase in the levels of dihydroorotate (DHO), the substrate for DHODH, within 2 hours of dosing indicating that DHODH inhibition is rapid. DHO levels declined as drug levels declined, consistent with the reversibility of DHODH inhibition by emvododstat. These preclinical findings provide a rationale for clinical evaluation of emvododstat in an ongoing Phase 1 study of patients with relapsed/refractory acute leukemias.

Preclinical and Early Clinical Development of PTC596, a Novel Small-Molecule Tubulin-Binding Agent.

PTC596 is an investigational small-molecule tubulin-binding agent. Unlike other tubulin-binding agents, PTC596 is orally bioavailable and is not a P-glycoprotein substrate. So as to characterize PTC596 to position the molecule for optimal clinical development, the interactions of PTC596 with tubulin using crystallography, its spectrum of preclinical in vitro anticancer activity, and its pharmacokinetic-pharmacodynamic relationship were investigated for efficacy in multiple preclinical mouse models of leiomyosarcomas and glioblastoma. Using X-ray crystallography, it was determined that PTC596 binds to the colchicine site of tubulin with unique key interactions. PTC596 exhibited broad-spectrum anticancer activity. PTC596 showed efficacy as monotherapy and additive or synergistic efficacy in combinations in mouse models of leiomyosarcomas and glioblastoma. PTC596 demonstrated efficacy in an orthotopic model of glioblastoma under conditions where temozolomide was inactive. In a first-in-human phase I clinical trial in patients with cancer, PTC596 monotherapy drug exposures were compared with those predicted to be efficacious based on mouse models. PTC596 is currently being tested in combination with dacarbazine in a clinical trial in adults with leiomyosarcoma and in combination with radiation in a clinical trial in children with diffuse intrinsic pontine glioma.

Limitations in the Grain Boundary Processing of the Recycled HDDR Nd-Fe-B System.

Fully dense spark plasma sintered recycled and fresh HDDR Nd-Fe-B nanocrystalline bulk magnets were processed by surface grain boundary diffusion (GBD) treatment to further augment the coercivity and investigate the underlying diffusion mechanism. The fully dense SPS processed HDDR based magnets were placed in a crucible with varying the eutectic alloys Pr68Cu32 and Dy70Cu30 at 2-20 wt. % as direct diffusion source above the ternary transition temperature for GBD processing followed by secondary annealing. The changes in mass gain was analyzed and weighted against the magnetic properties. For the recycled magnet, the coercivity (HCi) values obtained after optimal GBDP yielded ~60% higher than the starting recycled HDDR powder and 17.5% higher than the SPS-ed processed magnets. The fresh MF-15P HDDR Nd-Fe-B based magnets gained 25-36% higher coercivities with Pr-Cu GBDP. The FEG-SEM investigation provided insight on the diffusion depth and EDXS analysis indicated the changes in matrix and intergranular phase composition within the diffusion zone. The mechanism of surface to grain boundary diffusion and the limitations to thorough grain boundary diffusion in the HDDR Nd-Fe-B based bulk magnets were detailed in this study.

Nanoscale Pattern Decay Monitored Line by Line via In Situ Heated Atomic Force Microscopy.

We combine in situ heated atomic force microscopy (AFM) with automated line-by-line spectral analysis to quantify the relaxation or decay phenomenon of nanopatterned composite polymer films above the glass-transition temperature of the composite material. This approach enables assessment of pattern fidelity with a temporal resolution of ≈1 s, providing the necessary data density to confidently capture the short-time relaxation processes inaccessible to conventional ex situ measurements. Specifically, we studied the thermal decay of nanopatterned poly(methyl methacrylate) (PMMA) and PMMA nanocomposite films containing unmodified and PMMA-grafted silica nanoparticles (SiO2 NP) of varying concentrations and film thicknesses using this new approach. Features imprinted on neat PMMA films were seen to relax at least an order of magnitude faster than the NP-filled films at decay temperatures above the glass transition of the PMMA matrix. It was also seen that patterned films with the lowest residual thickness (34 nm) filled with unmodified SiO2 NP decayed the slowest. The effect of nanoparticle additive was almost negligible in reinforcing the patterned features for films with the highest residual thickness (257 nm). Our in situ pattern decay measurement and the subsequent line-by-line spectral analysis enabled the investigation of various parameters affecting the pattern decay such as the underlying residual thickness, type of additive system, and temperature in a timely and efficient manner.

Coercivity Increase of the Recycled HDDR Nd-Fe-B Powders Doped with DyF3 and Processed via Spark Plasma Sintering & the Effect of Thermal Treatments.

The magnetic properties of the recycled hydrogenation disproportionation desorption recombination (HDDR) Nd-Fe-B powder, doped with a low weight fraction of DyF3 nanoparticles, were investigated. Spark plasma sintering (SPS) was used to consolidate the recycled Nd-Fe-B powder blends containing 1, 2, and 5 wt.% of DyF3 grounded powder. Different post-SPS sintering thermal treatment conditions (600, 750, and 900 °C), for a varying amount of time, were studied in view of optimizing the magnetic properties and developing characteristic core-shell microstructure in the HDDR powder. As received, recycled HDDR powder has coercivity (HCi) of 830 kA/m, and as optimally as SPS magnets reach 1160 kA/m, after the thermal treatment. With only 1-2 wt.% blended DyF3, the HCi peaked to 1407 kA/m with the thermal treatment at 750 °C for 1 h. The obtained HCi values of the blend magnet is ~69.5% higher than the starting recycled HDDR powder and 17.5% higher than the SPS processed magnet annealed at 750 °C for 1 h. Prolonging the thermal treatment time to 6 h and temperature conditions above 900 °C was detrimental to the magnetic properties. About ~2 wt.% DyF3 dopant was suitable to develop a uniform core-shell microstructure in the HDDR Nd-Fe-B powder. The Nd-rich phase in the HDDR powder has a slightly different and fluorine rich composition i.e., Nd-O-F2 than in the one reported in sintered magnets (Nd-O-F). The composition of reaction zone-phases after the thermal treatment and Dy diffusion was DyF4, which is more abundant in 5 wt.% doped samples. Further doping above 2 wt.% DyF3 is ineffective in augmenting the coercivity of the recycled HDDR powder, due to the decomposition of the shell structure and formation of non-ferromagnetic rare earth-based complex intermetallic compounds. The DyF3 doping is a very effective single step route in a controlled coercivity improvement of the recycled HDDR Nd-Fe-B powder from the end of life magnetic products.

Surface interaction parameter measurement of solvated polymers via model end-tethered chains.

We present a method for the direct measurement of the relative energy of interaction between a solvated polymer and a solid interface. By tethering linear chains covalently to the surface, we ensured the idealized and constant configuration of polymer molecules for measurement, modeling, and parameter estimation. For the case of amine-terminated polystyrene bound to a glycidoxypropyl silane film submerged in cyclohexane-d12, we estimated the χ parameter for the temperature range 10.7 °C to 52.0 °C, and found a downward sloping trend that crosses the χ = 0.5 threshold at 37 °C to 40 °C, in agreement with solution estimates for the same system. We simultaneously estimated the surface interaction parameter χs at each temperature, finding a decreasing affinity of the chains for the surface with increasing temperature, consistent with empirical observations. The theoretical model shows some limitations in a stronger solvent (toluene-d8) that prevent rigorous parameter estimation, but we demonstrate a qualitative change in χ and χs towards stronger solvency and weaker surface interaction with increasing temperature.

High coercivity, anisotropic, heavy rare earth-free Nd-Fe-B by Flash Spark Plasma Sintering.

ABSTARCT: In the drive to reduce the critical Heavy Rare Earth (HRE) content of magnets for green technologies, HRE-free Nd-Fe-B has become an attractive option. HRE is added to Nd-Fe-B to enhance the high temperature performance of the magnets. To produce similar high temperature properties without HRE, a crystallographically textured nanoscale grain structure is ideal; and this conventionally requires expensive "die upset" processing routes. Here, a Flash Spark Plasma Sintering (FSPS) process has been applied to a Dy-free Nd30.0Fe61.8Co5.8Ga0.6Al0.1B0.9 melt spun powder (MQU-F, neo Magnequench). Rapid sinter-forging of a green compact to near theoretical density was achieved during the 10 s process, and therefore represents a quick and efficient means of producing die-upset Nd-Fe-B material. The microstructure of the FSPS samples was investigated by SEM and TEM imaging, and the observations were used to guide the optimisation of the process. The most optimal sample is compared directly to commercially die-upset forged (MQIII-F) material made from the same MQU-F powder. It is shown that the grain size of the FSPS material is halved in comparison to the MQIII-F material, leading to a 14% increase in coercivity (1438 kA m-1) and matched remanence (1.16 T) giving a BHmax of 230 kJ m-3.

Ultraviolet/Ozone as a Tool To Control Grafting Density in Surface-Initiated Controlled-Radical Polymerizations via Ablation of Bromine.

We used an ultraviolet-ozone (UVO) cleaner to create substrates for atom-transfer radical polymerization (ATRP) with varying surface initiator coverage. We collected complementary time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS) measurements to investigate the precise chemical origin of the variation in grafting density. At short exposure times, the atomic composition underwent minor changes except for the relative amount of bromine. At longer UVO exposure times, there is clear evidence of exposure-dependent surface initiator oxidation. We interpret these data as evidence of a bromine ablation process within the UVO cleaner, with additional oxidative modification of the rest of the surface. We then used these substrates to create a series of poly(methyl methacrylate) (PMMA) brushes varying in grafting density, demonstrating the utility of this tool for the control of polymer brush density. The measured brush grafting densities were correlated with the bromine concentration measured by both ToF-SIMS and XPS. XPS and brush thicknesses correlated strongly, following an exponential decay with a half-life of 18 ± 1 s.

Case study illustrating risks of garrison unit watch for soldiers at risk of suicide.

Unit watch over suicidal patients by nonmedical soldiers is often necessary in a deployed environment, but this strategy's risks may outweigh its benefits in a garrison environment. This case study illustrates risks of unit watches that are difficult for medical personnel to effectively mitigate. The suicidal soldier in question was placed on a unit watch in lieu of psychiatric hospitalization, utilizing a plan agreed upon by all parties. However, within 2 days, the plan had degenerated to an unacceptable degree. A commander is always legally responsible for subordinate soldiers' conduct, but from a patient safety perspective, medical professionals must account for the inevitable periods of decreased oversight within a unit. Medical professionals who recommend a unit watch must consider the risks associated with this course of action, including instances such as the error chain detailed in this case.

Chronic daily headache: diagnosis and management.

Chronic daily headache is defined as the presence of a headache on 15 days or more per month for at least three months. The most common types of chronic daily headache are chronic migraines and chronic tension-type headaches. If a red flag for a secondary cause of headache is present, magnetic resonance imaging of the head should be performed. All patients should be asked about medication overuse, which can increase the frequency of headaches. Patients who overuse medications for abortive therapy for headache should be encouraged to stop the medications entirely and consider prophylactic treatment. Several prophylactic treatments for chronic daily headache can reduce headache frequency and severity, as well as improve overall quality of life. Nonpharmacologic treatments include relaxation techniques, cognitive behavior therapy, acupuncture, osteopathic manipulation, and cervical exercises. Pharmacologic therapies include amitriptyline, gabapentin, onabotulinumtoxinA, propranolol, tizanidine, topiramate, and valproate.

Doctors and slaves: a medical and demographic history of slavery in the British West Indies, 1680-1834

In writing this book I have investigated facets of slave life that affected their health and well-being, such as culture shock, diet, work loads, punishment, housing, clothing, sanitation, and occupational hazards. I have looked at the demographic experience of the slaves, their birthrates, death rates, sex ratios, longevity, and above all, their failure to increase their population by natural means. I have looked at the principal diseases of the slaves, contemporary and modern theories of disease causation etiology, and methods of treatment and their efficacy. I have looked at problems of natality and infant and child care. I have investigated the state of medical science and art in Europe and Africa; the education of doctors, midwives, nurses, and apothecaries; the nature of plantation medical practice; and the quality of health care. Because of its size and economic and political importance, Jamaica has been given central attention in this study; however, other British Sugar Colonies have been investigated to the extent that demographic and medical records permit