Vincristine and Prednisone for the Induction of Remissions in Acute Childhood Leukaemia

A total of 65 children with acute lymphoblastic leukaemia and seven with other types of acute leukaemia received treatment with a combination of vincristine and prednisone. In all 122 courses of treatment were given. Of 22 patients with acute lymphoblastic leukaemia who received this as their first treatment, all achieved complete remission. The complete remission rates were 82% for patients with acute lymphoblastic leukaemia in their first relapse, 63% in the second relapse, and much lower in subsequent relapses and in the patients with other types of acute leukaemia. Alopecia and gastrointestinal and neuromuscular toxicity occurred respectively in 51%, 29%, and 21% of instances, only the last of these side-effects of vincristine being dose-related. Most of the complete remissions were obtained with a total dose of vincristine which carried only a low risk of neurotoxicity.     

Molecular drift of the bride of sevenless (boss) gene in Drosophila

DNA sequences were determined for three to five alleles of the bride-of- sevenless (boss) gene in each of four species of Drosophila. The product of boss is a transmembrane receptor for a ligand coded by the sevenless gene that triggers differentiation of the R7 photoreceptor cell in the compound eye. Population parameters affecting the rate and pattern of molecular evolution of boss were estimated from the multinomial configurations of nucleotide polymorphisms of synonymous codons. The time of divergence between D. melanogaster and D. simulans was estimated as approximately 1 Myr, that between D. teissieri and D. yakuba as approximately 0.75 Myr, and that between the two pairs of sibling species as approximately 2 Myr. (The boss genes themselves have estimated divergence times approximately 50% greater than the species divergence times.) The effective size of the species was estimated as approximately 5 x 10(6), and the average mutation rate was estimated as 1-2 x 10(-9)/nucleotide/generation. The ratio of amino acid polymorphisms within species to fixed differences between species suggests that approximately 25% of all possible single-step amino acid replacements in the boss gene product may be selectively neutral or nearly neutral. The data also imply that random genetic drift has been responsible for virtually all of the observed differences in the portion of the boss gene analyzed among the four species.      

The contractile basis of amoeboid movement: V. The control of gelation, solation, and contraction in extracts from dictyostelium discoideum

Motile extracts have been prepared from Dictyostelium discoideum by homogenization and differential centrifugation at 4 degrees C in a stabilization solution (60). These extracts gelled on warming to 25 degrees Celsius and contracted in response to micromolar Ca++ or a pH in excess of 7.0. Optimal gelation occurred in a solution containing 2.5 mM ethylene glycol-bis (β-aminoethyl ether)N,N,N',N'-tetraacetate (EGTA), 2.5 mM piperazine-N-N'-bis [2-ethane sulfonic acid] (PIPES), 1 mM MgC1(2), 1 mM ATP, and 20 mM KCI at ph 7.0 (relaxation solution), while micromolar levels of Ca++ inhibited gelation. Conditions that solated the gel elicited contraction of extracts containing myosin. This was true regardless of whether chemical (micromolar Ca++, pH >7.0, cytochalasin B, elevated concentrations of KCI, MgC1(2), and sucrose) or physical (pressure, mechanical stress, and cold) means were used to induce solation. Myosin was definitely required for contraction. During Ca++-or pH-elicited contraction: (a) actin, myosin, and a 95,000-dalton polypeptide were concentrated in the contracted extract; (b) the gelation activity was recovered in the material sqeezed out the contracting extract;(c) electron microscopy demonstrated that the number of free, recognizable F-actin filaments increased; (d) the actomyosin MgATPase activity was stimulated by 4- to 10-fold. In the absense of myosin the Dictyostelium extract did not contract, while gelation proceeded normally. During solation of the gel in the absense of myosin: (a) electron microscopy demonstrated that the number of free, recognizable F- actin filaments increased; (b) solation-dependent contraction of the extract and the Ca++-stimulated MgATPase activity were reconstituted by adding puried Dictyostelium myosin. Actin purified from the Dictyostelium extract did not gel (at 2 mg/ml), while low concentrations of actin (0.7-2 mg/ml) that contained several contaminating components underwent rapid Ca++ regulated gelation. These results indicated : (a) gelation in Dictyostelium extracts involves a specific Ca++-sensitive interaction between actin and several other components; (b) myosin is an absolute requirement for contraction of the extract; (c) actin-myosin interactions capable of producing force for movement are prevented in the gel, while solation of the gel by either physical or chemical means results in the release of F-actin capable of interaction with myosin and subsequent contraction. The effectiveness of physical agents in producting contraction suggests that the regulation of contraction by the gel is structural in nature.     

Increased Atmospheric SO2 Detected from Changes in Leaf Physiognomy across the Triassic–Jurassic Boundary Interval of East Greenland

The Triassic–Jurassic boundary (Tr–J; ∼201 Ma) is marked by a doubling in the concentration of atmospheric CO₂, rising temperatures, and ecosystem instability. This appears to have been driven by a major perturbation in the global carbon cycle due to massive volcanism in the Central Atlantic Magmatic Province. It is hypothesized that this volcanism also likely delivered sulphur dioxide (SO₂) to the atmosphere. The role that SO₂ may have played in leading to ecosystem instability at the time has not received much attention. To date, little direct evidence has been presented from the fossil record capable of implicating SO₂ as a cause of plant extinctions at this time. In order to address this, we performed a physiognomic leaf analysis on well-preserved fossil leaves, including Ginkgoales, bennettites, and conifers from nine plant beds that span the Tr–J boundary at Astartekløft, East Greenland. The physiognomic responses of fossil taxa were compared to the leaf size and shape variations observed in nearest living equivalent taxa exposed to simulated palaeoatmospheric treatments in controlled environment chambers. The modern taxa showed a statistically significant increase in leaf roundness when fumigated with SO₂. A similar increase in leaf roundness was also observed in the Tr–J fossil taxa immediately prior to a sudden decrease in their relative abundances at Astartekløft. This research reveals that increases in atmospheric SO₂ can likely be traced in the fossil record by analyzing physiognomic changes in fossil leaves. A pattern of relative abundance decline following increased leaf roundness for all six fossil taxa investigated supports the hypothesis that SO₂ had a significant role in Tr–J plant extinctions. This finding highlights that the role of SO₂ in plant biodiversity declines across other major geological boundaries coinciding with global scale volcanism should be further explored using leaf physiognomy.     

Septicaemia in the Neutropenic Patient

A total of 29 cases of septicaemia proved by blood culture in 22 severely neutropenic patients with acute leukaemia or aplastic anaemia have been studied. The recovery rate was 75% in the Gram-positive septicaemias and 60% in the Gram-negative septicaemias in which treatment response could be evaluated. Neutropenia predisposed to septicaemia and its degree seemed to be important. The underlying state of the bone marrow was an important prognostic factor; the neutrophil count at the time of diagnosis and the infecting organism were less important. Gentamicin was the single most useful antibiotic, and the infection was controlled largely with gentamicin and one other antibiotic, most often carbenicillin. Possibly a similar result could have been obtained with gentamicin alone, but since the bacterial flora in a given environment is changeable empirical antibiotic regimens should remain flexible.     

Saikosaponin-d,a novel SERCA inhibitor,induces autophagic cell death in apoptosis-defective cells

Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase pump, leading to autophagy induction through the activation of the Ca²⁺/calmodulin-dependent kinase kinase–AMP-activated protein kinase–mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells.     

Modelling external bone adaptation using evolutionary structural optimisation

External remodelling is significant in the bone healing process, and it is essential to predict the bone external shape in the design of artificial bone grafts. This paper demonstrates the effectiveness of the evolutionary structural optimisation (ESO) method for the simulation of bone morphology. A two-dimensional ESO strategy is developed which is capable of finding the modified bone topology beginning with any geometry under any loading conditions. The morphology of bone structure is described by the quantitative bone adaptation theory, which is integrated with the finite element method. The evolutionary topology optimisation process is introduced to find the bone shape. A rectangle, which occupies a larger space than the external shape of the bone structure, is specified as a design domain; the evolutionary process iteratively eliminates and redistributes material throughout the domain to obtain an optimum arrangement of bone materials. The technique has been tested on a wide range of examples. In this paper, the formation of trabecular bone architecture around an implant is studied; as another example, the growth of the coronal section of a vertebral body is predicted. The examples support the assertion that the external shape of bone structure can be successfully predicted by the proposed ESO procedure.     

A history of the study of solid tumour growth: The contribution of mathematical modelling

A miscellany of new strategies, experimental techniques and theoretical approaches are emerging in the ongoing battle against cancer. Nevertheless, as new, ground-breaking discoveries relating to many and diverse areas of cancer research are made, scientists often have recourse to mathematical modelling in order to elucidate and interpret these experimental findings. Indeed, experimentalists and clinicians alike are becoming increasingly aware of the possibilities afforded by mathematical modelling, recognising that current medical techniques and experimental approaches are often unable to distinguish between various possible mechanisms underlying important aspects of tumour development. This short treatise presents a concise history of the study of solid tumour growth, illustrating the development of mathematical approaches from the early decades of the twentieth century to the present time. Most importantly these mathematical investigations are interwoven with the associated experimental work, showing the crucial relationship between experimental and theoretical approaches, which together have moulded our understanding of tumour growth and contributed to current anti-cancer treatments. Thus, a selection of mathematical publications, including the influential theoretical studies by Burton, Greenspan, Liotta et al., McElwain and co-workers, Adam and Maggelakis, and Byrne and co-workers are juxtaposed with the seminal experimental findings of Gray et al. on oxygenation and radio-sensitivity, Folkman on angiogenesis, Dorie et al. on cell migration and a wide variety of other crucial discoveries. In this way the development of this field of research through the interactions of these different approaches is illuminated, demonstrating the origins of our current understanding of the disease.