Mice, men, mustard and methylated xanthines: the potential role of caffeine and related drugs in the sensitization of human tumours to alkylating agents.

The relationships between DNA damage from UV radiation, alkylating drugs and the methylated xanthines (MX) have been studied in normal and malignant rodent and human cells. A comparison of the level of DNA excision repair (repair replication and unscheduled DNA synthesis) confirms that some forms of alkylating-agent damage (probably mono-filar DNA adducts) are less completely removed by both normal and malignant rodent cells than by their human counterparts, rendering rodent cells more susceptible to the toxic potential of unexcised lesions. The toxicity of alkylating agents can be increased by the presence of several MXs during the period of DNA replication which follows infliction of the damage. Human cells appear capable of excising more DNA damage, rendering them somewhat less susceptible to enhancement of cytotoxicity by MX. This resistance of human cells is only quantitative, however, since 2 human cancer cell lines (HeLa and HT-29) could be sensitized to a variety of alkylating agents by appropriate concentrations of MX. Trimethylxanthine (caffeine) and the 2 clinically useful dimethylxanthines (theophylline and theobromine) appeared equally effective in sensitizing cells. The sensitization was dependent upon a slightly cytotoxic concentration of the MX and a suitably prolonged period of post-damage MX exposure. Of these 3 classic MXs, only theobromine might be clinically useful. The levels required for alkylating-agent sensitization exceed the clinically tolerable level of theophylline, and probably approach the tolerance of man to caffeine. The most likely mechanism by which MX sensitization is achieved is reversal of the inhibition of DNA replicon initiation which follows the infliction of significant DNA damage. Through the selection of suitable clinically useful alkylating agents (those dependent on active cellular transport for cell penetration) and appropriate MX scheduling, an enhanced therapeutic ratio might be achieved, potentially increasing the clinical usefulness of these alkylating agents. MX would thus form a useful class of agents adjuvant to conventional anti-cancer drugs

Mass-loaded spherical accretion flows

We have calculated the evolution of spherical accretion flows undergoing mass-loading from embedded clouds through either conduction or hydrodynamical ablation. We have observed the effect of varying the ratios of the mass-loading timescale and the cooling timescale to the ballistic crossing timescale through the mass-loading region. We have also varied the ratio of the potential energy of a particle injected into the flow near the outer region of mass-loading to the temperature at which a minimum occurs in the cooling curve. The two types of mass-loading produce qualitatively different types of behaviour in the accretion flow, since mass-loading through conduction requires the ambient gas to be hot, whereas mass ablation from clumps occurs throughout the flow. Higher ratios of injected to accreted mass typically occur with hydrodynamical ablation, in agreement with previous work on wind-blown bubbles and supernova remnants. We find that mass-loading damps the radiative overstability of such flows, in agreement with our earlier work. If the mass-loading is high enough it can stabilize the accretion shock at a constant radius, yielding an almost isothermal subsonic post-shock flow. Such solutions may be relevant to cooling flows onto massive galaxies. Mass-loading can also lead to the formation of isolated shells of high temperature material, separated by gas at cooler temperatures

“Do you think your main partner has other sex partners?” A simple question provides insight into sexual risk in Jamaica

To estimate the association between a simple measure of sexual partner concurrency and sexually transmitted infection (STI) we conducted a cross-sectional population-based household survey (n=1795) and targeted surveys of people at venues where people meet sexual partners (n=1580) to ask about sexual behavior. Persons interviewed at venues were tested for HIV, gonorrhoea, chlamydia, gonorrhea, and trichomoniasis. We compared the association between STI and reporting a partner had other partners. More women than men reported their main partner had other partners. Thirteen percent of all women in the population-based survey and 14.4% in the targeted survey reported having one partner in the past 12 months and that partner had additional partners. STI prevalence was significantly associated with reporting a partner had other partners (36.8% vs 30.2%; prevalence ratio [PR]1.2; 95% CI 1.1,1.4). Construction of complete sexual networks is costly and not routinely feasible. We recommend adding a question to cross-sectional surveys used to monitor sexual behavior about whether the respondent believes his or her partner has other sexual partners. Although subject to bias, the question was useful in Jamaica to identify a group of women with only one sexual partner at increased risk of infection

Extracellular Vimentin as a Target Against SARS-CoV-2 Host Cell Invasion

Infection of human cells by pathogens, including SARS-CoV-2, typically proceeds by cell surface binding to a crucial receptor. The primary receptor for SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2), yet new studies reveal the importance of additional extracellular co-receptors that mediate binding and host cell invasion by SARS-CoV-2. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens’ cellular uptake. Biophysical and cell infection studies are done to determine whether vimentin might bind SARS-CoV-2 and facilitate its uptake. Dynamic light scattering shows that vimentin binds to pseudovirus coated with the SARS-CoV-2 spike protein, and antibodies against vimentin block in vitro SARS-CoV-2 pseudovirus infection of ACE2-expressing cells. The results are consistent with a model in which extracellular vimentin acts as a co-receptor for SARS-CoV-2 spike protein with a binding affinity less than that of the spike protein with ACE2. Extracellular vimentin may thus serve as a critical component of the SARS-CoV-2 spike protein-ACE2 complex in mediating SARS-CoV-2 cell entry, and vimentin-targeting agents may yield new therapeutic strategies for preventing and slowing SARS-CoV-2 infection

Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery

Patients with anaplastic thyroid carcinoma can rarely be cured, but every effort should be made to prevent death due to suffocation. Between 1984 and 1999, 55 consecutive patients with anaplastic thyroid carcinoma were prospectively treated according to a combined regimen consisting of hyperfractionated radiotherapy, doxorubicin, and when feasible surgery. Radiotherapy was carried out for 5 days a week. The daily fraction until 1988 was 1.0 Gy×2 (A) and 1989–92 1.3 Gy×2 (B) . Thereafter 1.6 Gy×2 (C) was administered. Radiotherapy was administered to a total target dose of 46 Gy; of which 30 Gy was administered preoperatively in the first two protocols (A and B), while the whole dose was given preoperatively in the third protocol (C). The therapy was otherwise identical. Twenty mg doxorubicin was administered intravenously weekly. Surgery was possible in 40 patients. No patient failed to complete the protocol due to toxicity. In only 13 cases (24%) was death attributed to local failure. Five patients (9%) ‘had a survival’ exceeding 2 years. No signs of local recurrence were seen in 33 patients (60%); 5 out of 16 patients in Protocol A, 11 out of 17 patients in Protocol B, 17 out of 22 patients in Protocol C (P=0.017). In the 40 patients undergoing additional surgery, no signs of local recurrence were seen in 5 out of 9 patients, 11 out of 14 patients and 17 out of 17 patients, respectively (P=0.005)

Independent, Rapid and Targeted Loss of Highly Repetitive DNA in Natural and Synthetic Allopolyploids of Nicotiana tabacum

Allopolyploidy (interspecific hybridisation and polyploidy) has played a significant role in the evolutionary history of angiosperms and can result in genomic, epigenetic and transcriptomic perturbations. We examine the immediate effects of allopolyploidy on repetitive DNA by comparing the genomes of synthetic and natural Nicotiana tabacum with diploid progenitors N. tomentosiformis (paternal progenitor) and N. sylvestris (maternal progenitor). Using next generation sequencing, a recently developed graph-based repeat identification pipeline, Southern blot and fluorescence in situ hybridisation (FISH) we characterise two highly repetitive DNA sequences (NicCL3 and NicCL7/30). Analysis of two independent high-throughput DNA sequencing datasets indicates NicCL3 forms 1.6–1.9% of the genome in N. tomentosiformis, sequences that occur in multiple, discontinuous tandem arrays scattered over several chromosomes. Abundance estimates, based on sequencing depth, indicate NicCL3 is almost absent in N. sylvestris and has been dramatically reduced in copy number in the allopolyploid N. tabacum. Surprisingly elimination of NicCL3 is repeated in some synthetic lines of N. tabacum in their forth generation. The retroelement NicCL7/30, which occurs interspersed with NicCL3, is also under-represented but to a much lesser degree, revealing targeted elimination of the latter. Analysis of paired-end sequencing data indicates the tandem component of NicCL3 has been preferentially removed in natural N. tabacum, increasing the proportion of the dispersed component. This occurs across multiple blocks of discontinuous repeats and based on the distribution of nucleotide similarity among NicCL3 units, was concurrent with rounds of sequence homogenisation

Genomic Diversity in Two Related Plant Species with and without Sex Chromosomes - Silene latifolia and S. vulgaris

Genome size evolution is a complex process influenced by polyploidization, satellite DNA accumulation, and expansion of retroelements. How this process could be affected by different reproductive strategies is still poorly understood.We analyzed differences in the number and distribution of major repetitive DNA elements in two closely related species, Silene latifolia and S. vulgaris. Both species are diploid and possess the same chromosome number (2n = 24), but differ in their genome size and mode of reproduction. The dioecious S. latifolia (1C = 2.70 pg DNA) possesses sex chromosomes and its genome is 2.5× larger than that of the gynodioecious S. vulgaris (1C = 1.13 pg DNA), which does not possess sex chromosomes. We discovered that the genome of S. latifolia is larger mainly due to the expansion of Ogre retrotransposons. Surprisingly, the centromeric STAR-C and TR1 tandem repeats were found to be more abundant in S. vulgaris, the species with the smaller genome. We further examined the distribution of major repetitive sequences in related species in the Caryophyllaceae family. The results of FISH (fluorescence in situ hybridization) on mitotic chromosomes with the Retand element indicate that large rearrangements occurred during the evolution of the Caryophyllaceae family.Our data demonstrate that the evolution of genome size in the genus Silene is accompanied by the expansion of different repetitive elements with specific patterns in the dioecious species possessing the sex chromosomes