Increasing multidrug resistance in Gram-negative bacteria, in particular
Pseudomonas aeruginosa, Acinetobacter baumannii, and
Klebsiella pneumoniae, presents a critical problem. Limited therapeutic ...options have forced infectious disease clinicians and microbiologists to reappraise the clinical application of colistin, a polymyxin antibiotic discovered more than 50 years ago. We summarise recent progress in understanding the complex chemistry, pharmacokinetics, and pharmacodynamics of colistin, the interplay between these three aspects, and their effect on the clinical use of this important antibiotic. Recent clinical findings are reviewed, focusing on evaluation of efficacy, emerging resistance, potential toxicities, and combination therapy. In the battle against rapidly emerging bacterial resistance we can no longer rely entirely on the discovery of new antibiotics; we must also pursue rational approaches to the use of older antibiotics such as colistin.
Infections caused by multi-resistant Gram-negative bacteria, particularly
Pseudomonas aeruginosa, are increasing worldwide. In patients with cystic fibrosis (CF), resistance in
P. aeruginosa to ...numerous anti-pseudomonal agents is becoming common. The absence since 1995, of new substances active against resistant Gram-negative bacteria, has caused increasing concern. Colistin, an old antibiotic also known as polymyxin E, has attracted more interest recently because of its significant activity against multi-resistant
P. aeruginosa,
Acinetobacter baumannii and
Klebsiella pneumoniae, and the low resistance rates to it. Because its use as an anti-pseudomonal agent was displaced by the potentially less toxic aminoglycosides in 1970s, our knowledge of this drug is limited. However, there has been a significant recent increase in the data gathered on colistin, focussing on its chemistry, antibacterial activity, mechanism of action and resistance, pharmacokinetics, pharmacodynamics and new clinical application. It is likely that colistin will be an important antimicrobial option against multi-resistant Gram-negative bacteria, for some years to come.
The behavior of materials in sliding contact is challenging to determine since the interface is normally hidden from view. Using a custom microfabricated device, we conduct in situ, ultrahigh vacuum ...transmission electron microscope measurements of crystalline silver nanocontacts under combined tension and shear, permitting simultaneous observation of contact forces and contact width. While silver classically exhibits substantial sliding-induced plastic junction growth, the nanocontacts exhibit only limited plastic deformation despite high applied stresses. This difference arises from the nanocontacts' high strength, as we find the von Mises stresses at yield points approach the ideal strength of silver. We attribute this to the nanocontacts' nearly defect-free nature and small size. The contacts also separate unstably, with pull-off forces well below classical predictions for rupture under pure tension. This strongly indicates that shearing reduces nanoscale pull-off forces, predicted theoretically at the continuum level, but not directly observed before.
To investigate the associations between socio-demographic status, lifestyle factors, dietary patterns and urinary total phthalate concentration in a cohort of South Australian men.
We randomly ...selected 1527 males aged 39 to 84 from wave two of the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study. Total phthalate concentration was examined in fasting morning urine samples. Socio-demographic and lifestyle factors were assessed by questionnaire. Food intake was assessed by food frequency questionnaire (FFQ). Dietary patterns were constructed using factor analysis.
Total phthalates were detected in 99.6% of the urine samples. The overall geometric mean (95% CI) of total phthalate concentration was 112.4 (107.5-117.5) ng/mL. The least square geometric means (LSGMs) of total phthalate concentration were significantly higher among people who were obese (127.8 ng/mL), consuming less than two serves fruit per day (125.7 ng/mL) and drinking more than one can (375mL) of carbonated soft drink per day (131.9 ng/mL). Two dietary patterns were identified: a prudent dietary pattern and a western dietary pattern. Both the western dietary pattern (p = 0.002) and multiple lifestyle risk factors including smoking, obesity, insufficient physical activity and the highest quartile of the western dietary pattern (p<0.001), were positively associated with total phthalate levels. There was no significant relationship between total phthalate concentration and socio-demographic status.
Phthalate exposure is ubiquitous and positively associated with lifestyle risk factors in urban dwelling Australian men.
Colorectal cancer (CRC) remains one of the most lethal human malignancies, and pursuit of new therapeutic targets for treatment has been a major research focus. Cyclin‐dependent kinase 9 (CDK9), ...which plays a crucial role in transcription, has emerged as a target for cancer treatment. CDKI‐73, one of the most potent and pharmacologically superior CDK9 inhibitors, has demonstrated excellent anti‐tumour efficacy against several types of cancers. In this study, we evaluated its therapeutic potential against CRC. CDKI‐73 elicited high cytotoxicity against all colon cancer cell lines tested. Cell cycle and apoptosis analysis in HCT 116 and HT29 cells revealed that CDKI‐73 induced cell death without accumulation of DNA at any phase of the cell cycle. Moreover, it caused depolarisation of mitochondrial membrane, leading to caspase‐independent apoptosis. Knockdown by shRNA demonstrated the CDK9‐targeted mechanism of CDKI‐73, which also affected the Mnk/eIF4E signalling axis. In addition, RT‐qPCR analysis showed that CDKI‐73 down‐regulated multiple pro‐survival factors at the mRNA level. Its in vivo anti‐tumour efficacy was further evaluated in Balb/c nude mice bearing HCT 116 xenograft tumours. CDKI‐73 significantly inhibited tumour growth (***P < 0.001) without overt toxicity. Analysis of the tumour tissues collected from the xenografted animals confirmed that the in vivo anti‐tumour efficacy was associated with CDK9 targeting of CDKI‐73. Overall, this study provides compelling evidence that CDKI‐73 is a promising drug candidate for treating colorectal cancer.
Cyclin‐dependent kinase 9 (CDK9) is a crucial regulator of global transcription process. Its deregulation leads to the overexpression of anti‐apoptotic proteins on which cancer cells are highly dependent. This study demonstrates that inhibition of CDK9 by a highly potent pharmacological inhibitor, CDKI‐73, caused apoptosis of colorectal cancer cells effectively in vitro and in vivo through down‐regulation of multiple anti‐apoptotic factors.
Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic ...islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1and p18Ink4c. Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1and p18Ink4cpromoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27Kip1and p18Ink4cexpression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MLL plays a central role in menin's activity as a tumor suppressor.
Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the ...constitutive expression of anti-apoptotic proteins; both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and anti-apoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.
Background. Trimethylamine (TMA) is a short-chain tertiary aliphatic amine that is derived from the diet either directly from the consumption of foods high in TMA or by the intake of food high in ...precursors to TMA, such as trimethylamine-N-oxide (TMNO), choline and l-carnitine. The clinical significance of TMA may be related to its potential to contribute to neurological toxicity and ‘uraemic breath’ in patients with end-stage renal disease (ESRD). Methods. Concentrations of TMA and TMNO in plasma from 10 healthy adults (not on haemodialysis) and 10 adults with ESRD undergoing haemodialysis (pre- and post-dialysis) were determined by gas chromatography–mass spectrometry. Results. The concentrations of TMA and TMNO in pre-dialysis plasma (1.39±0.483 and 99.9±31.9 μM, respectively) were significantly (P<0.05) higher than the corresponding levels in healthy subjects (0.418±0.124 and 37.8±20.4 μM, respectively). However, there were no significant differences between post-dialysis and healthy subject plasma concentrations. In the ESRD patients, there was a significant (P<0.05) reduction in plasma TMA (from 1.39±0.483 to 0.484±0.164 μM) and TMNO (from 99.9±31.9 to 41.3±18.8 μM) during a single haemodialysis session. Conclusions. TMA and TMNO accumulate between haemodialysis sessions in ESRD patients, but are efficiently removed during a single haemodialysis session.
We simulate the contact between nanoscale hydrogen-terminated, single-crystal silicon asperities and surfaces using reactive molecular dynamics (MD) simulations. The results are consistent with ...recent experimental observations of a more than order-of-magnitude sliding-induced increase in interfacial adhesion for silicon-silicon nanocontact experiments obtained using in situ transmission electron microscopy (TEM). In particular, the MD simulations support the hypothesis that the increased adhesion results from sliding-induced removal of passivating species, in this case hydrogen, followed by rapid formation of Si–Si covalent bonds across the interface, with little plastic deformation of the asperities. The MD results concur with the additional hypothesis that subsequent readsorption of passivating species explains the experimental observation that adhesion reverts to low values upon subsequent contact. However, the simulations further reveal that the sliding-induced adhesion increase is only observed when there are a sufficient number of preexisting surface defects in the form of incomplete hydrogen coverage. Increased hydrogen coverage suppresses interfacial bonding, within the time span of the simulations. Furthermore, the relative alignment of the surface crystal axes plays a strong role in affecting the probability of bond formation during sliding and the subsequent adhesive pull-off force. Also, the hydrogen coverage and sliding distance significantly impact friction at low to moderate hydrogen coverages. Atomic-scale wear does occur during the sliding process primarily through Si–Si bond formation across the interface followed by pull-out of Si atoms from the tip. At low hydrogen coverages, wear is far more severe, Archard’s wear law is obeyed, and significant morphological changes of the asperity occur. The bond formation process is highly stochastic, but shows a general trend of greater numbers of bonds with greater sliding distances. Tips wear by losing large clusters of material, then smaller clusters and individual atoms, and eventually enter into a wearless regime as hydrogen termination increases.
Graphical Abstract
A hydrogen-terminated Si tip (green and blue) in sliding contact with a hydrogen-terminated Si substrate (yellow and red). The sliding direction is indicated by the black arrow. At this level of hydrogen termination, wear is initiated by the removal of hydrogen atoms from the tip (blue atoms at left of figure). Continued sliding causes the formation of interfacial Si-Si bonds followed by the transfer of Si and H from the tip to the surface.
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