For those who haven’t encountered it yet, chemicalize.org is a tool for adding chemical information to your web browsing – and it’s free! Provided by the chemistry software company, ChemAxon, under a Creative Commons license, chemicalize can convert chemical names to structures – either on a query basis or converting an entire web page. In addition, ChemAxon have now added a page of calculated properties that can be accessed by clicking the generated 2D structure.

The tool will convert trivial chemical names such as saquinavir, as well as IUPAC names such as 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one. Structure generation is based on ChemAxon’s name-to-structure software, although conversion of trivial names presumably relies on a database. I don’t know how comprehensive the database is, but it can certainly generate some interesting results when converting a web page – I hadn’t realised that trigger was a trivial name for something!

When a web page is converted, recognised structures are underlined in the text. Hovering over the underlined text produces a tooltip with the 2D structure of the molecule and this can be clicked to visit the calculated properties page. The properties page provides a variety of useful information including, logP, rotatable bond count, pKa etc. The layout of the properties page can also be adjusted by the user, with some standard layouts provided for medicinal or synthetic chemist.

You can see the chemicalized version of this post here and visit chemicalize.org for further information.

There has long been debate about the relative merits of a low-carbohydrate diet, as popularised by Atkins, compared to the more traditional low-fat approach to weight loss. A low-carbohydrate diet has also been anecdotally associated with adverse effects on health.

A newly published clinical study, led by researchers at the Center for Obesity Research and Education at Temple University, Philadelphia, has now shown remarkably little difference between the two regimes. The study followed over 300 subjects randomly assigned to either diet over a two year period and, importantly, combined the diets with comprehensive behavioural treatment.

In the low-carb group, carbohydrate intake was limited to 20 g/d for 3 months in the form of low–glycemic index vegetables with unrestricted consumption of fat and protein. After 3 months, participants were allowed to increase their carbohydrate intake (5 g/d per wk) until a stable and desired weight was achieved. The low-fat diet consisted of limited energy intake (1200 to 1800 kcal/d) with less than 30% of the calories derived from fat. For the behavioural treatment, each participant attended group sessions weekly for the first 20 weeks of the study, every other week for the next 20 weeks, and once every other month for the remainder of the study. In each session, participants discussed topics such as goal setting, self-monitoring, and limiting triggers to overeating.

Although attrition was high at 2 years, there were no differences in weight, body composition, or bone mineral density between the groups at any time point. Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol (“good” cholesterol) levels at all time points, increasing by approximately 23% at 2 years, suggesting that a low-carb diet may have some cardiovascular benefit.

Gary Foster, Director of Temple’s Center for Obesity Research and Education and lead author of the study said:

When comparing these two popular weight loss plans, none of the existing research had included a comprehensive, long-term, behavioural support component. This research tells us that people wanting to manage their weight need to be less concerned with which diet they choose, and more concerned with incorporating behavioural changes into their plan.

The study is published in Annals of Internal Medicine.

Two back-to-back studies published in the July 23^rd issue of Cell, one from Columbia University Medical Center and the other from Johns Hopkins researchers, further the hypothesis that metabolic control and bone remodelling are inextricably linked. Both studies point to osteocalcin, a hormone released by bone, as a key mediator of this link.

The Johns Hopkins study used a conditional knock-out in mice to specifically suppress the expression of the insulin receptor in osteoblasts, the bone-forming cells of the skeletal system. As the mutant mice aged they became fat, had elevated blood sugar, and were glucose intolerant and resistant to insulin, mirroring the picture of diabetes in humans. The researchers found that the mutant mice had fewer osteoblasts, reduced bone formation and lower levels of circulating undercarboxylated osteocalcin (the active form of the hormone). The study showed that signalling via the insulin receptor in osteoblasts suppressed Twist2, an inhibitor of osteoblast development, and enhanced expression of osteocalcin, a mediator of insulin sensitivity and secretion.

The Columbia study links the complete bone remodelling process to energy regulation. Osteocalcin is released from osteoblasts predominantly in an inactive, carboxylated form. The researchers demonstrated that insulin signalling in osteoblasts stimulates release of inactive osteocalcin and activates osteoclasts, which activate the osteocalcin via decarboxylation in a bone-resorption-dependent manner.

The studies clearly have potential impact on human therapy, although significant questions remain. As yet the receptor for undercarboxylated osteocalcin is unknown, so the mechanism by with the hormone stimulates insulin release is unclear. Further work will be necessary to understand the interplay between skeletal- and metabolic-homeostasis in humans.

The two papers are previewed in Cell.

Despite its reputation as a poison, arsenic has long been used in Chinese medicine and, more recently, arsenic trioxide has been successfully used to treat acute promyelocytic leukaemia (APL). The drug has poor activity against solid tumours, however, probably because it is rapidly excreted. Attempting to address this, researchers at Northwestern University have packaged arsenic trioxide in nanoparticles.

These nanoparticles, termed nanobins, are composed of nanoparticulate arsenic trioxide encapsulated in liposomes. A second chemical layer provides protection for both the cargo and normal cells until the particle reaches its target. The nanoparticles concentrate at their target, as a consequence of the leaky blood vessels that characterise solid tumours, and release their toxic payload.

In the current study, published in Clinical Cancer Research, the researchers investigated the activity of arsenic nanobins against a panel of human breast cancer cell lines. Although less cytotoxic than free arsenic trioxide in vitro, the nanobins had dramatically enhanced efficacy in an in vivo model of triple-negative breast cancer. The scientists observed reduced plasma clearance, increased tumour uptake and induction of tumour cell apoptosis for the nanobins.

Triple negative breast cancer, in which the receptors for oestrogen, progesterone and Her2 are absent, is an aggressive cancer that often responds poorly to conventional chemotherapy. There is a high risk of metastatis and survival rates are low. Although at an early stage, the researchers anticipate that the nanobin technology could provide the means to increase the efficacy of a number of cytotoxic drugs against a range of tumours, whilst reducing general toxicity.

The concept of bispecific antibodies – monoclonal antibodies able to recognise and engage two different antigens – has been explored for over twenty years. Development of therapies based on the approach has, however, been hampered by difficulties in their construction, poor efficacy and undesirable side-effects.

One particular subset of bispecific antibodies, the so-called bispecific T-cell engager (BiTE®), has nevertheless begun to show promise. Blinatumomab, developed by Micromet, targets the CD19 receptor of B-cells and CD3 on T-cells and is designed to direct cytotoxic T-cells to B-cell tumours. Interim data from a phase I trial in Non-Hodgkin’s Lymphoma patients have shown signs of clinical efficacy and additional clinical trials in acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are ongoing.

More recently, the Micromet team have reported on preclinical data using BiTE® antibodies targeting the EGFR receptor and CD3, incorporating the binding domains of either panitumumab or cetuximab. Panitumumab and cetuximab, as well as EGFR kinase inhibitors, are marketed for treatment of colorectal cancer (CRC) and primarily inhibit CRC growth by interfering with EGFR signalling. CRC patients whose tumours have mutated KRAS or BRAF, however, are resistant to treatment. This latest study, published in Proceedings of the National Academy of Sciences, showed that both EGFR-specific BiTE® antibodies mediated potent redirected lysis of KRAS- and BRAF-mutated CRC lines by human T cells at subpicomolar concentrations. The cetuximab-based BiTE® antibody also inhibited growth of tumours from KRAS- and BRAF-mutated human CRC xenografts, whereas cetuximab was not effective. The researchers also report preliminary safety data in non-human primates and conclude that EGFR-specific BiTE® antibodies may have potential to treat CRC that does not respond to conventional antibodies.

The human body is host to a plethora of microorganisms and, for the most part, their presence has no ill effects. Some, particularly intestinal bacteria, even provide benefit. From a microbial perspective, harming the host does not have any obvious survival benefit (unless it enables infection to spread, such as the sneezing induced by the cold virus). So why is it that inoffensive organisms occasionally turn nasty, evolving properties that are damaging or even deadly to us? A study funded by the US Public Health Service and the Wellcome Trust provides one answer to the question.

Since many pathogens interact with their host at mucosal surfaces and have to compete with other microflora, scientists at the University of Pennsylvania School of Medicine and Oxford University used a mouse model of nasal infection to investigate whether competition between microbes promoted virulence. They found that Haemophilus influenzae was able to out-compete Streptococcus pneumoniae by recruiting the host’s immune system. S. pneumoniae is normally harmless and ignored by the immune system, but the immune response stimulated by H. influenzae has unintended consequences. S. pneumoniae strains with polysaccharide capsules that confer resistance to the immune attack are able to survive at the expense of non-resistant strains, resulting in a S. pneumoniae population dominated by the resistant phenotype. Unfortunately, the resistant strains are also more dangerous – if they are able to enter the bloodstream they can multiply unchecked and go on to cause pneumonia, septicaemia and meningitis. So in this battle between S. pneumoniae and H. influenzae, with weapons provided by the host, S. pneumoniae prevails at the expense of the host.

The study is published in Current Biology.

The process of cell competition is believed to provide a mechanism to optimise tissue ‘fitness’ during development by eliminating weaker cells from the overall cell population. First described in Drosophila, a number of genes have been linked to cell competition but the precise details of the process are poorly understood. A new study conducted by scientists at the Spanish National Cancer Centre (CNIO), however, has furthered our understanding.

Using a combination of genomic analysis and functional assays, the team investigated how cells of Drosophila wing imaginal discs distinguished ‘winner’ and ‘loser’ cells. They found that six genes were upregulated early in loser cells and five of these encoded cell membrane proteins, suggesting that cell-cell communication is critical in the initial stages of cell competition. One of these membrane proteins, Flower (Fwe), was examined in detail.

Fwe is conserved in multicellular organisms and in the Drosophila study was found to be required and sufficient to label cells as winners or losers. The win/lose decision is mediated by three differentially expressed forms of fwe (fwe^ubi, fwe^LoseA and fwe^LoseB) and cells are identified as losers when relative differences in fwe^ubi and fwe^Lose levels are detected – stress conditions that uniformly affect the entire population result in cell survival. Although further work is necessary to elucidate the detail, the team proposes that, in outcompeted cells, the fwe transcript is alternatively spliced and fwe^Lose isoforms are induced at the expense of fwe^ubi. It is likely that downregulation of fwe^ubi and upregulation of fwe^Lose both contribute to establish the lose/win decision.

The cellular tagging by Flower isoforms may have biomedical implications beyond cell competition since imbalances in cell fitness also occur during ageing, cancer formation and metastasis.

The study is published in Developmental Cell.

Iminosugars, where the endocyclic oxygen of sugars is replaced by a basic nitrogen, constitute a class of carbohydrate analogues that has received considerable attention in recent years.

The discovery that the natural product, 1-deoxy nojirimycin, had potent inhibitory properties toward alpha-glucosidases sparked exploration of synthetic approaches to, and biological properties of, the class. This has led to the approval of miglitol (Glyset®) for treatment of type II diabetes and miglustat (Zavesca®) for treatment of type I Gaucher’s disease in patients for whom enzyme replacement therapy is not suitable. More recently, Zavesca® is the first drug to be approved for treatment of progressive neurological manifestations in adult or paediatric patients with Niemann-Pick type C disease.

Subsequent research has identified iminosugars as inhibitors of a broader range of enzymes and the class is providing leads for a variety of diseases including viral infections and tumour metastasis as well as diabetes and lysosomal storage disorders.

A forthcoming meeting, organised by Summit Corporation plc, will cover both historical and future perspectives of iminosugars. Entitled “Iminosugars: Past, Present and Future – Medicines for tomorrow”, the meeting will be held at St John’s College, Oxford (UK) on 28^th June. The full programme and registration details can be found on the Summit website.

MicroRNAs (miRNAs) are small (21-23 nucleotides), single-stranded RNA molecules that function as regulators of gene expression. The human genome encodes several hundred miRNAs and abnormal expression of these has been associated with cancer progression. We have previously reported on miRNA involvement in cholesterol regulation, amyotrophic lateral sclerosis and liver cancer. Now a collaboration between Rosetta Genomics, NYU Langone Medical Center and Vanderbilt School of Medicine has identified the potential utility of miR-33 for development of therapies targeting malignant mesothelioma (MM).

MM is a rare cancer that has been associated with exposure to asbestos dust (although a small proportion of patients have never been exposed). Taking anywhere between 20 and 50 years for symptoms to develop, the cancer affects the mesothelium, a thin layer of tissue surrounding the internal organs. The most common form of MM is pleural, involving the lining of the lungs, but it may also affect other tissues such as the peritoneum. Current treatment options, including surgery and chemotherapy, are limited and often confounded by late diagnosis because of the absence of symptoms.

This latest study found that MM cell lines derived from patients with aggressive disease failed to express miR-31, a microRNA that has also been linked to suppression of breast cancer metastasis. Functional studies, where miR-31 was reintroduced to the cells, showed that the microRNA could inhibit proliferation, migration, invasion, and clonogenicity of mesothelioma cells. miR-31 suppressed expression of a number of factors associated with maintenance of DNA replication and cell cycle progression, including the pro-survival phosphatase PPP6C. The mRNA for PPP6C, which contains three miR-31-binding sites in its 3′-UTR, was down-regulated when miR-31 was present and up-regulated in clinical MM specimens compared to matched normal tissues.

Whilst the study, published in the Journal of Biological Chemistry, reveals a key role for miR-31 in MM, considerable challenges remain to exploit this finding for therapy of the disease.

The eukaryotic translation initiation factor eIF5A, which exists in two isoforms, was originally thought to be involved in formation of the first peptide bond during mRNA translation, but more recent work has implicated it as a translation elongation factor. In mammalian cells it has variously been associated with mediation of proliferation, apoptosis and inflammatory responses, although its mechanisms of action have remained vague. It has also been identified as a cofactor of the Rev trans-activator protein of HIV-1. eIF5A is unique in that it is the only known protein to contain the amino acid hypusine, formed posttranslationally via the sequential action of deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) acting at a specific lysine residue.

Based on the role of eIF5A in inflammation, a multi-institutional research team led by scientists at Indiana University School of Medicine has explored involvement of the protein in pancreatic islet dysfunction during the development of diabetes. In a low-dose streptozotocin mouse model of diabetes the team found that depletion of eIF5A (using siRNA) protected the mice from pancreatic β-cell loss and hyperglycemia. The depletion of eIF5A resulted in impaired translation of inducible nitric oxide synthase (iNOS)-encoding mRNA within islet cells. Further studies using an inhibitor of DHS, N¹-guanyl-1,7-diaminoheptane (GC7), demonstrated a requirement for hypusination in the action of eIF5A.

The study, published in the Journal of Clinical Investigation, demonstrates a role for eIF5A in inflammation-induced damage to islet cells. Since the negative effects of eIF5A depend on hypusination, DHS may represent a viable therapeutic target for diabetes. Further work will be necessary to establish the role of this pathway in development and progression of the human disease.