By identifying new compounds that selectively block mitochondrial respiration in pathogenic fungi, Whitehead Institute scientists have identified a potential antifungal mechanism that could enable combination therapy with fluconazole, one of today’s most commonly prescribed fungal infection treatments. The approach could also prevent the development of drug resistance.

‘Our research adds weight to the idea that effective antifungal drugs can target even those mitochondrial proteins that are highly conserved in humans and fungi, and that this could be a way to make a broad spectrum antifungal combination therapy that would be less susceptible to resistance,’ says Benjamin Vincent, a former graduate student in Whitehead Member Susan Lindquist’s lab who is now a scientist at Yumanity Therapeutics.

Fungi cause bothersome diaper rashes, oral thrush, athlete’s foot, and vaginal yeast infections, but they are also responsible for life-threatening infections in the immune-compromised, including patients receiving transplants, people with HIV/AIDS, cancer patients, and the elderly. Severe invasive fungal infections have a mortality rate of 30-50% and cause an estimated 1.5 million deaths worldwide annually.

Doctors rely on three main drug classes-the azoles (e.g., fluconazole), the echinocandins, and amphotericin-to treat these severe infections, but often with limited success. Many strains of pathogenic yeast, such as Candida albicans (C. albicans) can develop resistance to these drugs. Although combining therapies is a potent method to combat drug resistance in bacteria, antifungal drugs often perform poorly when used in combination due to their complex pharmacology and antagonistic antifungal mechanisms. When used individually, current antifungal drugs can have significant toxicities that are markedly enhanced when the drugs are used in combination.

‘Pharmaceutical companies are abandoning the development of antifungals,’ says Lindquist, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. ‘Fungi are much more similar to us than bacteria, so it is hard to find agents that attack them but not us.’

To identify new potential antifungals that could be combined with fluconazole, a team of Whitehead and MIT scientists screened 300,000 compounds, selecting one with the most apparent potential-Inz-1-for further study. Their work is described online this week in the journal Cell Chemical Biology.

Inz-1 inhibits the growth of C. albicans in media lacking glucose but only partially impairs growth when glucose is present, indicating that Inz-1 interferes with mitochondrial function. Indeed, the researchers determined that Inz-1 targets the cytochrome B protein required for mitochondrial production of ATP. The authors then worked with synthetic chemist Jean-Baptiste Langlois in the laboratory of Stephen Buchwald in the MIT Department of Chemistry to iteratively synthesize and test analogs of Inz-1 to improve its properties. This work led to Inz-5, which exhibited dramatically improved potency and selectivity for fungal cytochrome B. Although cytochrome B is highly conserved across humans and many pathogenic fungi, including Cryptococcus neoformans, Aspergillus fumigatus, and Rhizopus oryzae, Inz-5 exploits important differences in the amino acid sequence of the protein that enable selectivity for fungi.

Because the compound is metabolized too rapidly for study in mice, the team mimicked its effects by knocking out cytochrome B in C. albicans and infecting mice with this mutant strain. Overall, the cytochrome B knock-out strain is much less virulent, and mice infected with it survive much longer than those with the wild-type strain. Curiously, the mutant yeast seems to cause more infections in the brain and central nervous system than unaltered C. albicans. Treatment with fluconazole effectively clears infection caused by this mutant, indicating that combination antifungal therapy could be highly effective when one of the agents targets mitochondrial respiration.

Not only does hitting cytochrome B disable C. albicans’ virulence, but the fungus’s altered mitochondrial function means that the yeast is unable to adapt to the nutrient-deprived conditions present within the host, particularly inside macrophages. Instead of punching its way out of a macrophage that has engulfed it, the yeast remains trapped and loses its fight against the immune system.

Although Inz-1’s therapeutic promise is limited by its poor stability in animals, the compound proves that conserved cellular processes can be viable targets for selective antifungal therapeutics and could provide targets for effective combination antifungal therapy.

Whitehead Institute wi.mit.edu/news/archive/2016/disrupting-mitochondrial-function-could-improve-treatment-fungal-infections

By cleverly combining two medical imaging techniques, A*STAR scientists have found a way to produce high-resolution images of the lungs that is both high resolution and accounts for lung movement due to breathing. The method is expected to greatly assist clinicians when they target tumours in the lungs during radiotherapy.
Cancerous tumours in the lungs are often treated by irradiating them with high-energy X-rays, but this therapy is complicated by the fact that tumours are moving targets, due to the expansion and contraction of the lungs as the patient breathes.
Currently, two biomedical imaging techniques are used to help clinicians locate tumours in the lungs, both of which have their advantages and disadvantages. Three-dimensional computed tomography (3D-CT) provides high-resolution images, but it can only provide snapshots in time and there are safety concerns surrounding exposure to X-rays. In contrast, four-dimensional magnetic resonance imaging (4D-MRI) does not employ ionizing radiation and allows continuous tracking of the lung motion, but its low spatial resolution yields blurred images.
Now, Soo Kng Teo and co-workers at the A*STAR Institute of High Performance Computing in Singapore have combined these two techniques to realize the best of both approaches – a high-resolution imaging method that accurately accounts for lung movement.
The researchers used 3D-CT to obtain a sharp static image of the lungs. They mathematically combined this static image with the four-dimensional (the three spatial dimensions plus time) information extracted from images obtained using 4D-MRI. This enabled them to achieve a high spatial resolution to realize excellent clarity and show movement of a lung tumour over several breathing cycles.
They tested their imaging technique on six lung-cancer patients and obtained impressive results: the average error was less than two millimetres.
As with all medical innovations, adoption of the technique in hospitals depends on obtaining the backing of medical equipment companies and meeting the many regulatory requirements. ‘The biggest hurdle will be convincing equipment manufacturers to adopt the imaging method,’ says Teo.

A*STAR http://tinyurl.com/hucefzb

Patients undergoing oncologic liver operations who participated in an enhanced recovery programme returned sooner to their normal life function and adjuvant cancer therapies than patients who were treated with a traditional approach to perioperative care, according to a new study.
‘What really matters is life function. Until now, we have been trying to add up a patient’s pain, nausea, and fatigue, but what we really needed to look at is how those symptoms actually impact a patient’s life function, because as it turns out, each patient experiences symptoms differently,’ said lead investigator Thomas A. Aloia, MD, FACS, associate professor, department of surgical oncology, The University of Texas MD Anderson Cancer Center, Houston. ‘We found that you could have very symptomatic people who were quite functional, and you could have mildly symptomatic people who were completely disabled.’
This single-centre study involved 118 patients undergoing both open and laparoscopic hepatectomy (surgical resection of the liver). In addition to traditional quality metrics like complications and length of stay, researchers collected data from a patient-reported outcomes tool called the MD Anderson Symptom Inventory (MDASI). All patients rated symptom severity and life interference using this validated survey, first preoperatively and again at every outpatient visit until 31 days after their operations.
Typically, surgeons counsel patients that they are not going to feel better for a month after the operation, and that their full recovery will take about six to eight weeks. ‘Enhanced recovery,’ however, is a multicomponent perioperative care protocol created to speed patients’ recovery and return to normal life functions such as working and driving.
This type of fast-track care plan involves preoperative patient education, fewer narcotic painkillers used during and after an operation (which have side effects that can lengthen the hospital stay), and a quicker return to eating and walking as soon as possible after the operation.
In this study, 75 patients in the enhanced recovery group were compared with 43 patients in the traditional care group. All preoperative and postoperative care was the same for both groups, except the enhanced recovery part of it. The aim was to compare the difference between patients’ functional outcomes.
The researchers found that patients treated in the enhanced recovery group were 2.6 times more likely to achieve their baseline functional status within 31 days than those who were treated with the traditional protocol.
‘The only independent factor that correlated to faster return to baseline functional status, both in terms of absolute value and short time to recovery, was being on an enhanced recovery protocol,’ Dr. Aloia said. ‘It wasn’t the size of the liver resection, the approach [laparoscopic versus open operation], or whether we used an epidural catheter for pain control or not.’
In this study, enhanced recovery patients reported lower postoperative pain scores and experienced fewer complications and decreased length of stay. The breakthrough from this study is that most enhanced recovery studies stop measuring their outcome at length of hospital stay, with the sole purpose of shortening the hospital visit.
‘At a cancer centre, length of stay is pretty low on our list of importance; our true metric of success is getting people after cancer surgery back to cancer therapy,’ Dr. Aloia said.
The researchers also found that patients in the enhanced recovery group were more likely to return to chemotherapy (a measure researchers at this centre created and call Return to Intended Oncologic Therapy or RIOT), (95 percent vs. 87 percent), and at a shorter time interval compared with patients in the traditional group (44.7 days vs. 60.2 days). Because some of the patients were not indicated to receive further cancer treatment in this part of the analysis, these results aren’t statistically significant. Still, the researchers have no doubt that the trend is clear.
‘With this study, we may have got one step closer to a scientific definition of recovery that could be used in other disease sites,’ Dr. Aloia said. ‘As enhanced recovery strategies evolve we may now have a tool to compare one approach with another to find out which one is better.’

American College of Surgeonshttp://tinyurl.com/h9yz499

Researchers at the University of Warwick have worked with Coventry-based Medherant, a Warwick spinout company, to produce and patent the world’s first ever ibuprofen patch delivering the drug directly through skin to exactly where it is needed at a consistent dose rate.
They have invented a transparent adhesive patch that can consistently deliver a prolonged high dose of the painkiller ibuprofen directly through the skin. The University of Warwick researchers and Medherant have found a way to incoporate significant amounts of the drug (up to 30% weight) into the polymer matrix that sticks the patch to the patient’s skin with the drug then being delivered at a steady rate over up to 12 hours. This opens the way for the development of a range of novel long-acting over-the-counter pain relief products which can be used to treat common painful conditions like chronic back pain, neuralgia and arthritis without the need to take potentially damaging doses of the drug orally. Although there are a number of popular ibuprofen gels available these make it difficult to control dosage and are inconvenient to apply.
This novel patch incorporates polymer technology developed by the global adhesive company Bostik and exclusively licensed for transdermal use to Medherant.
The key features of Medherant’s new patch technology are:
The patch remains highly tacky and thus adheres well to skin even when the drug load reaches levels as high as 30% of the weight/volume of the patch. The drug load made possible by this new technology can be 5 -10 times than that found in some currently used medical patches and gels.
High drug load and a consistent drug release profile means the Medherant patches out-perform other patches and gels in their ability to deliver a consistent and significant dose of drug over a prolonged time from a small patch.
It is a cosmetically pleasing transparent design with stronger adhesion than other commercial products – remaining stuck over its time of action but easy and comfortable to remove.
University of Warwick research chemist Professor David Haddleton said:
‘Many commercial patches surprisingly don’t contain any pain relief agents at all, they simply soothe the body by a warming effect. Our technology now means that we can for the first time produce patches that contain effective doses of active ingredients such as ibuprofen for which no patches currently exist. Also, we can improve the drug loading and stickiness of patches containing other active ingredients to improve patient comfort and outcome.’

University of Warwick http://tinyurl.com/h9jqsyh