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

TAU researcher’s cutting-edge innovation pinpoints top candidates for assisted reproductive technology. More than 10percent of American women aged 15-44 struggle to conceive or maintain full-term pregnancies, according to the Centers for Disease Control and Prevention (CDC). Assisted reproductive technology (ART), through which eggs are fertilized with sperm in a lab and then returned to a woman’s uterus, is often the last resort for reproductively-challenged couples. But the physical, emotional, and financial toll they exact is high because the success rates of ART treatments are low – only 20-30percent, according to the CDC.
New microscopic technology from Tel Aviv University promises to be a game-changer in the field of reproductive assistance. A team of TAU scientists have devised a new method of microscopy allowing scientists to perform clinical sperm analysis without the use of staining, which can affect the viability of sperm samples.
Sperm cells are nearly transparent under standard microscopy methods. Their optical properties differ only slightly from those of their surroundings, resulting in a weak image contrast. Sperm cells cannot be stained, if fertilization is the goal, because the process might damage the resulting fetuses. The challenge is to pinpoint strong sperm candidates without staining, while still being able to characterize their viability.
The research was led by Dr. Natan Shaked, PhD, of the Department of Biomedical Engineering at TAU’s Faculty of Engineering and his masters student, Dr. Miki Hifler, MD. Sperm cells for the study were obtained from the Male Fertility Clinic at Chaim Sheba Medical Center in Israel.
There are two effective ART methods available today. The first is in vitro fertilization (IVF), in which a woman is treated with drugs that cause her ovaries to produce multiple eggs. These are placed in a Petri dish with a man’s sperm for fertilization for three to five days, then implanted in the woman’s uterus. The second is intracytoplasmic sperm injection (ICSI), in which a single sperm is injected into a mature egg and then transferred to a woman’s uterus. Dr. Shaked’s method is applicable to both methods, but is especially helpful in ICSI.
‘Until now, clinicians have chosen the best’ sperm according to their speed, but speed is not necessarily an indicator of DNA quality,’ Dr. Shaked says. ‘Some of the best sperm candidates are slow or even immobile because their tails have malfunctioned. If we can better determine the full structure and composition of the sperm, the success rate of ART treatments will be higher. Success means more births without congenital defects. In cases where sample staining is impossible – such as in vitro fertilization and ICSI – our device provides a promising new direction.’
His new device, a small ‘black box’ attached to an existing microscope, is smaller, cost-effective, and easier to align than conventional interferometric imaging methods. It is joined to new automated software that produces a thickness map of the sample and other physical parameters to evaluate the sperm’s viability in real time.
Dr. Shaked believes his new imaging process, which harnesses phase imaging methods to record the passage of light through a sample to assess its thickness, can quantify the quality of sperm used in ART, leading to more successful ART treatments.

American Friends of Tel Aviv University http://tinyurl.com/h5665oc

Using antidepressants during pregnancy greatly increases the risk of autism, Professor Anick Berard of the University of Montreal and its affiliated CHU Sainte-Justine children’s hospital revealed. Prof. Berard, an internationally renowned expert in the fields of pharmaceutical safety during pregnancy, came to her conclusions after reviewing data covering 145,456 pregnancies. ‘The variety of causes of autism remain unclear, but studies have shown that both genetics and environment can play a role,’ she explained. ‘Our study has established that taking antidepressants during the second or third trimester of pregnancy almost doubles the risk that the child will be diagnosed with autism by age 7, especially if the mother takes selective serotonin reuptake inhibitors, often known by its acronym SSRIs.’
Berard and her colleagues worked with data from the Quebec Pregnancy Cohort and studied 145,456 children between the time of their conception up to age ten. In addition to information about the mother’s use of antidepressants and the child’s eventual diagnosis of autism, the data included a wealth of details that enabled the team to tease out the specific impact of the antidepressant drugs. For example, some people are genetically predisposed to autism (i.e., a family history of it.) Maternal age, and depression are known to be associated with the development of autism, as are certain socio-economic factors such as being exposed to poverty, and the team was able to take all of these into consideration.
‘We defined exposure to antidepressants as the mother having had one or more prescription for antidepressants filled during the second or third trimester of the pregnancy. This period was chosen as the infant’s critical brain development occurs during this time,’ Prof. Berard said. ‘Amongst all the children in the study, we then identified which children had been diagnosed with a form of autism by looking at hospital records indicating diagnosed childhood autism, atypical autism, Asperger’s syndrome, or a pervasive developmental disorder.
Finally, we looked for a statistical association between the two groups, and found a very significant one: an 87% increased risk.’ The results remained unchanged when only considering children who had been diagnosed by specialists such as psychiatrists and neurologists.
The findings are hugely important as six to ten percent of pregnant women are currently being treated for depression with antidepressants.

University of Montreal http://tinyurl.com/zgflp3h

A drug that blocks neurotransmitters could reduce nausea and vomiting caused by chemotherapy, research co-authored by a Sanford Health physician and published in the New England Journal of Medicine finds.
Sanford oncologist and cancer researcher Steven Powell, M.D., was among a team of researchers who discovered that the drug olanzapine, which is FDA approved for use as an antipsychotic agent, significantly improved nausea prevention in patients who were receiving chemotherapy for cancer treatment. The drug blocks neurotransmitters involved with nausea and vomiting.

‘We’ve long known the nausea and vomiting that come along with chemotherapy are a major problem and affect the quality of life of our patients,’ said Powell. ‘The findings of this study, fortunately, provide physicians with a tool to better address the needs of those they are treating for cancer.’
Researchers noted that within the first day after treatment, 74 percent of study participants experienced no nausea or vomiting when their chemotherapy was paired with olanzapine. When a placebo was used instead of olanzapine, that figure dropped to 45 percent. This benefit continued for five days after chemotherapy treatment for many patients.

Sanford Health www.sanfordresearch.org/newsevents/news/NewsDetail25278.cfm?Id=0,1887

An outcomes study led by Alexi Wright, MD, MPH, a researcher and a gynecological oncologist in the Susan F. Smith Center for Women’s Cancers at Dana-Farber, surveyed families of older patients who had died of advanced lung and colorectal cancer, asking what factors were associated with ‘excellent’ end-of-life care for their loved ones.
The families were more likely to assess care as excellent – by relatively large margins – when:

• the patient had hospice care for more than three days, compared with fewer than three days or none;
• the individual wasn’t admitted to an intensive care unit (ICU) in the last 30 days of life;
• the patient died at home or some other location outside the hospital, such as a hospice facility.

‘Our study findings are a powerful argument for the importance of advance care planning,’ Wright said. ‘The more information patients have, the more likely they are to receive the kind of medical care they want near death. And patients’ deaths influence family members’ perceptions of their quality of care.’
Wright reported that end-of-life care could be of higher quality if there are efforts to enroll patients in hospice earlier – not when death is imminent – and to avoid intensive care unit admissions in the final weeks.
Terminally ill patients should have the legal option to choose physician-assisted death, even if – as is often the case in USA States where it is legal- they don’t use it, wrote Susan Block, MD, founding chair, Department of Psychosocial Oncology and Palliative Care at Dana-Farber and two other authors of a ‘Viewpoint’ opinion piece.
Patients nearing the end of life want control over their bodies and their lives as ‘a small measure of self-preservation,’ they noted. Such individuals can gain peace of mind when they have a ‘back-up’ plan, they added.
‘When physicians are willing to explore and work with a patient requesting physician-assisted death, patients can experience substantial benefits that are more apparently under an open legal process,’ said the authors.

Dana-Farber Cancer Institute http://tinyurl.com/jx6wwxz