Carly Szabo, Assistant Editor

Infectious disease prevention may soon take a huge step forward as scientists proclaim that a molecule may have the capability to annihilate viral particles in semen.

Researchers at the University of Pennsylvania, as well as Ulm University in Germany, hypothesized that CLR01, referred to as the “tweezer” molecule due to its shape, binds to certain residues in semen and interferes with the fibril assembly. To test this theory, the scientists performed replica exchange molecular dynamics simulations using the available structure of PAP248-286, the best characterized of the amyloid-forming peptides in semen.

This analysis revealed that in silico, CLR01 bound at least 7 of the 8 positively charged residues in PAP248-286 without grossly altering peptide secondary structure. The evidence suggests that CLR01 could prevent PAP248-286 assembly into SEVI fibrils. In layman’s terms, the molecule attaches itself to certain residues within PAP248-286, preventing the development of the HIV virus within the SEVI fibrils in semen.

Scientists purport that the preventative measure for HIV could be developed into a vaginal or anal gel that instantly destroys viral particles.

“We think that CLR01 could be more effective than other microbicides that are in development because of its dual action, its safety in terms of side effects and its potential broad application,” said Professor James Shorter, coauthor on a part of the find published in eLife.

CLR01’s effectiveness comes from its ability to block amyloid fibrils activity, the polymers in semen which make HIV so infectious. Because CLR01 works in 2 fashions, both destroying HIV particles and preventing them from manifesting, scientists believe they have discovered a dual form of attack against the virus. Since the molecule destroys only the viral membrane but does not impact any other membranes in the body, scientists suggest it be used in a gel form as a preventative measure against the disease.

Because of its ability to block amyloid fibrils activity, the team has also suggested it be deployed against a host of other viruses, including hepatitis C and even flu or Ebola.

CLR01 has been studied for many years but never in relation to HIV. Previous trials have revealed CLR01 prevents proteins from grouping together, leaving it to be proposed as a preventative measure against Parkinson’s, Alzheimer’s and Huntington’s disease.

As the study was conducted in lab mice and zebrafish, scientists hope to move forward with human-based trials next. The promising study leaves many hopeful about the state of knowledge about HIV and the preventative measures that can be taken to avoid the virus. 

Articles

Research may lead to gel that prevents transmission of HIV, hepatitis C and the Ebola virus.

'Tweezer' Molecule May Improve Infectious Disease Prevention

Immunosuppressive drug linked to central nervous system lymphoma in solid organ transplant patients.

The immunosuppressive drug mycophenolate mofetil (MMF) has been linked to an increased risk of central nervous system (CNS) lymphoma in solid organ transplant patients, according to a study from Johns Hopkins researchers.

The same study, however, also found that another class of immunosuppressive drugs called calcineurin inhibitors (CNIs), given singularly or in combination with MMF, appears to protect transplant patients against the rare form of lymphoma.

MMF and CNIs are administered to transplant patients to decrease the body’s natural immunity and to prevent new organs from being rejected.

“MMF remains one of the best current medications for immunosuppression that we have but a better understanding of its association with CNS lymphoproliferative disease will be crucial to further improving patients’ transplant regimes based on all of the risks these patients face,” said Amy Duffield, MD, PhD, assistant professor of pathology and oncology at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center.

Blood cancers like lymphomas and leukemia can be complications of solid organ transplants, but these cancers rarely start in the central nervous system, explained Genevieve Crane, MD, PhD, a fellow in hematopathology at The Johns Hopkins Hospital.

Physicians have recently begun to notice a rise in these primary central nervous system (PCNS) lymphoproliferative disorders in transplant patients, however. The new study is the first of its kind to be large enough to identify a link between MMF treatment and these PCNS tumors, Crane noted.

The researchers identified 177 cases of post-transplant lymphoproliferative disorder among patients seen between 1986 and 2014 at The Johns Hopkins Hospital. Of the 177 cases, 29 were diagnosed with PCNS disease.

The team did not notice any post-transplant PCNS cases diagnosed between 1986 and 1997, but the diagnosis increased significantly over the next decades with the proportion of post-transplant PCNS cases fourfold higher between 2005 and 2014.

The researchers had prescription records on 16 patients who developed PCNS lymphoproliferative disease.

Of those, 15 had been taking MMF in the year prior to, or at the time of, their lymphoproliferative disease diagnosis. However, only 37 of 102 patients who had lymphoma outside the central nervous system had taken MMF.

Scientists also found that patients who took CNIs either singularly or in combination with MMF appeared to be more protected from developing PCNS disease.

Of those who had a post-transplant disease, PCNS disease was found in 66.7% of the cases among 6 patients who took MMF but not a CNI, 23.9% of the cases among the 46 patients who took both an MMF, and a CNI; and just 1.7% of the cases in the 60 people who took only a CNI.

Researchers found these trends to be largely similar in a set of 6.966 patients with post-transplant lymphoproliferative disease.

The records of these patients were taken from an organ transplant database managed by the Organ Procurement and Transplantation Network and the United Network for Organ Sharing.

“Most solid organ transplant patients now receive MMF as part of their initial regimen,” Crane explained. “There is a standard daily dose, and it does not require monitoring of drug levels in the blood. This is one of the major advantages of MMF.”

CNIs are also widely used in transplant patients, but require monitoring to make sure that patients don’t get a toxic dose.

Of the 30,000 people receiving solid organ transplants each year in the United States, 1 to 2% develop lymphoproliferative disease and 10 to 15% of that group develop the CNS type, according to Crane.

Depending on the dosage, MMF cost can range between $67 and $90 per month. CNIs, however, are more expensive, costing between $126 and $578 per month. CNIs also require periodic blood tests to monitor levels of the drug.

“More research needs to be done to confirm our results, but our work suggests that, at least in some patients, the combination of MMF and CNIs may be protective against CNS lymphoproliferative disease in a way that had not previous been appreciated,” Crane concluded. 

Transplant Drug Linked to Increased Risk of Lymphoma

Rhabdomyosarcoma is the most common soft tissue sarcoma in children.

New research suggests that a novel genetic test can identify which patients will suffer more aggressive forms of the childhood cancer rhabdomyosarcoma.

The study was able to positively identify high-risk children who might benefit from more intensive treatment by examining the activity of 5 genes in a tumor sample. The findings could lead to personalized treatments for children with cancer based on the genetic activity of their tumors.

The 5-gene signature, known as MG5, was developed by researchers at The Institute of Cancer Research (ICR) in London. The test was validated in samples from 68 patients led by scientists from the Children’s Oncology Group in the United States, in collaboration with the ICR.

The test for gene expression is the first of its kind to accurately predict which children with a type of rhabdomyosarcoma called fusion-negative will have more aggressive forms of the disease.

These fusion-negative tumors are deficient in particular genetic defects often found in rhabdomyosarcoma that results in 2 genes, PAX3 and FOXO1, becoming fused together.

Rhabdomyosarcoma is the most common soft tissue sarcoma in children and strongly resembles muscle tissue. The severity of the condition depends on numerous factors, including where in the body it originally developed.

“Our research showed a significant link between a particular gene signature from tumor samples and higher-risk, aggressive rhabdomyosarcoma,” said UK study lead Professor Janet Shipley, professor of Cancer Molecular Pathology at ICR. “This study is an important step towards introducing an approach that identifies children who are unlikely to benefit from current, standard treatments and can be offered more intensive or new treatment strategies that will improve their outcome.

"We now hope to bring our test for this gene signature to the clinic as soon as possible. Our aim is to identify these high-risk cases of rhabdomyosarcoma more quickly in the clinic, and ultimately improve treatment for these children.”

Previous studies have shown that fusion-negative patients have a lower risk profile for developing aggressive disease than fusion-positive cases.

The new study showed something different, however, that the ICR’s MG5 test splits fusion-negative patients into 2 groups.

Those patients with higher scores have significantly worse rates of survival than those with lower scores, indicating that the test could ultimately be included in an assessment of children with rhabdomyosarcoma across Europe and the United States to determine the best treatment option.

 “We’re determined to bring the same kind of molecular advances that are starting to transform treatment for adult cancer patients to children too,” said Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London. “A key step is to begin dividing up children’s cancers depending on their genetics and gene activity, so that we can adjust their treatment according to the aggressiveness of the disease. That should help us to increase the chances of survival in those with aggressive cancer, while easing the side-effects from treatment in less deadly forms.” 

Novel Genetic Test Predicts Aggressive Forms of Childhood Cancer

Study may lead to enhanced efficacy of breast cancer drugs.

Scientists have long known that cancer comes as the result of normal cellular functions going wrong on a genetic level.

However, increasing evidence points to the human microbiome as the key player in either setting the stage for cancer or even directly causing some forms of it.

A study from the Perelman School of Medicine at the University of Pennsylvania has identified for the first time an association between 2 microbial signatures and triple negative breast cancer (TNBC), the most aggressive form of the disease.

“Viruses and other microorganisms probably have much more to do with cancer, at least the propagation of cancer and promotion of it, than is really known,” said James C. Alwine, PhD, a professor of Cancer Biology and associate director for core services at the Abramson Cancer Center.

The group of scientists used a microarray technology called PathoChip, which contains 60,000 molecular probes to identify all known viruses and pathogenic bacteria, fungi, parasites, and other microorganisms, to screen tissue samples from 100 TNBC patients.

In addition, researchers examined 40 matched and non-matched controls. Matched controls are non-tumor tissue from TNBC patients and non-matched controls are breast tissue from health patients.

The researchers discovered a distinct microbial signature that distinguished TNBC tissue from normal samples, which could be broken down into 2 groups: 1 predominantly viral and the other predominantly bacterial, with some fungi and parasites.

“If we look at this closely, we may also find some smaller clusters within those major groups that could give us some insights to unique identifiers for individuals in these clusters,” said Erle S. Robertson, PhD, a professor of Microbiology and associate director for global cancer research and co-leader of the tumor virology program at the Abramson Cancer Center. “The team found about 30 organisms that provide a specific type of signature to give us clues for developing a diagnostic tool.”

Herpesviruses, Parapoxviruses, Retroviruses, Hepadnaviruses, Polyomaviruses, and Papillomaviruses were among the most likely to be detected in the study. Bacterial signatures included Arcanobacterium, 

While the detection of these and other pathogens in TNBC tissues does provide some insight for scientists, Alwine and researchers emphasize that this does not necessarily mean that they actually cause cancer.

“There are a lot of different ways to look at this,” he said. “It’s possible that some of the organisms we’re looking at have a causative effect, but we don’t know that. We can’t say until it’s been thoroughly tested by many more experiments.”

One possibility is that the organisms could be adding something to the cellular microenvironment that helps damaged cells to become malignant or pushes them over the edge into cancer.

A separate possibility is that certain organisms may simply find tumor tissue to be a more comfortable environment, without necessarily being involved in the processes of cancer.

“They might just be there because it’s a good place to hang out,” Alwine said.

Either possibility yields important information to scientists about how to better develop diagnostic tools.

 “We’re looking at different cancers to find out whether or not there are specific signatures that go with specific cancers,” Robertson said. “We are also trying to come up with ways in which we can look at blood samples to see if we can potentially develop a test to detect these signatures, which might provide an early surveillance system for identifying patients who might be prone to developing these malignancies. The microbial signatures may also have therapeutic implications.”

“Many of these microorganisms can metabolize drugs and so their presence might diminish the effect of some drugs and might guide the ability to decide what to use for treatment of cancer,” Alwine said.

In collaboration with the breast oncology group at Penn Medicine, the research team plans to further explore these possibilities.

“We’re not trying to say that any of these organisms are directly causing cancer,” Alwine said. “We’re trying to identify the specific cancer signature, so that we can figure out ways to treat, control, or modify the cancer or treat the tumor-associate microbes, to prevent these malignancies in the first place. We’ve now opened up the doors to look more specifically at what these organisms are actually doing.” 