Posts

conceptual image of bladder cancer

Sensitivity to physical versus chemical factors in CAP

conceptual image of bladder cancer

To date, reactive oxygen species and reactive nitrogen species have been regarded as the key factors causing the observable cellular death of cold atmospheric plasma (CAP)-treated cancer cells. The chemical basis of the conventional CAP treatment highlights apoptosis as the main CAP-triggered cell death mechanism.

However, in a recent study published in the Journal of Physics, Michael Hsieh, M.D., Ph.D., director of Transitional Urology at Children’s National Hospital, and other experts demonstrated a strong anti-melanoma effect based on physically-based CAP treatment. The study, which also tested bladder cancer, compared the anti-cancer effect of chemically-based versus physically-based CAP treatment on four typical cancer cell lines in vitro.

Illustration of Bifidobacterium

Probiotic use in pediatric medicine

Illustration of Bifidobacterium

Probiotics have received significant attention within both the scientific and lay communities for their potential health-promoting properties, including the treatment or prevention of various conditions in children.

In a recent article published by Pediatric Research, Michael Hsieh, M.D., Ph.D., director of Transitional Urology at Children’s National Hospital, and other experts review the published data on use of specific probiotic strains for three common pediatric conditions: the prevention of urinary tract infections and antibiotic-associated diarrhea and the treatment of atopic dermatitis.

schistosome

Parasite-derived molecule could accelerate recovery from UTI

schistosome

Eggs from S. haematobium may produce the molecule IPSE to reduce the immune response against them, which happens to dampen UTI-induced bladder inflammation.

IPSE, a urogenital parasite-derived immunomodulatory molecule, can suppress bladder pathogenesis and anti-microbial peptide gene expression in bacterial urinary tract infection (UTI) according to a new study led by Michael Hsieh, Ph.D., director of Transitional Urology at Children’s National Hospital.

Half of all girls and women, and about 5% of boys and men, will have at least one urinary tract infection (UTI) in their lifetimes.

“Although antibiotics are very helpful for these infections, there are concerns that overuse of antibiotics may contribute to antibiotic-resistant infections,” Dr. Hsieh said. “There are also concerns that antibiotic therapy for UTI does not uniformly resolve infection-induced or inflammation-associated symptoms quickly.”

Parasitic infections are often associated with bacterial co-infections for unclear reasons. This may be true for urogenital schistosomiasis (caused by Schistosoma haematobium infection) and bacterial urinary tract co-infection (UTI), the study noted. Dr. Hsieh and other leading experts previously reported that this co-infection is facilitated by S. haematobium eggs triggering interleukin-4 (IL-4) production and sought to dissect the underlying mechanisms.

“Despite S. haematobium’s ability to make hosts more susceptible to UTI, we have identified IPSE, a bladder parasite protein, as a potential anti-inflammatory agent to accelerate recovery from UTI,” Dr. Hsieh explained. “S. haematobium eggs may produce IPSE to reduce the immune response against them, which happens to dampen UTI-induced bladder inflammation. It may be possible to develop IPSE as novel therapeutic to accelerate recovery from UTI.”

The study’s data showed that IPSE may play a major role in S. haematobium-associated urinary tract co-infection, although in an unexpected way. The study’s findings also indicated that IPSE either works in concert with other IL-4 -inducing factors to increase susceptibility of S. haematobium-infected hosts to bacterial co-infection or does not contribute to enchaining vulnerability to this co-infection.

You can find the full study published in Parasites and Vectors. Learn more about the Children’s National Department of Urology.

Schistosoma

Parasitic eggs trigger upregulation in genes associated with inflammation

Schistosoma

Of the 200 million people around the globe infected with Schistosomiasis, about 100 million of them were sickened by the parasite Schistosoma haematobium.

Of the 200 million people around the globe infected with Schistosomiasis, about 100 million of them were sickened by the parasite Schistosoma haematobium. As the body reacts to millions of eggs laid by the blood flukes, people can develop fever, cough and abdominal pain, according to the Centers for Disease Control and Prevention. Schistosomiasis triggered by S. haematobium can also include hematuria, bladder calcification and bladder cancer.

Despite the prevalence of this disease, there are few experimental models specifically designed to study it, and some tried-and-true preclinical models don’t display the full array of symptoms seen in humans. It’s also unclear how S. haematobium eggs deposited in the host bladder modulate local tissue gene expression.

To better understand the interplay between the parasite and its human host, a team led by Children’s National Hospital injected 6,000 S. haematobium eggs into the bladder wall of seven-week-old experimental models.

After four days, they isolated RNA for analysis, comparing differences in gene expression in various treatment groups, including those that had received the egg injection and experimental models whose bladders were not exposed to surgical intervention.

Using the Database for Annotation, Visualization and Integrated Discovery (DAVID) – a tool that helps researchers understand the biological meaning of a long list of genes – the team identified commonalities with other pathways, including malaria, rheumatoid arthritis and the p53 signaling pathway, the team recently presented during the American Society of Tropical Medicine and Hygiene 2019 annual meeting. Some 325 genes were differentially expressed, including 34 genes in common with previous microarray data.

“Of particular importance, we found upregulation in genes associated with inflammation and fibrosis. We also now know that the body may send it strongest response on the first day it encounters a bolus of eggs,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National, and the research project’s senior author. “Next, we need to repeat these experiments and further narrow the list of candidate genes to key genes associated with immunomodulation and bladder cancer.”

In addition to Dr. Hsieh, presentation co-authors include Lead Author Kenji Ishida, Children’s National; Evaristus Mbanefo and Nirad Banskota, National Institutes of Health; James Cody, Vigene Biosciences; Loc Le, Texas Tech University; and Neil Young, University of Melbourne.

Financial support for research described in this post was provided by the National Institutes of Health under award No. R01-DK113504.

clatharin cage viewed by electron microscopy

IPSE infiltrates nuclei through clathrin-mediated endocytosis

clatharin cage viewed by electron microscopy

IPSE, one of the important proteins excreted by the parasite Schistosoma mansoni, infiltrates human cellular nuclei through clathrin-coated vesicles, like this one.

IPSE, one of the important proteins excreted by the parasite Schistosoma mansoni infiltrates human cellular nuclei through clathrin-mediated endocytosis (a process by which cells absorb metabolites, hormones and proteins), a research team led by Children’s National Hospital reported during the American Society of Tropical Medicine and Hygiene 2019 annual meeting.

Because the public health toll from the disease this parasite causes, Schistosomiasis, is second only to malaria in global impact, research teams have been studying its inner workings to help create the next generation of therapies.

In susceptible host cells – like urothelial cells, which line the urinary tract – IPSE modulates gene expression, increasing cell proliferation and angiogenesis (formation of new blood vessels). On a positive note, neurons appear better able to fend off its nucleus-infiltrating ways.

“We know that IPSE contributes to the severity of symptoms in Schistosomiasis, which leads some patients to develop bladder cancer, which develops from the urothelial lining of the bladder. Our team’s carefully designed experiments reveal IPSE’s function in the urothelium and point to the potential of IPSE playing a therapeutic role outside of the bladder,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National and the research project’s senior author.

In addition to Dr. Hsieh, research co-authors include Evaristus Mbanefo, Ph.D.; Kenji Ishida, Ph.D.; Austin Hester, M.D.; Catherine Forster, M.D.; Rebecca Zee, M.D., Ph.D.; and Christina Ho, M.D., all of Children’s National; Franco Falcone, Ph.D., University of Nottingham; and Theodore Jardetzky, Ph.D., and Luke Pennington, M.D., Ph.D., candidate, both of Stanford University.

Financial support for research described in this post was provided by the National Institutes of Health under award No. R01-DK113504.

Hepatocytes

H-IPSE internalized by just a limited range of cells

Hepatocytes

A team led by Children’s National Hospital found that H-IPSE is internalized by just a limited range of cells, including hepatocytes.

Schistosoma mansoni is a parasite that hides out in snails, breaks free into waterways, and then infects humans, spending much of its life inside blood vessels, laying eggs and jeopardizing public health when those eggs are excreted in urine or feces. As parasitic diseases go, the ailment it causes, Schistosomiasis, is second only to malaria in global impact, according to the Centers for Disease Control and Prevention.

In order to elude the human host’s defenses, S. mansoni uses self-defense tactics that researchers are trying to better understand in order to outmaneuver the parasite. A research team led by Children’s National Hospital is trying to tease out the multiple steps that enable this parasite to reproduce and generate millions of eggs without killing its host.

The parasite’s eggs secrete a number of proteins, with IPSE as one of the most abundant, the team recently presented during the American Society of Tropical Medicine and Hygiene 2019 annual meeting. That protein binds immunoglobulin, which induces basophils and mast cells to release IL-4. After sequestering chemokines, H-IPSE infiltrates the cell nucleus (thus H-IPSE is called an infiltrin), modulating gene expression.

“H-IPSE tips the immune system balance, making it more likely to trigger a Th2 anti-inflammatory response,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National and the research project’s senior author. “It downregulates pro-inflammatory pathways, but we wanted to know more about which specific human cells it targets.”

Using Trypan Blue, a stain that selectively colors certain cells bright blue, they solved the mystery, finding that H-IPSE is internalized by just a limited range of cells. What’s more, some cell types, like urothelial cells and hepatocytes (the liver’s chief functioning cells, which activate innate immunity), are more susceptible than neurons, endothelial cells or immature dendritic cells.

In addition to Dr. Hsieh, presentation co-authors include Olivia Lamanna, Evaristus Mbanefo and Kenji Ishida, all of Children’s National; Franco Falcone, of University of Nottingham; and Theodore Jardetzky and Luke Pennington, of Stanford University.

Rebecca Zee

Children’s urology fellow wins best basic science award

Rebecca Zee

Rebecca Zee, a Children’s urology fellow, was awarded the best basic science prize at the Societies for Pediatric Urology annual meeting for her abstract describing a novel treatment to prevent ischemia reperfusion injury following testicular torsion.

Occurring in 1 in 4,000 males, testicular torsion occurs when the testis twists along the spermatic cord, limiting blood supply to the testicle. Despite prompt surgical intervention and restoration of blood flow, up to 40 percent of patients experience testicular atrophy due to a secondary inflammatory response, or ischemia reperfusion injury. Cytisine, a nicotine analog that the Food and Drug Administration approved for smoking cessation, recently has been found to activate a novel anti-inflammatory cascade, limiting the post-reperfusion inflammatory response.

“Administration of cytisine was recently found to limit inflammation and preserve renal function following warm renal ischemia,” Zee says. “We hypothesized that cytisine would similarly prevent ischemia reperfusion injury and limit testicular atrophy following testicular torsion.”

Using an established experimental model, Zee and colleagues induced unilateral testicular torsion by anesthetizing the adult male experimental models and rotating their right testicles by 720 degrees for two hours. In the treatment arm, the preclinical models were given cytisine as a 1.5 mg/kg injection one hour before or one hour after creating the testicular torsion. Eighteen hours after blood flow was restored to the right testis, total leukocyte infiltration and inflammatory gene expression were evaluated. Thirty days later, the researchers measured testicular weight and evaluated pro-fibrotic genes.

“We found that the administration of cytisine significantly decreases long-term testicular atrophy and fibrosis following testicular torsion,” says Daniel Casella, M.D., a urologist at Children’s National Health System and the study’s senior author. “What is particularly exciting is that we found similar long-term outcomes in the group that was given cytisine one hour after the creation of testicular torsion. This scenario is much more clinically applicable, given that we would not be able to treat patients until they present with testicular pain,” Dr. Casella adds.

Additional research is needed to determine the optimal cytisine dosing and administration regimen, however the researchers are hopeful that they can transition their findings to a pilot clinical trial in the near future.

In addition to Zee and Dr. Casella, the multi-institutional team included Children’s co-authors Nazanin Omidi, Christopher Bayne, Michael Hsieh, M.D., and Evaristus Mbanefo, in addition to Elina Mukherjee and Sunder Sims-Lucas, Ph.D., from the University of Pittsburgh.

Financial support for this work was provided by the Joseph E. Robert Jr. Center for Surgical Care.