Categories
Public Health

Study Shows Reddit’s Potential as an Early Warning System for New Designer Drugs

In a new study, researchers demonstrated the use of data mining of social networks like Reddit to predict increased use of novel psychoactive substances (NPS).

Reddit is a social network and media aggregator divided into subreddits pertaining to certain topics, like college football, art, movies, and world news. Niche subreddits exist for many topics, including specific drugs.

Users on subreddits like r/ResearchChemicals discuss designer drugs (including analogs) and other newly discovered substances. Analogs are two drug compounds that have similar molecular structures and/or effects. Sometimes, an analog of an illegal drug has similar effects and properties to its illegal counterpart but has yet to be made illegal.

Under the Federal Analogue Act, compounds “substantially similar” to controlled substances are meant to be treated as if they were the controlled substances themselves. However, designer drugs are often overlooked or may take years for federal authorities to address.

Reddit post on “research chemicals” subreddit discussing novel psychoactive substances.

Researchers from Florida Atlantic University, the University of Florida, and New York University gathered and analyzed data on mentions of newly discovered NPS on Reddit. They found that users mentioned certain NPS months to years before the substances became prevalent in toxicology reports. Such reports are conducted to identify a culprit substance when a patient has overdosed or is subjected to a toxic exposure.

The study mentioned that NPS mentioned on Reddit before any exposures were recorded include:

  • Carfentanil
  • U-47700
  • Eutylone
  • Flualprazolam
  • N-ethylpentylone
  • Isotonitazene
  • Brorphine

Carfentanil, for example, was first mentioned on Reddit in February 2013–almost 4 years before its first reported exposure in October 2016.

Reddit mentions of N-ethylpentylone peaked 5 months before the number of reported cases. (Barenholtz et al, 2021)

The study found that seven of the eight analyzed NPS were mentioned on Reddit before there were any reported cases of the substances in toxicology reports.

Five of the eight analyzed NPS peaked in Reddit mentions months before the substances peaked in reported exposures.

The researchers posit that these data mining methods could prove to be a useful tool for early detection of NPS trends by public health authorities and legislatures.

This article is based on the following works:

– Barenholtz et al. (2021, August 5). Online surveillance of novel psychoactive substances (NPS): Monitoring Reddit discussions as a predictor of increased NPS-related exposures. https://doi.org/10.1016/j.drugpo.2021.103393

Categories
Cardiology

Surgeons at Duke University First to Implant New Total Artificial Heart Into Patient

Scientist with Total Artificial Heart device (carmatsa.com)

A team of surgeons at Duke University led by Dr. Carmelo Milano and Dr. Jacob Schroder were the first to implant a new generation of Total Artificial Heart (TAH) in a 39-year-old male patient with heart failure after receiving FDA approval for human trials.

Home - Carmat :Carmat
The total artificial heart made by French company CARMAT acts to replace that of an organic diseased heart of patients with heart failure, hoping to one day replace the need for living donor heart transplantation. (carmatsa.com)

CARMAT’s Total Artifical Heart product, called Aeson, is a new TAH that solves many of the issues with current treatment options associated with biventricular heart failure. Current options include human organ transplantation, which carries high risk of rejection. Such rejection can lead to the need for repeat cardiac transplant or even death. Other treatment options such as biventricular assist devices (BiVADs) carry high risk of neurological complication incidence such as stroke caused by accumulation of clots or seizures that can lead to life debilitating changes.

CARMAT’s Aeson is only the second TAH on the market. Aeson has made notable improvements over competitor SynCardia’s total artificial heart. CARMAT’s TAH is quieter and has a variable heart rate that adjusts based on patient activity, while SynCardia is notably louder and has a fixed heart rate.

Aeson replaces the patient’s heart by pumping blood to the pulmonary tract and systemic system. It does this through the use of battery-powered electrohydraulic rotary pumps with attached sensors that respond to changes in pressure and cardiac demands.

The French company’s device can be used as an intermediate heart prior to transplantation, or even as a complete replacement for living donor hearts. This development has radical implications to heart failure treatment, as American patients can expect to wait more than six months for a transplant.

Dr. Jacob Schroder (Assistant Professor of Surgery) and Dr. Carmelo (Professor of Surgery) installing the CARMAT TAH. (CBS17)

The surgery at Duke University was the first of its kind in the United States. It consisted of an 8-hour surgery in which Dr. Jacob Schroder and Dr. Carmelo Milano worked to remove Matthew Moore’s (a 39-year-old patient with biventricular heart failure on the transplant waiting list) left and right ventricles of his heart. They then installed the device successfully replacing the structures removed.

Each device costs around $190,000, not including the costs of critical care staff and other medications. However, this price point is significantly lower than the average cost for a human heart transplant, which is about $1.4 million.

CARMAT hopes to solve long wait lists and high costs with its TAH, Aeson, potentially offering a permanent solution in which a heart will always be available for any patient in need.

This article is based on the following sources

– Bailey, S. (2021, March 25). This new artificial heart responds to the patient. CNN Business. https://www.cnn.com/2021/03/25/business/carmat-artificial-heart-spc-intl/index.html
– Duke University School of Medicine. (2021, July 16). New generation artificial heart implanted in patient at Duke – First in U.S. https://medschool.duke.edu/blog/new-generation-artificial-heart-implanted-patient-duke-first-us
– Rapp, N., & Vandermey, A. (2017, September 14). Here’s what every organ in the body would cost to transplant. Fortune. https://fortune.com/2017/09/14/organ-transplant-cost/
– Tan, K. (2021, July 29). Duke surgical team successfully implants new generation artificial heart in patient, first in U.S. Duke Chronicle. https://www.dukechronicle.com/article/2021/07/duke-university-hospital-health-artificial-heart-transplant-research-study-carmat
– University of California, San Francisco Health. (n.d.). FAQ: Heart transplant. https://www.ucsfhealth.org/education/faq-heart-transplant

Categories
Oncology

Researchers Create Synthetic Microenvironment for Pancreatic Ductal Adenocarcinoma Organoids

Histopathology of pancreatic ductal adenocarcinoma (Tayao et al. 2016)

When PDA (pancreatic ductal adenocarcinoma) cancer cells form in the body, the extracellular matrix is remodeled to create an immunosuppressive environment which is rigid and poorly perfused. Through the normalization of these matrices, therapeutic treatments can be administered more effectively which makes the replication and synthesis of such models instrumental to the development of the efficacies of remedial treatments. 

As a result, a team from the Cancer Research UK Manchester Institute has developed a synthetic hydrogel-based model for pancreatic organoids that aims to replicate the extracellular microenvironments of both normal and pancreatic cancer cells in vitro.  

To formulate a working prototype, they analyzed 10 normal and 12 tumorous pancreatic samples using liquid chromatography with tandem mass spectrometry and identified 83 proteins that were relevant to the structural function of the matrix. Through the comparison of the matricellular proteins involved in cellular adhesion, they found that the proteins fibronectin (FN), versican, and laminin-332 were upregulated in cancerous cells. Additionally, they found that the proteins laminin 521 and types 1 & 4 collagen were abundant in both normal and cancerous cells, highlighting the potential importance of matrisomal components in PDA development. 

To form the gel, researchers used an eight-arm PEG-based hydrogel system through a network of peptides to help mimic the environment in which PDA organelles could develop. They found that contrary to traditional assays that were supported through FN-mimicking peptides, the use of collagen-mimicking peptides helped to increase the variety of murine pancreatic cancer organoids (mPCOs) that were supported by the hydrogel system. This change has allowed for the increased the growth efficiency of the organoids and supports the efficacy of their microenvironment.

Researchers also found that their models were able to support stromal co-cultures as they were able to replicate phenotypes of elongated, mesenchymal-structured fibroblasts that were similar to what they would find in vivo. The morphology data of tested species were consistent with  myCAF, iCAF and apCAF (cancer-associated fibroblasts) subsets and illustrated that the environments they developed were able to successfully mirror those of live specimens. These results support the idea that stromal cells in the synthetic setting are able to display relevant phenotypes that are consistent with in vivo models.

The University of Manchester-led study found that their new scaffold models were not only able to replicate the stiffness range of both cancerous and normal tissue but were also able to facilitate the growth of associated organoids and induced stromal samples. The researchers hope that their research will help other scientists replicate essential cell-ECM interactions as well as grow cultures of epithelial and stromal cells to help facilitate growth of organoids to better understand the mechanisms behind PDA and its development.

This article is based on the following sources and clinical studies.

– Below, C.R., Kelly, J., Brown, A. et al. (2021, September 13). A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids. https://doi.org/10.1038/s41563-021-01085-1
– Tayao, M. (2016, March 16). Loss of BAP1 Expression Is Very Rare in Pancreatic Ductal Adenocarcinoma. https://dx.doi.org/10.1371%2Fjournal.pone.0150338

Categories
Pharmacology

How “Docking Software” Helped Discover Compounds That Could Boost Stroke, TBI Recovery

Example of molecular docking of a ligand in the main protease of SARS-CoV-2. Yellow: ligand position determined by computer simulation. Black: ligand position determined by experiment. Source: Joshua Vermaas/ORNL, US Department of Energy.

Using the University of Florida’s HiPerGator supercomputer with the University of California San Francisco’s DOCK software, researchers have identified two dipeptides as small molecule activators of the peptidase neurolysin enzyme.

Render of peptidase neurolysin enzyme.

Peptidase neurolysin is an enzyme that has been found to be “one of the brain’s potent, self-protective mechanisms promoting preservation and recovery of the brain after acute injury” (Karamyan). Karamyan’s research posited that in the case of these injuries, neurolysin is responsible for:

  • reducing fluid buildup around the brain (cerebral edema)
  • reducing neural cell death caused by excess neurotransmitters (excitotoxicity)
  • reducing inflammatory response in the brain (neuroinflammation)

Searching for ways to make neurolysin more effective, lead researcher Vardan Karamyan, PhD (Texas Tech University Health Sciences Center Department of Pharmaceutical Sciences) enlisted the help of David Ostrov, PhD (University of Florida College of Medicine Department of Pathology, Immunology and Laboratory Medicine).

Neurolysin is similar in structure to a molecule called ACE2 (angiotensin converting enzyme-2), the main receptor for the virus that causes COVID. Dr. Ostrov previously identified drugs that bind ACE2, and he used the same strategy to identify drug candidates that bind neurolysin.

Superposition of neurolysin (copper) on ACE2 (teal).

Ostrov used UF’s HiPerGator supercomputer to screen 139,725 compounds from a repository at the National Cancer Institute Developmental Therapeutics Program to identify candidates that could fit a site on neurolysin that would facilitate an increase in the enzyme’s function. This was achieved using the DOCK program package, developed by UCSF.

DOCK’s molecular docking simulations were used to identify if and how a ligand (drug-like small molecule) can bind to the active site of a macromolecule (in this case, neurolysin). This is usually done to find ways to promote or inhibit a macromolecule’s function, making molecular docking software a key component in the ever-expanding world of computational drug discovery.

According to the UFHealth Newsroom, UF’s HiPerGator supercomputer completed the query in 15 hours–only 1.4% of the time it would take a desktop computer to complete the same task.

In the lab, the researchers tested the function of DOCK’s best matches on rat neurolysin. They found that the dipeptides L-histidlyl-L-tyrosine and L-histidlyl-L-histidine enhanced the activity of neurolysin.

According to Ostrov, human clinical trials with the mentioned drug candidates could begin within 2 years if FDA approved drugs are found to enhance neurolysin activity. An approved drug could assist or facilitate recovery in stroke and traumatic brain injury (TBI) patients.

This article is based on the following sources

– Bennett, D. (2021, September 7). UF health researcher, collaborators discover compounds that might boost stroke recovery. University of Florida Health. https://ufhealth.org/news/2021/uf-health-researcher-collaborators-discover-compounds-might-boost-stroke-recovery
– Karamyan, V. T. (2019, October). Peptidase neurolysin is an endogenous cerebroprotective mechanism in acute neurodegenerative disorders. https://doi.org/10.1016/j.mehy.2019.109309
– Statements from David A. Ostrov, PhD (University of Florida College of Medicine, Department of Pathology, Immunology and Laboratory Medicine)