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HSPP- April- May-June, 2018 – Newsletter

Clinical Trials – What you need to Know

Did you know the public clinical trials registry, ClinicalTrials.gov, was created in February 2000 in support of a 1997 federal law requiring public registration of clinical trials? It was designed as a web-based catalog of clinical trials to serve as a resource for the patient and research community alike. The law has since expanded to require more types of clinical trials research to be registered, and for some trials, results are also required to be posted.

Did you know there are at least 4 organizations that may require you to register your study on ClinicalTrials.gov? The FDA, National Institutes of Health (NIH), International Committee of Medical Journal Editors (ICMJE) and World Health Organization (WHO) each have rules about registering. For more details on each, please click here.

Did you know the NIH and ICMJE have expanded their definitions of a clinical trial to include behavioral trials? Click here for NIH’s definition. Click here for the ICMJE definition.

Did you know that for studies that require results to be posted per the federal law with completion dates after 1/18/17, a final version of the IRB-approved protocol document and statistical analysis plan must be uploaded to the ClinicalTrials.gov record? Limited information may be redacted. For details, click here.

Should your study be registered with ClinicalTrials.gov?

For more information, see our webpages or contact Ellen Ciesielski (eciesielski@uchc.edu, 860-679-6004) in Research Compliance Services.

 

Inclusion of Children in Research

When a Principal Investigator (PI) proposes a research project that will involve an intervention or interaction with children, the PI must demonstrate to the IRB that the additional protections afforded to children by regulations have been addressed. The Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) have each established regulations governing the inclusion of children in research and the UConn Health IRB has incorporated these regulations into policy.  When proposing a research study that will include children as subjects investigators should review the following material:

  • IRB Policy 2011-006.0, Additional Protections for Certain Populations – General Policy,
  • IRB Policy 2011-006.3, Additional Protections for Certain Populations – Children,
  • Form D, Additional Protections for Children Involved as Subjects in Research

In order for the IRB to approve a research protocol that will enroll children, the IRB must assess the information provided by the PI and be able to determine that the research falls within one or more of the following permissible categories and that the plans for obtaining the assent of the child and permission of the parents are appropriate. The examples provided within each category were taken from the Collaborative Institutional Training Initiative (CITI) Program.

Category 1: Research not involving greater than minimal risk.

Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

To be approvable under this category, the IRB must find that the research presents no greater than “minimal risk” to children, and that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians. The IRB may determine that permission from one parent is sufficient.

Examples of Research Projects That May Fall Within Category 1

  • A study to determine the relationship between maternal age and head circumference at birth. Measurement of head circumference is part of the normal newborn examination, and is therefore minimal risk.
  • A study to determine the incidence of asymptomatic proteinuria in school age children. The research involves the analysis of a voided urine collection, which is minimal risk.

Category 2: Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.

This category is inclusive of research in which more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject’s well-being. The IRB may approve research under this category only if the IRB finds and documents that:

(a) The risk is justified by the anticipated benefit to the subjects;

(b) The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and

(c) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians.   The IRB may determine that permission from one parent is sufficient.

Examples of Research Projects That May Fall Within Category 2:

A pilot study of a shorter duration of antibiotic treatment for uncomplicated otitis media. The potential benefit associated with the shorter duration of treatment is increased compliance, and a reduced rate of antibiotic-related diarrhea. The risk associated with the shorter duration of therapy is a higher likelihood of treatment failure.

The risk associated with this research (e.g. treatment failure) appears to be greater than minimal but can be justified by the anticipated benefit (reduce rate of antibiotic diarrhea); and there is the prospect of direct benefit to the child (increased compliance, shorter exposure time, and a reduced rate of antibiotic-related diarrhea). If the risk-benefit relationship is as favorable as the one seen with standard care (e.g. use of the antibiotic for standard time frame), this research would be approvable under this category.

Use of a placebo, or routine monitoring for safety, is not considered to provide direct benefit to subjects.

Category 3: Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition.

 

This category is inclusive of research in which more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject. To be approvable under this category, the children to be enrolled must have the disorder or condition under study (i.e. a healthy control group would not be allowable) and the IRB must find and document that:

(a) The risk represents a minor increase over minimal risk;

(b) The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations;

(c) The intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or condition; and

(d) Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians. In most cases permission from both parents is required.

Examples of Procedures That May Involve Minor Increase Over Minimal Risk:

  • Catheterized urine collection
  • Skin biopsy or bone marrow biopsy
  • MRI scan with sedation

Example of Research That May Fall Within Category 3:

A study to determine the clinical relevance of a new technique to quantitate minimal residual disease (MRD) during therapy for acute lymphoblastic leukemia in children. The study requires one additional bone marrow aspirate be performed during the course of treatment. Therapy for the subject will not be altered based on the results of the assay. However, if it can be shown that the presence of MRD predicts poor outcome, in the future, patients with MRD can receive more intensive treatment and increase their chance of cure.

It can be argued that the risk of a bone marrow aspirate in a child is only a minor increase over minimal risk. Further, the risk appears commensurate with risks inherent in the subject’s actual medical situation, and the research may yield knowledge of vital importance about the child’s disease (leukemia).

Category 4: Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children

 

For research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children the IRB must find and document:

  1. That the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and
  1. b)   For studies funded or supported by DHHS, the Secretary, or for studies subject to FDA oversight the Commissioner, after consultation with a panel of experts in pertinent   disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either:

(1)       that the research in fact satisfies the conditions of one of the aforementioned categories, as applicable, or

(2)       (i) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (ii) the research will be conducted in accordance with sound ethical principles; (iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians.

General Requirements for Assent and Permission:  

 Assent means an affirmative agreement to participate in research used with those who are not competent or not of legal age to provide informed consent. Failure to object may not be construed as assent.

 For children to participate in research, the IRB must determine that adequate provisions are made for soliciting the assent of the children when in the judgment of the IRB the children are capable of providing assent. The IRB will take into account the ages, maturity, and psychological state of the children involved. The judgment may be made for all children to be involved in research under a particular protocol, or for each child. When the IRB determines that assent is required, it shall also determine whether and how assent must be documented.

The IRB may determine that assent is not a necessary condition for proceeding with the research if the capability of some or all of the children is so limited that they cannot reasonably be consulted or that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research.

Permission is the agreement of parent(s) or guardian to the participation of their child in research. Permission is generally documented by have the parent(s)/guardian sign an informed consent document.

For research studies not involving greater than minimal risk (Category 1 ) and research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (Category 2) the IRB may find that the permission of one parent or guardian is sufficient. For research studies involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition (Category 3), and for research studies not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children (Category 4), both parents/guardians must give their permission unless one is deceased, unknown, incompetent or not reasonably available, or unless only one parent has legal responsibility for the care and custody of the child.

If the IRB determines that a research protocol is designed for conditions or for a subject population for which parental or guardian permission is not a reasonable requirement to protect the subject (e.g., neglected or abused children) it may waive the consent requirements provided an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and provided further that the waiver is not inconsistent with Federal, state or local law.

The choice of an appropriate mechanism would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity status and condition.

 

Inclusion or Wards in Research

 Children who are wards of the state or any other agency, institution, or entity can be included in research involving greater than minimal risk and no prospect of direct benefit to the individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition (Category 3) or research that is not approvable under a defined regulatory category but that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children (Category 4) only if the research is related to their status as wards, or is conducted in schools, camps, hospitals, organizations, or similar settings in which the majority of children involved as subjects are not wards.

Each child must have an advocate appointed who has the background and experience to act in, and agrees to act in, the best interests of the child, and who is not associated in any way with the research, researchers, or guardian organization.

 

ResearchMatch training

ResearchMatch.org is a national online recruitment tool, funded by the National Institutes of Health and maintained at Vanderbilt University. ResearchMatch connects researchers with individuals interested in participating in research studies, through its secure, online matching tool. There is no cost to UConn Health researchers to use ResearchMatch.

To learn more about using ResearchMatch for your studies, register for the free ResearchMatch Researcher Webinar Training/Live Demo on Thursday, July 12, 2018 from 3:00 p.m. – 4:00 p.m. The training is open to all research staff. After registering, you will receive a confirmation email with instructions on joining the training.

The team at ResearchMatch will show you how to register your studies, create a cohort of potential volunteers and send out contact messages and surveys. They will also cover how to send a pre-screening (eligibility) survey, contact the volunteers that replied ‘yes’ to your initial message, and manage your enrollment continuum.

To register for the training, click here:

https://attendee.gototraining.com/r/9112903382698216193

For additional information, contact Ellen Ciesielski (eciesielski@uchc.edu; 860-679-6004).

Additional Information on Newly Published Research Policies

The newly published policies for Animal Use in Research, Teaching and Testing and Research Involving Human Subjects revise the existing UConn Storrs policies to establish a uniform regulatory compliance statement that applies to all campuses under which the programs at UConn Health and Storrs operate.  A single, overarching policy will help in the development of other policies and procedures to help facilitate cross-campus initiatives.

Key revisions:

  • Clarification of who the policies apply to (both policies)
  • Revisions to definitions to make them consistent with the regulatory definition (both policies)
  • Clarification regarding the role of the Institutional Official and committees (IACUC and IRB)
  • Clarification of the authority of the attending veterinarian to be consistent with regulatory requirements (Animal Use policy)
  • Clarification of the authority of the IRB to be consistent with regulatory requirements (Human Subjects Research policy)
  • Revisions to the enforcement section to make the sections consistent with other university policies (both policies)
  • Updated list of authorities (both policies)

 

The Human Stem Cell Research policy clarifies and updates the existing University-wide policy regarding the type and scope of research to which the policy applies.

 

The ClinicalTrials.gov policy establishes a new University-wide policy to address FDA, NIH and CMS requirements that applicable trials are registered.

 

Animal Use in Research, Teaching and Testing: https://policy.uconn.edu/?p=113

Human Stem Cell Research Approval: https://policy.uconn.edu/?p=2453

Human Subjects Research: https://policy.uconn.edu/?p=406

ClinicalTrials.gov: https://policy.uconn.edu/?p=7310

 

For additional information, contact Ellen Ciesielski (eciesielski@uchc.edu, 860-679-6004)

 

Revised & New University-Wide Research Policies

 

The Office of the Vice President for Research (OVPR) Research Compliance Services would like to share some important updates regarding university policies for animal use, human subjects, and stem cell research. These policies were revised to be consistent with federal requirements and are now in effect for all campuses, including UConn Health.  A new university-wide policy to address FDA, NIH, and CMS requirements for registration of applicable trials to ClinicalTrials.gov has also been published.

 

Please see links to published policies below.

 

ClinicalTrials.gov: https://policy.uconn.edu/?p=7310

Animal Use in Research, Teaching and Testing: https://policy.uconn.edu/?p=113

Human Stem Cell Research Approval: https://policy.uconn.edu/?p=2453

Human Subjects Research: https://policy.uconn.edu/?p=406

 

For additional information, contact Ellen Ciesielski (eciesielski@uchc.edu, 860-679-6004).

 

Designing a Smart Sensor Network for Tracking Submarines

Read on UConn Today.

Illustration of network concept. (Getty Images)
Illustration of network concept. A UConn researcher at the National Institute for Undersea Vehicle Technology is developing a ‘smart sensor network’ that is both energy-efficient and resilient, to track targets such as enemy submarines. (Getty Images)

A team of UConn engineers is developing an energy-efficient “smart sensor network” to track targets of interest, such as the proximity of enemy submarines or ships to Navy vessels.

The U.S. Navy currently uses underwater Intelligence, Surveillance, & Reconnaissance (ISR) sensor networks that run on full power, which can be a problem for long-term operations. The more accurate the sensor, the more power they consume.

The sensor networks currently being used could consist of several multi-modal sensor nodes, called sensor buoys, where each node acts independently and contains a diverse sensor suite, a data-processing unit, a transmitter and receiver, and a GPS device. The sensor suite can be composed of different types of sensors to detect and track targets, such as underwater microphones and active sonars.

Batteries typically burn out within  a few days,  just as cell phones suck up more power when running multiple operations.

Traditionally, these sensor nodes operate on full power, running all devices simultaneously, but the batteries that power them typically burn out within a few days of operation,  just as cell phones suck up more power when running multiple operations. This causes sensing failures which, in turn, leads to holes in coverage and affects tracking performance.

This poses a challenge to the Navy, since it deploys thousands of acoustic sensor networks throughout the ocean, where battery replacement can be time-consuming or impossible.

To address the challenge, Shalabh Gupta, a UConn engineer and researcher at the National Institute for Undersea Vehicle Technology, devised the concept of a “smart sensor network” that is energy-efficient as well as resilient to failures.

Intelligent Energy-efficient Sensor Network. (Illustration by Hayley Joyal '18 (SFA))
Intelligent Energy-efficient Sensor Network. (Illustration by Hayley Joyal ’18 (SFA))

In a smart sensor network, sensor nodes adapt their sensing modalities based on the information about the targets’ whereabouts. Thus, the nodes around the target, such as a ship or submarine, activate their high-power sensing devices to track the target accurately, pinpointing its location, velocity, and trajectory.

On the other hand, the nodes that are located farther away from the target cycle between low-power sensing and sleep states to minimize energy consumption while still remaining aware.

Thus, if a low-power sensor detects a target, the node switches to high-power sensing to track it. Similarly, the high-power sensing devices that are tracking the target predict the target’s trajectory and alert other sensors within range of the target’s path, so that they switch to high power. Once the target has passed outside of a sensor’s range, it reverts to low-power mode.

The smart sensor networks also provide resilience. If a few nodes in the network fail, then the nodes surrounding the hole in coverage formed by the failed nodes jointly optimize to expand their sensing ranges to cover the gap.

“These networks have to contain built-in, distributed intelligence,” says Gupta, an assistant professor of electrical and computer engineering.

His first research paper on the algorithm, coauthored by graduate student James Hare, was published online in IEEE Transactions on Cybernetics in August 2017.

With this advance, crews on ships and submarines will be able to track enemy watercraft with batteries that last about 60 to 90 percent longer, Gupta says.

Gupta’s lab has prototypes of the sensors for ground use, and has been talking with Navy personnel about using them for the underwater acoustic sensor network.  He is currently seeking funding to build underwater sensors.

 

Piecing Together Our Planet Pixel by Pixel

Read on UConn Today.

UConn researcher Chandi Witharana is using remote sensing as 'a virtual passport' to monitor vast expanses of land in remote areas, including the Arctic tundra. (Chandi Witharana)
UConn researcher Chandi Witharana is using remote sensing as ‘a virtual passport’ to monitor vast expanses of land in remote areas, including the Arctic tundra. (Torre Jorgenson, University of Alaska-Fairbanks)
At first glance, the high-resolution satellite images of the Arctic tundra look like the lacy skin of a cantaloupe melon. But this characteristic feature of the tundra is perfect for studying the rapidly changing landscape of the region using remote sensing technologies. (Chandi Witharana)
At first glance, the high-resolution satellite images of the Arctic tundra look like the lacy skin of a cantaloupe melon. But this characteristic feature of the tundra is perfect for studying the rapidly changing landscape of the region using remote sensing technologies. (Torre Jorgenson, University of Alaska-Fairbanks)

At first glance, the high-resolution images of the polygons look like the lacy skin of a cantaloupe melon – perhaps not what would be expected of images of the Arctic tundra. But this characteristic feature of the tundra is a perfect focus for remote sensing technologies and for studying the rapidly changing landscape of the region.

From the Antarctic to the Arctic and areas in between, Chandi Witharana is applying powerful remote sensing technology to study global problems.

Witharana, a visiting assistant professor in UConn’s Department of Natural Resources and the Environment, says remote sensing is “a virtual passport” to these remote areas, allowing him to carefully monitor the harsh landscape from his grizzly bear-free computer laboratory on campus.

He and his collaborators are currently mapping thousands of square meters of the Pan-Arctic, using satellite images to collect data. The images offer a resolution so powerful that anything larger than 30 centimeters can be imaged from space, enabling the researchers to study areas across the globe that would be difficult or impossible to survey otherwise.

For the Pan-Arctic project, satellite images are taken roughly every two days, over a massive stretch of land encompassing parts of Alaska, Canada, and Siberia.

Each point or pixel within each image is identified by its geographical location, using latitude and longitude, and this geo-referencing is used to mesh the data together using super computers. The researchers then compare various features between images taken over time, noting changes or trends.

In the Arctic tundra, the researchers are seeing degradation proceeding at an alarming rate.

“Previously it was thought that topography was fixed, needing millions of years to change,” says Witharana. “But this degradation is happening within the span of a decade.”

Without remote sensing technologies, collection of this type of data over such vast expanses of land would be cost-prohibitive, dangerous, and potentially impossible for humans to accomplish, since many areas are remote and cannot be reached even by helicopter.

A satellite image of a refugee camp. (Chanda Witharana)
A satellite image of a refugee camp. (Torre Jorgenson, University of Alaska-Fairbanks )

Remote sensing is also a vital tool for an entirely different kind of extreme – wars and their effects on civilian populations. Working with the United Nations, Witharana studied how people migrate under forced conditions, where refugee settlements are established, and the number of those affected.

Due to the chaos inherent in war, the only unbiased and accurate measures of refugee populations are those gathered using remote sensing, says Witharana. “You cannot trust any other source in conflict situations. It is not possible to report exact numbers from the ground.”

Witharana has not only used the technology for his own research, he has introduced it to K-12 STEM classrooms as part of the Next Generation Science Standards. Using their own virtual passports, students can apply tools like Google Earth and StreetView to go on virtual hikes, exploring the Antarctic landscape and areas such as Deception Island and Bailey Head, and study the penguin population.

After a little tweaking, Witharana says, the technology can become a valuable tool in gathering information about almost anything you are interested in. The possibilities are as vast as the landscapes surveyed.

“This is everyday science, it is artwork, and it is a rich educational tool.”

Witharana is also participating in UConn’s Metanoia on the Environment, and will be holding a satellite image gallery during the week of Earth Day. The gallery will present appealing patterns, shapes, colors, and textures of the natural and human-made landscape, as well as sentient views of forced migration, violence, and destruction triggered by autocracy, racial aggression, and ethnic tension. The intent is to prompt viewers to observe and recognize the beauty in the world, and to contemplate the role humans play in its shaping.

This project is funded by the National Science Foundation Arctic System Science Program Award # 1720875.

New Compound Helps Activate Cancer-Fighting T Cells

Read on UConn Today.

An illustration showing interactions between components of the AH10-7 compound (yellow), an immune system antigen presenting cell (gray) and an invariant natural killer T cell (green and blue) that spark activation of iNKT cells in “humanized” mice. (Image courtesy of Jose Gascon/UConn)
An illustration showing interactions between components of the AH10-7 compound (yellow), an immune system antigen-presenting cell (gray), and an invariant natural killer T cell (green and blue) that spark activation of iNKT cells in ‘humanized’ mice. (Image courtesy of Jose Gascon/UConn)
Researchers Amy Howell and José Gascón of the chemistry department discuss a molecular simulation on a laptop monitor in the academic wing of the Chemistry Building. (Sean Flynn/UConn Photo)
Researchers Amy Howell and José Gascón of the chemistry department discuss a molecular simulation on a laptop monitor in the academic wing of the Chemistry Building. (Sean Flynn/UConn Photo)

Invariant natural killer T (iNKT) cells are powerful weapons our body’s immune systems count on to fight infection and combat diseases like cancer, multiple sclerosis, and lupus. Finding ways to spark these potent cells into action could lead to more effective cancer treatments and vaccines.

While several chemical compounds have shown promise stimulating iNKT cells in mice, their ability to activate human iNKT cells has been limited.

Now, an international team of top immunologists, molecular biologists, and chemists led by University of Connecticut chemistry professor Amy Howell reports in Cell Chemical Biology the creation of a new compound that appears to have the properties researchers have been looking for.

The compound – a modified version of an earlier synthesized ligand – is highly effective in activating human iNKT cells. It is also selective – encouraging iNKT cells to release a specific set of proteins known as Th1 cytokines, which stimulate anti-tumor immunity.

One of the limitations of earlier compounds was their tendency to cause iNKT cells to release a rush of different cytokines. Some of the cytokines turned the body’s immune response on, while others turned it off. The conflicting cytokine activity hampered the compounds’ effectiveness.

The new compound – called AH10-7 – is uniquely structured so that does not happen.

“One of the goals in this field has been to identify compounds that elicit a more biased or selective response from iNKT cells, and we were able to incorporate features in AH10-7 that did that,” says Howell, who has been studying the role of glycolipids in modulating the human immune system for more than 20 years.

The robust study, years in the making, also applied advanced structural and 3-D computer modeling analysis to identify the underlying basis for the new compound’s success. These highly detailed insights into what is happening at the molecular level open up new paths for research and could lead to the development of even more effective compounds.

“We synthesized a new compound, demonstrated its effectiveness with biological data, and learned more about its interactions with proteins through X-ray crystallography and computational analysis,’’ says UConn associate professor of chemistry José Gascón, a specialist in quantum and molecular mechanics. “We are providing protocols so that other scientists can rationally design related molecules that elicit desired responses from iNKT cells.”

The molecular analysis helped validate and explain experimental results.

“By exposing a crystalized form of the molecular complex to a high-intensity X-ray beam at the Australian Synchrotron, we were able to obtain a detailed 3-D image of the molecular interplay between the invariant natural killer T cell receptor and AH10-7,” says corresponding author Jérôme Le Nours, a structural biologist with the Biomedicine Discovery Institute at Monash University in Australia. “This enabled us to identify the structural factors responsible for AH10-7’s potency in activating iNKT cells. This valuable insight could lead to the development of even more effective anti-metastatic ligands.”

Efforts to harness the therapeutic potential of human iNKT cells began 20 years ago with the discovery that natural and synthetic forms of glycolipid ligands known as alpha-galactosylceramides, or α-GalCers for short, were potent activators of iNKT cells. Scientists immediately recognized their possible value in fighting cancer and other diseases. These α-GalCer ligands serve as tiny dock masters in our immune system, helping antigen-presenting cells attract and bind with iNKT cells so they can be activated to kill cancerous cells or fight off pathogens and other foreign invaders.

Comparison of tumor suppression in the lungs of wild mice (top row) and 'humanized' mice (bottom row). First column represents untreated mice. Second column, mice treated with the KRN7000 synthesized compound. Third column, mice treated with the new compound AH10-7. Results show the newly synthesized compound AH10-7 is at least as effective as KRN7000 in suppressing growth of melanoma cells. (Images courtesy of Dr. Steven Porcelli and Weiming Yuan)
Comparison of tumor suppression in the lungs of wild mice (top row) and ‘humanized’ mice (bottom row). First column represents untreated mice. Second column, mice treated with the KRN7000 synthesized compound. Third column, mice treated with the new compound AH10-7. Results show the newly synthesized compound AH10-7 is at least as effective as KRN7000 in suppressing growth of melanoma cells. (Images courtesy of Dr. Steven Porcelli and Weiming Yuan)

The first promising version of a synthesized α-GalCer was a compound known as KRN7000. While KRN7000 powerfully stimulated iNKT cells in both mice and humans, it triggered the release of a flood of many types of cytokines, limiting its potential for clinical applications. Since then, researchers have been searching for new variations of KRN7000 that maintain their effectiveness in activating human iNKT cells while also favoring release of the powerful tumor fighting Th1 cytokines.

In the current study, Howell and colleagues made two significant modifications to an α-GalCer ligand in an attempt to make it more effective. They found that adding a hydrocinnamoyl ester on to the sugar stabilized the ligand and kept it close to the surface of the antigen-presenting cell, thereby enhancing its ability to dock with and stimulate human iNKT cells. In addition, trimming off part of the molecule’s sphingoid base appears to initiate the critical Th1 cytokine bias. Both changes, working in tandem, strengthened the effectiveness of the entire molecular complex in terms of activating human iNKT cells, Howell says.

To further validate AH10-7’s effectiveness, the researchers tested the new compound in wild mice as well as partially “humanized” mice, whose genomes were modified to mimic the human iNKT cell response. Notably, AH10-7 was shown to be at least as effective as KRN7000 in suppressing the growth of melanoma cells in the partially humanized mice.

Dr. Steven Porcelli, an immunologist with the Albert Einstein College of Medicine in N.Y., also served as a corresponding author on the study.

The research was supported in part by NIH grants U01 GM111849, R01 GM087136, R01 AI45889, and R01 AI 091987.

A complete list of the contributing researchers and funding resources for the study “Dual Modifications of α-Galatosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity” can be found here.

The Tragic Story of America’s Only Native Parrot

Read on UConn Today.

The last recorded Carolina parakeet (Conuropsis carolinensis) died nearly 100 years ago. (Wikimedia Commons)
The last recorded Carolina parakeet died nearly 100 years ago. Now, some scientists consider the Carolina parakeet one of the top candidates for ‘de-extinction.’ (Wikimedia Commons)

It was winter in upstate New York in 1780 in a rural town called Schoharie, home to the deeply religious Palatine Germans. Suddenly, a flock of gregarious red and green birds flew into town, seemingly upon a whirlwind.

The townspeople thought the end of the world was upon them. Though the robin-sized birds left quickly, their appearance was forever imprinted on local lore. As author Benjamin Smith Barton wrote, “The more ignorant Dutch settlers were exceedingly alarmed. They imagined, in dreadful consternation, that it portended nothing less calamitous than the destruction of the world.”

The history of the Carolina parakeet’s decline parallels the history of American growth over the course of the 19th century. All that prosperity came with many terrible costs.

You and I know that the birds weren’t a precursor of mankind’s demise – but in a way, there was impending doom ahead. These birds were Carolina parakeets, America’s only native parrot. Exactly 100 years ago this February, the last captive Carolina parakeet died, alone in a cage in the Cincinnati Zoo, the same zoo where the last captive passenger pigeon, named Martha, died four years earlier. The last “official” wild Carolina parakeet was spotted in Florida just two years later.

Why did these birds go extinct? It remains a mystery. Given that parrots today are at greater risk for extinction than other major bird groups, is there anything scientists can learn from the Carolina parakeet?

Unraveling parakeet mysteries

Over the past six years, I’ve been collecting information about where the Carolina parakeet was observed over the past 450 years.

I spent hours upon hours reading historical documents, travel diaries, and other writings, ranging from the 16th century all the way into the 1940s. I’ve often become lost in the stories surrounding these parrot observations – from the first accounts of Europeans exploring the New World, to the harrowing tales of settlers traveling the Oregon Trail in the 1800s, to grizzled egg hunters scouring the swamps of Florida in the early 1900s.

Conuropsis carolinensis (Linnaeus, 1758), the extinct Carolina parakeet, is on public display at the Field Museum of Natural History in Chicago, Illinois. (Wikimedia Commons)
Conuropsis carolinensis (Linnaeus, 1758), the extinct Carolina parakeet, on public display at the Field Museum of Natural History in Chicago, Illinois. (Wikimedia Commons)

I also dug through natural history museum collections, looking at what many would just see as just some old, dusty, creepy dead birds. But I see them differently: beautiful in their own way, each with a story to tell.

My goal was to unravel some of the lasting mysteries about the Carolina parakeet – like where it lived. Historically, people used to determine a species range by plotting the most extreme observations of that species on a map, drawing a polygon around them and called it a day. Because of this, people long thought Carolina parakeets lived from upstate New York all the way to Colorado and down to the Texas coast.

But birds are often seen in areas where they don’t normally go. For instance, the range of the snowy owl – like Hedwig of “Harry Potter” fame – doesn’t really extend all the way to Bermuda, though one was once spotted there.

What’s more, scientists don’t know what really drove these parakeets to extinction. Some thought it was habitat loss. Some thought it was hunting and trapping. Some thought disease. A few even thought it was competition with nonnative honey bees for tree cavities, where the parakeets would roost and nest.

Thanks to the data I compiled, as well as cutting-edge machine learning approaches to analyze those data, my colleagues and I were able to reconstruct the Carolina parakeets’ likely range and climate niche. It turned out to be much smaller than previously believed. Generally, their range extended from Nebraska east to Ohio, south to Louisiana and Texas. The eastern subspecies lived mostly along the southeastern coast from Alabama, through Florida, and up to Virginia.

We were also able to confirm the longstanding hypothesis that the parakeets in the northwest part of their range migrated southeast in the winter, to avoid the blistering cold of the Midwest.

Why it matters

John James Audubon's 'Carolina Parakeets.' (Wikimedia Commons)
John James Audubon’s ‘Carolina Parakeets.’ (Wikimedia Commons)

In a world that faces extinction on a scale not seen in the past 65 million years, some of you may wonder: Aren’t there more important things to study?

While this may seem rather minor, some scientists consider the Carolina parakeet one of the top candidates for “de-extinction.” That’s a process in which DNA is harvested from specimens and used to “resurrect” extinct species, not unlike “Jurassic Park” (but way less action and decidedly less Jeff Goldblum).

If someone were to spend millions of dollars doing all of the genetic and breeding work to bring back this species, or any other, how will they figure out where to release these birds? Given the effects of climate change, it’s no longer a given that scientists could release birds exactly where they used to be and expect them to flourish.

Whether or not de-extinction is a worthwhile use of conservation effort and money is another question, best answered by someone other than me. But this is just an example of one potential use of this type of research.

In many ways, the history of the Carolina parakeet’s decline parallels the history of American growth over the course of the 19th century. All that prosperity came with many terrible costs. As the U.S. expanded and remade the landscape to suit its needs, many native species lost out.

Today, parrots face a serious threat of extinction. Parrot diversity tends to be highest in areas around the world that are rapidly developing, much like the U.S. during the 19th century. So whatever lessons the Carolina parakeet can teach us may be crucial moving forward.

I continue to study Carolina parakeets, and other recently extinct species, in the effort to hear and relate these lessons. As cliche as it is to say, those who cannot remember the past are condemned to repeat it.

Originally published in The Conversation.

How Privacy Concerns Drive Website Business Models

Read on UConn Today.

Icon of Facebook, WhatsApp, and Messenger (Facebook's proprietary messaging app) alongside other social media apps on a Samsung Galaxy smartphone's touchscreen. (Erik Tham/Getty Images)
Limiting online privacy intrusion may be best accomplished through the invisible hand of the market itself, says business professor Ram Gopal. (Erik Tham/Getty Images)

As is evident with the current Facebook crisis, third parties pose a significant potential privacy risk to visitors. But Facebook is not the only website using them. The convenience of easy sign-ins with Google or Twitter accounts also results in immediate identification with third parties.

Currently, there is effectively no tracking of where your data goes, and no ability for a consumer to know what is done with their data.

Even before the Facebook data breach, a U.S. Senate report found that visits to online news sites may involve connecting with hundreds of other parties, and the “sheer volume of such activity makes it difficult for even the most vigilant consumer to control the data being collected or protect against its malicious use.”

If simply landing on a website can cause substantial and instantaneous sharing with third parties, this begs the question, “What’s going to limit this privacy intrusion?”

Regulatory organizations such as the Federal Trade Commission and the European Union are looking into policy enforcement strategies.

But an overlooked method of limiting this privacy intrusion is through the invisible hand of the market itself. Our work focuses on the possibility that websites dealing with visitors who are more concerned about their privacy will be faced with a market that curbs their behavior.

In a paper published in a recent issue of MIS Quarterly, we found that when visitor privacy concerns for a website are high relative to the competition, the website will have a smaller niche market of customers willing to pay high subscription prices in exchange for privacy protection.

We concentrated on two sources of income for websites: subscriptions and the sale of visitor data to third parties. A website using the subscription model needs a large base of visitors, but it can also sell visitor information in secondary markets through advertising or other third parties. Therefore, the website must strike a balance between subscription and third party monetization in this two-sided market.

An overlooked method of limiting this privacy intrusion is through the invisible hand of the market itself.

At the other extreme, a website facing low visitor privacy concerns can tap into a larger market of customers willing to exchange their personal information to access the website. We found that the website’s profits are highest when visitors have moderate privacy concerns – not too low and not too high – especially when the competition faces very high privacy concerns.

We also analyzed how the third party industry structure is impacted by visitor privacy concerns.

We found that higher visitor privacy concerns will result in the website using fewer third parties, and the result is a higher concentration in the third party market for that industry. Higher industry security requirements result in higher barriers to entry, which also increase the industry concentration of third parties.

These findings about the third party market corroborate the finding that third party concentration is higher in markets with high privacy concerns, such as healthcare. Ironically, in a concentrated market, the fewer – but more powerful – third parties collect data from manywebsites. These third parties gain a more comprehensive visitor profile, which has greater value, but also greater privacy risk to visitors.

In the wake of the Facebook data breach, it is evident that policymakers and regulatory organizations must monitor the third party market for potential privacy violations.

Additionally, requiring transparency with respect to the exact third parties and the types of data they are receiving would allow consumers to make better decisions regarding their privacy. Adding tracking features for consumers to see where their data goes beyond these third parties would create additional and potentially important transparency.

Currently, there is effectively no tracking of where your data goes, and no ability for a consumer to know what is done with their data.

Bones in All the Wrong Places

Read on UConn Today.

Skeleton of Harry Eastlack (1933-1973), who had a rare disorder called fibrodysplasia ossificans progressiva caused by a genetic mutation that transforms connective tissue, such as muscle, ligaments, and tendons, into bone, resulting in progressive fusion of all the joints in the skeletal system. (Memento Mütter Museum, under a Creative Commons License)
Skeleton of Harry Eastlack (1933-1973), who had a rare disorder called fibrodysplasia ossificans progressiva caused by a genetic mutation that transforms connective tissue, such as muscle, ligaments, and tendons, into bone, resulting in progressive fusion of all the joints in the skeletal system. (Memento Mütter Museum, under a Creative Commons License)

By the time he died in 1973, Harry Eastlack had two skeletons; the one he was born with, and the one that grew around it, gradually encasing him in a prison of his own bone. Forty-five years later, UConn researchers have shown in the Feb. 2, 2018 of Nature Communications that a certain type of cell is responsible for Eastlack’s disease. Their results could help others with this disease, as well as hint at why millions of people suffer from bony growths after sports and deep tissue injuries.

Fibrodysplasia ossificans progressiva (FOP) affects only 1 person in 2 million. It’s caused by a spontaneous mutation that affects only a single protein. But the effect is devastating.

“In FOP, the most mild injuries – a childhood vaccination, a bruise – triggers massive bone growth. And nothing can be done about it. It can’t be surgically removed, because that triggers more bone,” says UConn stem cell biologist David Goldhamer. “If bone grows across a joint, that joint locks, and it will never move again.” Inevitably, FOP sufferers grow more and more bone, slowly getting locked in this secondary skeleton. Many die in midlife, often of respiratory problems due to their inability to breathe well. Eastlack died at age 39 from pneumonia.

Goldhamer began studying FOP when he was at the University of Pennsylvania and a doctor who treated FOP patients approached him. What is special about muscle tissue, the doctor asked. Why does muscle give rise to these bony growths? After meeting FOP patients and their families, Goldhamer was inspired to use his expertise in muscle biology to address these questions. He has researched FOP ever since, and he finally has answers to the doctor’s questions.

A microCT picture of pseudocolored heterotopic ossification. (John B. Lees-Shepard, Michael J. Schneider Jr., and David J. Goldhamer/UConn Photo)

The mystery bone-making culprit, it turns out, isn’t related to muscle. Instead, it’s a type of cell called Fibro/Adipogenic Progenitors (FAPs). FAPs hang out in muscle tissue, but it’s not entirely clear what they do. No one had any idea they were capable of making cartilage and bone.

Goldhamer, post doc John Lees-Shepard, and assistant research professor Masakazu Yamamoto at UConn, as well as colleagues at the University of Michigan and Alexion Pharmaceuticals, examined FAPs with a mutation in the ACVR1 protein. University of Pennsylvania scientists had already identified the mutation as the cause of FOP. What Goldhamer and his colleague showed is what it does: it alters a single type of protein that acts as a receptor on the surface of FAP cells, and this mutant receptor somehow tells FAPs to develop into cartilage and bone at injury sites.

Now Goldhamer and his colleagues are trying to understand the basic biology of how and why the disease progresses, in the hopes that future FOP patients won’t meet the same fate as poor Harry Eastlack.