Pathology News Highlights
New treatment path discovered at Yale for rare form of rickets
A new study from a team of clinicians and investigators from Yale and other institutions compared the response of patients with a severe form of rickets called ARHR2 treated with conventional therapy to that of mice treated with an enzyme replacement therapy. The replacement therapy was developed by Dr. Demetrios Braddock, Associate Professor of Pathology. The investigators found that while conventional therapy improved the rickets in ARHR2, it did not correct the underlying osteoporosis and also predisposed patients to increased renal calcifications. The finding was particularly worrisome in adolescents with the disease known to develop debilitating calcifications in their joints, arteries, and cardiovascular system as they entered early adulthood. In contrast, adding the enzyme therapy to the conventional therapy in a mouse model of ARHR2 eliminated histologic evidence of rickets, led to bigger and stronger bones, and eliminated the risk of increased renal calcifications induced by the conventional therapy. The study was published in the Jan. 19 edition of the Journal of Bone and Mineral Research.
ARHR2 is a rare but devastating disease resulting from deficiency in an enzyme called ‘ENPP1’ which regulates tissue mineralization. Half of the children born with homozygous ENPP1 deficiency will die within the first 6 months of life due to cardiac calcifications in a disease phase known as ‘Generalized Arterial Calcification of Infancy’ (GACI). The children who survive GACI may stabilize and improve, but soon develop a severe bone wasting disease due to elevation of a hormone called FGF23 which induces a phosphate wasting rickets called ‘Autosomal Recessive Hypophosphatemic Rickets Type-2’ (ARHR2). The phosphate wasting in ARHR2 is currently treated with phosphate replacement. While the treatment does improve the rickets, Braddock and his team were concerned that giving phosphate to patients predisposed to tissue calcification could pose risks to ARHR2 patients. They reached out to clinicians at the National Institutes of Health and the University of Hamburg who were treating these patients for additional information on the treatment response.
Braddock said: “The study could not have been performed without the close collaboration and involvement of the dedicated physicians treating patients with this severe disease. Their concern for their patients was evident in their enthusiasm and willingness to share their experiences and frustrations with us as we investigate alternative therapies to better address the disease pathogenesis.”
Researchers Develop a Mice Model to Identify and Study the Vascular Dynamics of CCM Lesions Leading to Cerebral Hemorrhage, Strokes, and Seizures
Yale researcher Huanjiao Jenny Zhou (Pathology) and additional School of Medicine researchers have established a Cerebral Cavernous Malformations (“CCM”) mice model which “identifies and uncovers the mechanism in which CCM3 mutation induced caveolae-Tie2 signaling contributes to CCM pathogenesis.”
Cerebral cavernous malformations (CCMs) are “vascular abnormalities which primarily occur in adulthood and lead to cerebral hemorrhage, stroke, and seizures.” CCMs can be initiated by an “endothelial cell (EC) loss of any one of the three Ccm genes: CCM1 (KRIT1), CCM2 (OSM), or CCM3 (PDCD10).”
Dr. Zhou and her research colleagues utilize mice “with a brain EC-speciﬁc deletion of Pdcd10 (Pdcd10BECKO)” which typically survive between 6-12 months. During this period, the mice develop bona ﬁde CCM lesions in all regions of their brain which allowed the research team to study the “vascular dynamics of CCM lesions by using transcranial two-photon microscopy.”
These researchers have not only created a CCM mice model which studies vascular abnormalities, but they have also identified “caveolae-mediated Tie2 receptor signaling in the presence of its ligand Angpt2 which can offer a therapeutic approach to treat CCM disease.”
Other members of the Yale research team include: Lingfeng Qin, Quan Jiang, Haifeng Zhang, Busu Li, Qun Lin, her collaborators Katie N. Murray, Jaime Grutzendler and Wang Min in the Program of Vascular Biology and Therapeutics, Departments of Pathology, Neurobiology and Cell Biology You can read more about this exciting research in the January 25th online edition of Nature Communications.
Yale and New Haven to begin saliva testing mini-program in New Haven learning hubs after fall term obstacles
After a months-long struggle, Yale researchers and New Haven officials are implementing a saliva testing program within some community spaces around the city, though not within New Haven’s public schools as researchers originally hoped. The Yale Pathology Lab will process the samples.
The testing program uses SalivaDx, an affordable and streamlined method of using saliva to test for the coronavirus that has gained national acclaim since its development at Yale. Yale researchers have secured grants and coordinated with the city to fund a testing program for adults working in some of the city’s learning hubs — spaces inside some city churches and recreation centers where small groups of students can take classes if they do not have internet, a safe and quiet environment or adequate nutrition at home.
The researchers developed SalivaDx to be an open-source, uncommercialized protocol, with no kit required, in an effort to make it accessible to labs across the country. They have extended the emergency use authorization to more than 96 labs in 35 different states.
Cancer Research Awards presented to Ranjit Bindra and Don Nguyen
Yale Pathologist Dr. Harold Sanchez discusses how autopsies have changed during COVID-19
Dr. Harold Sanchez, Assistant Professor in the Department of Pathology at Yale School of Medicine and a Pathologist for Yale Medicine, appeared on WTNH News 8 to tell about autopsies and what can be learned from them during the COVID-19 pandemic. He discusses how autopsies have changed during the pandemic and what role autopsies have had in giving doctors a better understanding of the damage that the virus can do.
View the video on WTNH.com [3:45 minutes]
National Women’s Hockey League partners with Yale on COVID-19 testing
The National Women’s Hockey League (NWHL) is working with Yale to provide saliva-based COVID-19 testing for players and staff during the upcoming season and Isobel Cup playoffs in Lake Placid, New York. The PCR viral RNA testing method — known as SalivaDirect — was developed by researchers at the Yale School of Public Health (YSPH). It was granted an emergency use authorization by the U.S. Food and Drug Administration after researchers performed clinical validation in collaboration with YSPH, Yale New Haven Hospital, and Yale Pathology Labs (YPL).
National Women’s Hockey League Partners with Yale on COVID-19 Testing
The National Women’s Hockey League (NWHL) is working with Yale to provide saliva-based COVID-19 testing for players and staff during the upcoming season and Isobel Cup Playoffs in Lake Placid.
“Yale Pathology Labs (YPL) was the first to offer SalivaDirect™ to the public and the National Women’s Hockey League is the first women’s professional sports league to implement SalivaDirect™ testing,” said Stephanie Weirsman, physician liaison for YPL. “The NWHL is proud to be working with Yale Pathology Labs,” said NWHL Commissioner Tyler Tumminia.
Additionally, NWHL and YPL are working jointly on a quality improvement initiative which involves obtaining paired saliva and nasal samples for NWHL players and staff for dual testing purposes. This dual testing is beneficial both to the NWHL players and staff who receive two concurrent results, as well as to the clinical lab which can provide additional data for the COVID-19 diagnostic molecular testing program.
High-Impact Publication in Journal “Cell”
In the article, “Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection”, Yale Pathology research members Qin Yan, Katerina Politi, Wesley Cai, Shang-Min Zhang, Fernando de Minguel, and Huacui Chen participated in characterization of the epigenetic regulators identified from a genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, MERS-CoV, bat coronavirus HKU5 expressing SARS-CoV-1 spike protein, or VSV expressing SARS-CoV-2 spike protein.
The research team has identified pro-viral host factors including epigenetic regulators (HMGB1, SWI/SNF, KDM6A, and JMJD6), and receptor ACE2 and protease Cathepsin L. They have demonstrated that HMGB1 regulates ACE2 expression, which is critical for the entry of coronaviruses SARS-CoV-2, SARS-CoV-1, and NL63. The team has also shown that “small molecule antagonists of identified gene” can inhibit the SARS-CoV-2 infection of both human and monkey cells.
In conclusion, the research teams’ above findings are critical for further understanding of the pathogenesis of SARS-CoV-2 and treatment of COVID-19.
Sacred Heart, University of Saint Joseph roll out saliva-based COVID-19 test for students, staff
The University of Saint Joseph in West Hartford began using the SalivaDirect testing method for COVID-19 this past Monday. On Tuesday, Sacred Heart University (Fairfield) also rolled out the testing. With rising concerns of possible outbreaks, the both universities aim to increase the number of students tested and with more rapid results.
SHU Moves to Saliva Testing for Covid-19
Sacred Heart University is now working with Yale to begin saliva-based COVID-19 testing beginning this week. The testing method SalivaDirectTM will be used. The method, less invasive and less expensive than nasal-swab testing, was developed by researchers at the Yale School of Public Health (YSPH). Clinical validation was performed in collaboration between YSPH, Yale-New Haven Hospital and Yale Pathology Labs (YPL). YPL is the first lab to offer SalivaDirectTM to the public, and Sacred Heart is among the first educational institutions to adopt SalivaDirectTM testing. "YPL’s Outreach Program is committed to bringing these standards of excellence to local communities and beyond,” says Angelique W. Levi, M.D., YPL Outreach director and associate professor of pathology.
Yale designates labs in three states to provide SalivaDirect™ COVID-19 test
Yale has designated three independent laboratories to perform the university-developed SalivaDirect™ COVID-19 test. Along with Yale Pathology Labs — the first to offer the test — Access Medical Laboratories, Hennepin County Medical Center (HCMC), and Mirimus, Inc., represent the initial wave of providers for the innovative testing method. They will make SalivaDirect™ available to people in Florida, Minnesota and New York by late September.
New COVID-19 testing process, SalivaDirect™ and receiving recent FDA authorization
Quick and affordable saliva-based COVID-19 test developed by Yale scientists receives FDA Emergency Use Authorization
The Pathology Clinical Molecular Diagnostic Lab, Directed by Dr. Pei Hui, has been authorized by FDA to test Covid-19 using saliva specimen as part of the FDA EUA, Led by Nate Grubaugh and Anne Wyllie from Yale School of Public Health. This lab would be the first laboratory to offer this test in the coming days. Congratulations to Dr. Pei Hui's leadership for this great achievement and thank the entire team for their efforts and contributions! This success represents an example of how our pathology clinical laboratory can closely collaborate with basic scientists to rapidly bring research to clinical diagnosis.
$15M NIDA Grant Awarded to Serena Spudich, Mark Gerstein, and Yuval Kluger
$15M NIDA Grant Awarded to Serena Spudich, Mark Gerstein, and Yuval Kluger
Principal Investigators Dr. Serena Spudich, MD, MA (Neurology), Dr. Mark Gerstein, PhD (Molecular Biophysics and Biochemistry), and Dr. Yuval Kluger, PhD (Pathology) were recently awarded a $15 million grant from the National Institute on Drug Abuse (NIDA) to establish a Data Center to coordinate, analyze, and make accessible single-cell and other molecular data sets generated by Single-Cell Opioid Responses in the Context of HIV (SCORCH) and other NIDA-funded HIV and substance use disorder projects. The grant will commence on August 1st, 2020 with a project period of five years. This prestigious award is for a multi-disciplinary proposal and will involve Principal Investigators and key personnel: Drs. Ya-Chi Ho, MD, PhD, MMS (Microbial Pathogenesis), Anita Huttner, MD (Pathology), Nenad Sestan, MD, PhD (Neuroscience), and Le Zhang, PhD (Neurology). According to the project narrative:
Opioid use disorder (OUD) and HIV infection can affect cognition and behavior both independently and in combination, but knowledge is limited regarding how brain cells and circuits are altered in association with these conditions. Furthermore, HIV can persist in the brain long term, though the precise cellular locations of HIV infection and whether this infection is worsened by coexistent OUD and HIV are also unknown. The work proposed in this application will help determine which cells and which areas of the brain are involved in these conditions separately and together, thus improving our understanding of the brain effects of OUD and HIV.