Pathology News Highlights

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.”

access Journal article here

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.

access journal article here

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.

read the full article in the Yale Daily

The Class of 1961 Cancer Research Awards were presented to Ranjit Bindra, MD, PhD, Professor Therapeutic Radiology and Don Nguyen, PhD, Associate Professor of Pathology and Medicine (Medical Oncology). They were honored for their significant accomplishments in cancer research at Yale University as members of the faculty, coupled with the expectation for future outstanding contributions to the cause of cancer and the development of novel cancer treatments.

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]

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).

read Yale News article here

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.

read full press release here

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.

access journal article here