Search

It has been my great good fortune in this life to work, in different ways and at different times, with two extraordinary educators. I have known Pedro Noguera, now Dean of the Rossier School of Education at USC, for upwards of 30 years, since he was my undergraduate professor at UC Berkeley. I have known Michael Matsuda, Superintendent of the Anaheim Union High School District (AUHSD), since we initiatied a robust partnership for leadership preparation between our two institutions in 2018. In Hebrew, a shadchan is a matchmaker. When I read the call for this special issue of VUE, with its focus on schools as community institutions, I thought of them both. My role was mainly that of shadchan; I proposed the Conversations in Urban Educationersation to the two of them, and edited the published version into something comprehensible for a reader outside of the California context. Dean Noguera and Superintendent Matsuda had met before; on December 16, 2021, Noguera interviewed Matsuda via Zoom, and the district produced a transcript. That interview, edited for comprehension as well as flow, is provided below.Matsuda has served as the superintendent of AUHSD for eight years. It is a large, urban school district located in Orange County, not far from Disneyland. AUHSD is a majority minority school district that covers five cities, including Anaheim. The district enrolls over 29,000 students, and about 45 different languages are spoken by the families it serves. It is a gateway community that serves large numbers of refugee immigrants. Demographically, the district is predominantly Latin-X, (65%), with another 20% of its students from Asian and Pacific Islander backgrounds. The overwhelming majority of students are from low-income households, with a substantial number (approximately 4,000) who lack stable housing.

The dilemma of how to categorize and classify diseases has been debated for centuries. The field of medical genetics has historically approached nosology based on clinical phenotypes observed in patients and families. Advances in genomic sequencing and understanding of genetic contributions to disease often provoke a need to reassess these classifications. The Clinical Genome Resource (ClinGen) has developed frameworks to classify the strength of evidence underlying monogenic gene-disease relationships, variant pathogenicity, and clinical actionability. It is therefore necessary to define the disease entity being evaluated, which can be challenging for genes associated with multiple conditions and/or a broad phenotypic spectrum. We therefore developed criteria to guide "lumping and splitting" decisions and improve consistency in defining monogenic gene-disease relationships. Here, we outline the precuration process, the lumping and splitting guidelines with examples, and describe the implications for clinical diagnosis, informatics, and care management.

PURPOSESeveral groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease, and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed.METHODSThe GenCC drafted harmonized definitions for differing levels of gene-disease validity based on existing resources, and performed a modified Delphi survey with three rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members.RESULTSBased on 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contains 15,241 gene-disease assertions on 4,569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%.CONCLUSIONTerminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.

The discovery of BRCA1 and BRCA2 in the 1990s revolutionized the way we research and treat breast, ovarian, and pancreatic cancers. In the case of pancreatic cancers, germline mutations occur in about 10–20% of patients, with mutations in BRCA1 and BRCA2 being the most common. BRCA genes are critical in DNA repair pathways, particularly in homologous recombination, which has a serious impact on genomic stability and can contribute to cancerous cell proliferation. However, BRCA1 also plays a fundamental role in cell cycle checkpoint control, ubiquitination, control of gene expression, and chromatin remodeling, while BRCA2 also plays a role in transcription and immune system response. Therefore, mutations in these genes lead to multiple defects in cells that may be utilized when treating cancer. BRCA mutations seem to confer a prognostic benefit with an improved overall survival due to differing underlying biology. These mutations also appear to be a predictive marker, with patients showing increased sensitivity to certain treatments, such as platinum chemotherapy and PARP inhibitors. Olaparib is currently indicated for maintenance therapy in metastatic PDAC after induction with platinum-based chemotherapy. Resistance has been found to these therapies, and with a 10.8% five-year OS, novel therapies are desperately needed.

Vandetanib is a once-daily oral multikinase inhibitor that targets the rearranged during transfection (RET) tyrosine kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor. Among its observed toxicity profile is QT prolongation, diarrhea, and rash, including photosensitivity. This article presents 3 patients with photoinduced cutaneous side effects of vandetanib, including both photoallergic and phototoxic reactions. We review the spectrum of cutaneous photosensitivity reactions and the necessity of histopathologic evaluation to distinguish photoallergic and phototoxic reactions. Given its high prevalence of specifically photoinduced side effects and the variety of the histologic and clinical presentations, reinforcing attentive sun protection could potentially prevent dose reduction or drug cessation in patients treated with vandetanib.