Faculty Bibliography

Synthetic binding proteins are human-made binding proteins that use non-antibody proteins as the starting scaffold. Molecular display technologies, such as phage display, enable the construction of large combinatorial libraries and their efficient sorting and, thus, are crucial for the development of synthetic binding proteins. Monobodies are the founding system of a set of synthetic binding proteins based on the fibronectin type III (FN3) domain. Since the original report in 1998, the monobody and related FN3-based systems have steadily been refined, and current methods are capable of rapidly generating potent and selective binding molecules to even challenging targets. The FN3 domain is small (∼90 amino acids) and autonomous and is structurally similar to the conventional immunoglobulin (Ig) domain. Unlike the Ig domain, however, the FN3 lacks a disulfide bond but is highly stable. These attributes of FN3 present unique opportunities and challenges in the design of phage and other display systems, combinatorial libraries, and library sorting strategies. This article reviews key technological innovations in the establishment of our monobody development pipeline, with an emphasis on phage display methodology. These give insights into the molecular mechanisms underlying molecular display technologies and protein-protein interactions, which should be broadly applicable to diverse systems intended for generating high-performance binding proteins.

Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a pre-clinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC.

In the United States, it is estimated that 0.3% of Americans aged 65 and older, or almost 172,000 individuals, identify as transgender. Aging comes with a unique set of challenges and experiences for this population, including health care disparities, mental health concerns, and social isolation. It is crucial for clinicians to use a patient-centered and trauma-informed care approach to address their specific needs and provide evidence-based quality health care, including preventive screenings, mental health support, and advocating for legal protections.

WHAT IS THIS SUMMARY ABOUT?/UNASSIGNED:in October 2023. The study goal was to learn whether nivolumab works as an adjuvant therapy (that is, helps to keep cancer from coming back when it is given after surgery) for stage 2 melanoma (skin cancer) that has not spread to other parts of the body. Nivolumab is an immunotherapy that activates a person's immune system so it can destroy cancer cells. In melanoma, staging describes the severity of the cancer. Melanoma staging ranges from 0 (very thin and confined to the upper layer of the skin) to 4 (spread to distant parts of the body), with earlier stages removed by surgery. The people in this study had stage 2 melanoma that had not spread to the lymph nodes or other organs in the body. HOW WAS THE STUDY DESIGNED?/UNASSIGNED:People 12 years and older with stage 2 melanoma that had not spread and had been removed by surgery were included in CheckMate 76K. People were randomly assigned to receive either nivolumab (526 patients) or placebo (264 patients). A placebo resembles the test medicine but does not contain any active medicines. The researchers assessed whether people who received nivolumab lived longer without their cancer returning and/or spreading to other parts of their bodies (compared with placebo) and if nivolumab was well tolerated. WHAT WERE THE RESULTS?/UNASSIGNED:Researchers found that people who received nivolumab were 58% less likely to have their cancer return and 53% less likely of having their cancer spread to distant parts of their body, compared with placebo. These reductions in risk with nivolumab were seen in different subgroups of people with a range of characteristics, and regardless of how deep the melanoma had gone into the skin. People taking nivolumab had more side effects than those taking placebo, but most were mild to moderate and manageable. WHAT DO THE RESULTS MEAN?/UNASSIGNED:Results from CheckMate 76K support the benefit of using nivolumab as a treatment option for people with stage 2 melanoma post-surgery.

BACKGROUND:Currently, only about half of U.S. adults achieve current physical activity guidelines. Routine physical activity is not regularly assessed, nor are patients routinely counseled by their health care provider on achieving recommended levels. The three-question physical activity vital sign (PAVS) was developed to assess physical activity duration and intensity and identify adults not meeting physical activity guidelines. Clinical decision support provided via a best practice advisory in an electronic health record (EHR) system can be triggered as a prompt, reminding health care providers to implement the best practice intervention when appropriate. Remote patient monitoring of physical activity can provide objective data in the EHR. OBJECTIVES/OBJECTIVE:This study aimed to evaluate the feasibility and clinical utility of embedding the PAVS and a triggered best practice advisor into the EHR in an ambulatory preventive cardiology practice setting to alert providers to patients reporting low physical activity and prompt health care providers to counsel these patients as needed. METHODS:Three components based in the EHR were integrated for the purpose of this study: patients completed the PAVS through their electronic patient portal prior to an office visit; a best practice advisory was created to prompt providers to counsel patients who reported low levels of physical activity; and remote patient monitoring via Fitbit synced to the EHR provided objective physical activity data. The intervention was pilot-tested in the Epic EHR for 1 year (July 1, 2021-June 30, 2022). Qualitative feedback on the intervention from both providers and patients was obtained at the completion of the study. RESULTS:Monthly assessments of the use of the PAVS and best practice advisory and remote patient monitoring were completed. Patients' completion of the PAVS varied from 35% to 48% per month. The best practice advisory was signed by providers between 2% and 65% and was acknowledged by 2% to 22% per month. The majority (58%) of patients were able to sync a Fitbit device to their EHR for remote monitoring. DISCUSSION/CONCLUSIONS:Although uptake of each component needs improvement, this pilot demonstrated the feasibility of incorporating a PA promotion intervention into the EHR. Qualitative feedback provided guidance for future implementation.

BACKGROUND:There is interest in reshaping the Supplemental Nutrition Assistance Program (SNAP) to better support family nutrition. OBJECTIVE:The Grocery Assistance Program Study (GAPS) for Families evaluated the effects of prohibiting the purchase of certain sugary foods using program funds on the nutritional quality of foods purchased and consumed by program participants. DESIGN/METHODS:A randomized experimental trial was carried out with participants randomized to one of three food benefit conditions. Baseline and follow-up measures collected included interviewer administered 24-hour dietary recalls, food purchase receipts, food security, height, and weight. PARTICIPANT/SETTING/UNASSIGNED:Adult-child dyads in households eligible for SNAP but currently not enrolled were recruited from the Minneapolis/St Paul MN metropolitan area from May of 2018 through May of 2019. A total of 293 adult-child dyads received the intervention as allocated. Of these dyads, 233 adults completed follow-up measures and met criteria for inclusion in the analytic sample, resulting in an attrition rate of 20.5%. For children, a total of 224 completed follow-up measures and met criteria for inclusion in the analytic sample, resulting in an attrition rate of 23.5%. INTERVENTION/METHODS:Participants were randomized to one of three conditions: restriction (not allowed to buy sugar sweetened beverages [SSB], sweet baked goods or candy with program funds); restriction paired with incentive (30% incentive for fruits and vegetables [FV] purchased with funds); and control (funds provided with no restrictions or incentives). Funds were provided on a four-week cycle for 20 weeks via a study provided debit card. MAIN OUTCOME MEASURES/METHODS:The primary outcome was the Healthy Eating Index (HEI)-2015 total score. Additional outcomes included selected HEI-2015 component scores; energy intake; food security; body weight; and purchasing of SSB, sweet baked goods, candies, fruits, and vegetables. STATISTICAL ANALYSIS/METHODS:Linear regression analyses were conducted with change in the outcome regressed on treatment condition for the primary outcome analyses. RESULTS:There were no differences observed between conditions in change in the nutrition and food security measures examined. Purchases of SSB and sweet baked goods and candies significantly differed by experimental condition. Purchase of restricted foods was lower at follow-up in the restriction and restriction paired with incentive conditions compared to the control condition. For example, spending on SSB at follow-up was significantly lower in the restriction ($2.66/week) and restriction paired with incentive ($2.06/week) conditions in comparison to control condition ($4.44/week) (p<.0003 and p<.0001 respectively). CONCLUSIONS:This study failed to find evidence in support of prohibiting the purchase of sugary foods with food program funds as a strategy to improve program participant nutrition, even when paired with a FV incentive. Research carried out in the context of the SNAP program is needed for a more robust evidence base.

IMPORTANCE/UNASSIGNED:Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. OBJECTIVE/UNASSIGNED:To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. EXPOSURE/UNASSIGNED:Skin biopsy for detection of phosphorylated α-synuclein. MAIN OUTCOMES/UNASSIGNED:Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. RESULTS/UNASSIGNED:Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.