Faculty Bibliography

OBJECTIVES:This secondary analysis evaluated opioid-specific validation results of the Tobacco, Alcohol, Prescription Medication, and Other Substances (TAPS) tool for screening in primary care. METHODS:This study is a secondary data analysis of the TAPS validation study. Performance of the TAPS tool for screening for unhealthy opioid use (with a score of 1+ for heroin and/or prescription opioids representing a positive screen) was evaluated. Discriminative ability was examined in comparison with reference standard measures across the spectrum of unhealthy opioid use: timeline follow-back with and without oral fluid testing identifying past-month use and the modified Composite International Diagnostic Interview for past-year problem use, opioid use disorder (OUD), and moderate-severe OUD. RESULTS:In a sample of 2000 primary care patients, 114 screened positive for opioids on the TAPS tool. With a TAPS cutoff equal to 1+, the TAPS accurately identified past-month use, problem use, any OUD, and moderate-severe OUD (sensitivities = 68%-85%, specificities = 97%-98%, area under the curve = 0.80-0.91). When past-month use was expanded to include timeline follow-back with oral fluid testing, accuracy declined (52% sensitivity [95% confidence interval, 43%-60%], 98% specific [95% confidence interval, 97%-98%]). CONCLUSIONS:While further testing in a larger population sample may be warranted, given their brevity, simplicity, and accuracy when self-administered, the TAPS opioid items can be used in primary care settings for a spectrum of unhealthy opioid use; however, self-disclosure remains an issue in primary care settings.

SHP2 (PTPN11) acts upstream of SOS1/2 to enable RAS activation. Allosteric SHP2 inhibitors (SHP2i) in the clinic prevent SHP2 activation, block proliferation of RTK- or cycling RAS mutant-driven cancers, and overcome "adaptive resistance." To identify SHP2i resistance mechanisms, we performed genome-wide CRISPR/Cas9 knockout screens on two SHP2i-sensitive cell lines, recovering genes expected to cause resistance (NF1, PTEN, CDKN1B, LZTR1, and RASA2) and novel targets (INPPL1, MAP4K5, epigenetic modifiers). We screened 14 additional lines with a focused CRISPR library targeting common "hits" from the genome-wide screens. LZTR1 deletion conferred resistance in 12/14 lines, followed by MAP4K5 (8/14), SPRED2/STK40 (6/14), and INPPL1 (5/14). INPPL1, MAP4K5, or LZTR1 deletion reactivated ERK signaling. INPPL1-mediated sensitization to SHP2i required its NPXY motif but not lipid phosphatase activity. MAP4K5 acted upstream of MEK through a kinase-dependent target(s); LZTR1 had cell-dependent effects on RIT and RAS stability. INPPL1, MAP4K5, or LZTR1 deletion also conferred SHP2i resistance in vivo. Defining the SHP2i resistance landscape could suggest effective combination approaches.

OBJECTIVES:Behavioral health diagnoses are frequently underreported in administrative health data. For a pragmatic trial of a hospital addiction consult program, we sought to determine the sensitivity of Medicaid claims data for identifying patients with opioid use disorder (OUD). METHODS:A structured review of electronic health record (EHR) data was conducted to identify patients with OUD in 6 New York City public hospitals. Cases selected for review were adults admitted to medical/surgical inpatient units who received methadone or sublingual buprenorphine in the hospital. For cases with OUD based on EHR review, we searched for the hospitalization in Medicaid claims data and examined International Classification of Diseases, Tenth Revision discharge diagnosis codes to identify opioid diagnoses (OUD, opioid poisoning, or opioid-related adverse events). Sensitivity of Medicaid claims data for capturing OUD hospitalizations was calculated using EHR review findings as the reference standard measure. RESULTS:Among 552 cases with OUD based on EHR review, 465 (84.2%) were found in the Medicaid claims data, of which 418 (89.9%) had an opioid discharge diagnosis. Opioid diagnoses were the primary diagnosis in 49 cases (11.7%), whereas in the remainder, they were secondary diagnoses. CONCLUSION:In this sample of hospitalized patients receiving OUD medications, Medicaid claims seem to have good sensitivity for capturing opioid diagnoses. Although the sensitivity of claims data may vary, it can potentially be a valuable source of information about OUD patients.

During the initial COVID-19 surge, one public hospital in NYC updated their post-discharge outreach approach for patients with substance use disorder, as part of the CATCH (Consult for Addiction Treatment and Care in Hospitals) program. Beginning April 1, 2020, three peers and two addiction counselors attempted telephonic outreach to patients who received a CATCH consultation during hospitalization from program launch (October 7, 2019) through March 31, 2020 (n = 329). Outreach calls could include counseling, in-depth peer support, and referrals to substance use services (SUS)-a significant expansion of the services offered via outreach pre-pandemic. CATCH staff successfully reached 29.5% of patients and provided 77.6% of them with supportive counseling and referrals. Thirty percent of unsuccessful calls were due to inactive numbers, and only 8% of patients without housing were reached. Telephonic outreach established a low-barrier connection between patients and SUS that may be valuable during any period, including non-COVID times. Future interventions that address social determinants such as housing and cell phone access concomitantly with substance use should be considered by addiction consultation services to potentially reduce acute care utilization and improve health outcomes.

UNLABELLED:. Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE/CONCLUSIONS:tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

BACKGROUND:Patients presenting to emergency departments (EDs) after a nonfatal opioid-involved overdose are at high risk for future overdose and death. Responding to this risk, the New York City (NYC) Department of Health and Mental Hygiene operates the Relay initiative, which dispatches trained peer "Wellness Advocates" to meet patients in the ED after a suspected opioid-involved overdose and follow them for up to 90 days to provide support, education, referrals to treatment, and other resources using a harm reduction framework. METHODS:In this article, we describe the protocol for a multisite randomized controlled trial of Relay. Study participants are recruited from four NYC EDs and are randomized to receive the Relay intervention or site-directed care (the control arm). Outcomes are assessed through survey questionnaires conducted at 1-, 3-, and 6-months after the baseline visit, as well as through administrative health data. The primary outcome is the number of opioid-related adverse events, including any opioid-involved overdose or any other substance use-related ED visit, in the 12 months post-baseline. Secondary and exploratory outcomes will also be analyzed, as well as hypothesized mediators and moderators of Relay program effectiveness. CONCLUSION/CONCLUSIONS:We present the protocol for a multisite randomized controlled trial of a peer-delivered OD prevention intervention in EDs. We describe how the study was designed to minimize disruption to routine ED operations, and how the study was implemented and adapted during the COVID-19 pandemic. This trial is registered with ClinicalTrials.gov [NCT04317053].

TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.

Intracellular oncoproteins can be inhibited with targeted therapy, but responses are not durable. Immune therapies can be curative, but most oncogene-driven tumors are unresponsive to these agents. Fragments of intracellular oncoproteins can act as neoantigens presented by the major histocompatibility complex (MHC) but recognizing minimal differences between oncoproteins and their normal counterparts is challenging. We have established a platform technology that exploits hapten-peptide conjugates generated by covalent inhibitors to create distinct neoantigens that selectively mark cancer cells. Using the FDA-approved covalent inhibitors sotorasib and osimertinib, we developed "HapImmuneTM" antibodies that bind to drug-peptide conjugate/MHC complexes but not to the free drugs. A HapImmuneTM-based bispecific T cell engager selectively and potently kills sotorasib-resistant lung cancer cells upon sotorasib treatment. Notably, it is effective against KRASG12C mutant cells with different HLA supertypes, HLA-A*02 and A*03/11, suggesting loosening of MHC restriction. Our strategy creates targetable neoantigens by design, unifying targeted and immune therapies.

Background: Despite considerable efforts devoted to the development of prevention interventions aiming at reducing unhealthy alcohol use in tertiary students, their delivery remains often challenging. Interventions including information technology are promising given their potential to reach large parts of the population. Objective: This study aims to develop a secondary prevention smartphone app with an iterative qualitative design involving the target population. Methods: The app development process included testing a first prototype and a second prototype, developed based on the results of 2 consecutive qualitative assessments. Participants (aged ≥18 years, screened positive for unhealthy alcohol use) were students from 4 tertiary education institutions in the French-speaking part of Switzerland. Participants tested prototype 1 or prototype 2 or both and provided feedback in 1-to-1 semistructured interviews after 2-3 weeks of testing. Results: The mean age of the participants was 23.3 years. A total of 9 students (4/9 female) tested prototype 1 and participated in qualitative interviews. A total of 11 students (6/11 female) tested prototype 2 (6 who tested prototype 1 and 5 new) and participated in semistructured interviews. Content analysis identified 6 main themes: "General Acceptance of the App," "Importance of the Targeted and Relevant App Content," "Importance of Credibility," "Importance of the App Usability," "Importance of a Simple and Attractive Design," "Importance of Notifications to Ensure App Use over Time." Besides a general acceptance of the app, these themes reflected participants"™ recommendations toward increased usability; to improve the design; to include useful and rewarding contents; to make the app look serious and credible; and to add notifications to ensure its use over time. A total of 11 students tested prototype 2 (6 who tested prototype 1 and 5 new) and participated in semistructured interviews. The 6 same themes emerged from the analysis. Participants from phase 1 generally found the design and content of the app improved. Conclusions: Students recommend prevention smartphone apps to be easy to use, useful, rewarding, serious, and credible. These findings may be important to consider when developing prevention smartphone apps to increase the likelihood of app use over time.

BACKGROUND:Despite high rates of substance use among justice-involved populations, the use of substance screening tools in justice settings varies. METHODS:Data are from the National Jail Health Care Study, which surveyed jails across the U.S. about their health care practices (n=371). Jails were asked to voluntarily submit their medical intake forms. A content analysis of intake forms (n=63) specific to questions about substance use was completed. RESULTS:Seventy-three percent (73%) of intake forms used non-standardized questions to assess current substance use, and 27% did not ask any questions about substance use. Alcohol use was most assessed (52%), followed by tobacco (30%), and marijuana (22%). Less than 11% of jails asked about use of opioids and 40% of forms asked about withdrawal history. CONCLUSIONS:The lack of adequate substance use screening in jails hinders identification of substance use disorders, potential for withdrawal symptoms, and appropriate connection to treatment resources.