A novel IgE antibody targeting the prostate-specific antigen as a potential prostate cancer therapy

Prostate cancer (PCa) is the second leading cause of cancer deaths in men in the United States. The prostate-specific antigen (PSA), often found at high levels in the serum of PCa patients, has been used as a marker for PCa detection and as a target of immunotherapy. The murine IgG1 monoclonal antibody AR47.47, specific for human PSA, has been shown to enhance antigen presentation by human dendritic cells and induce both CD4 andCD8 T-cell activation when complexed with PSA. In this study, we explored the properties of a novel mouse/human chimeric anti-PSA IgE containing the variable regions of AR47.47 as a potential therapy for PCa. Our goal was to take advantage of the unique properties of IgE in order to trigger immune activation against PCa.Fil: Daniels-Wells, Tracy R. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Helguera, Gustavo Fernando. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Departamento de Tecnologia Farmaceutica; Argentina; University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Leuchter, Richard K. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Quintero, Rafael. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Kozman, Maggie. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Rodríguez, José A.. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América; University of California. The Molecular Biology Institute; Estados Unidos de América;Fil: Ortiz-Sánchez, E. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América; Biomedical Research in Cancer. Basic Research Division. National Institute of Cancerology; Mexico.;Fil: Martínez-Maza, Otonel. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Schultes, Brigit C.. Advanced Immune Therapeutics; Estados Unidos de América;Fil: Nicodemus Christopher. Advanced Immune Therapeutics; Estados Unidos de América;Fil: Penichet, Manuel. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América; University of California. The Molecular Biology Institute; Estados Unidos de América

Targeting HER2/neu with a fully human IgE to harness the allergic reaction against cancer cells

Breast and ovarian cancer are two of the leading causes of cancer deaths among women in the United States. Overexpression of the HER2/neu oncoprotein has been reported in patients affected with breast and ovarian cancers, and is associated with poor prognosis. To develop a novel targeted therapy for HER2/neu expressing tumors, we have constructed a fully human IgE with the variable regions of the scFv C6MH3-B1 specific for HER2/neu. This antibody was expressed in murine myeloma cells and was properly assembled and secreted. The Fc region of this antibody triggers in vitro degranulation of rat basophilic cells expressing human FcεRI (RBL SX-38) in the presence of murine mammary carcinoma cells that express human HER2/neu (D2F2/E2), but not the shed (soluble) antigen (ECDHER2) alone. This IgE is also capable of inducing passive cutaneous anaphylaxis in a human FcεRIα transgenic mouse model, in the presence of a cross-linking antibody, but not in the presence of soluble ECDHER2. Additionally, IgE enhances antigen presentation in human dendritic cells and facilitates cross-priming, suggesting that the antibody is able to stimulate a secondary T-cell anti-tumor response. Furthermore, we show that this IgE significantly prolongs survival of human FcεRIα transgenic mice bearing D2F2/E2 tumors. We also report that the anti-HER2/neu IgE is well tolerated in a preliminary study conducted in Macaca fascicularis (cynomolgus) monkeys. In summary, our results suggest that this IgE should be further explored as a potential therapeutic against HER2/neu overexpressing tumors, such as breast and ovarian cancers.Fil: Daniels, Tracy R.. University of California at Los Angeles; Estados UnidosFil: Leuchter, Richard K.. University of California at Los Angeles; Estados UnidosFil: Quintero, Rafaela. University of California; Estados UnidosFil: Helguera, Gustavo Fernando. University of California at Los Angeles; Estados Unidos. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rodríguez, José A.. University of California at Los Angeles; Estados UnidosFil: Martínez Maza, Otoniel. University of California at Los Angeles; Estados UnidosFil: Schultes, Birgit C.. Advanced Immune Therapeutics, Inc.; Estados Unidos. Momenta Pharmaceuticals, Inc.; Estados UnidosFil: Nicodemus, Christopher F.. Advanced Immune Therapeutics, Inc.; Estados UnidosFil: Penichet, Manuel L.. University of California at Los Angeles; Estados Unido

Relationship between exercise intensity and stress levels among U.S. medical students.

BackgroundPhysical activity may protect the mental health of medical students, yet it is unknown which types and intensities of physical activity have the greatest potential to improve medical student well-being.ObjectiveWe characterize the relationship between exercise intensity and stress levels of U.S. medical students, thereby informing the design of future well-being interventions.DesignTwo cross-sectional validated surveys assessing stress and physical activity were administered one year apart at the David Geffen School of Medicine at UCLA. A total of 1,046 out of 1,392 medical students responded (75%). An ordered logistic regression was used to determine the association between stress and each level of exercise intensity (inactivity, moderate-activity, and health-enhancing physical activity [HEPA]). These exercise intensity groupings were compared to the CDC guidelines for aerobic exercise.ResultsWhile achieving either moderate-activity or HEPA is compliant with the CDC guidelines for aerobic exercise, the additional intensity of exercise required to achieve HEPA was associated with a 26% increase in the probability of being in the lowest stress quartile and a 22% decrease in the probability of being in the highest stress quartile. Medical student physical activity levels were on-par with the national average per the CDC exercise guidelines (65% vs. 58%), but medical student HEPA levels were significantly lower than the national average (27% vs. 64%; OR 0.21; 95% CI 0.12-0.37).ConclusionsThere is a large disparity in rates of the highest intensity physical activity (HEPA) between medical students and the age-adjusted national average, which has previously been overlooked by the binary CDC exercise guidelines. The fact that HEPA levels are not optimized and more strongly associated with lower stress levels relative to less intense forms of exercise makes it a promising new target for future well-being interventions among medical trainees

Examining the role of COVID-19 testing availability on intention to isolate: A Randomized hypothetical scenario.

BackgroundLittle information exists on how COVID-19 testing influences intentions to engage in risky behavior. Understanding the behavioral effects of diagnostic testing may highlight the role of adequate testing on controlling viral transmission. In order to evaluate these effects, simulated scenarios were conducted evaluating participant intentions to self-isolate based on COVID-19 diagnostic testing availability and results.MethodsParticipants from the United States were recruited through an online survey platform (Amazon Mechanical Turk) and randomized to one of three hypothetical scenarios. Each scenario asked participants to imagine having symptoms consistent with COVID-19 along with a clinical diagnosis from their physician. However, scenarios differed in either testing availability (testing available v. unavailable) or testing result (positive v. negative test). The primary outcome was intention to engage in high-risk COVID-19 behaviors, measured using an 11-item mean score (range 1-7) that was pre-registered prior to data collection. Multi-variable linear regression was used to compare the mean composite scores between conditions. The randomized survey was conducted between July 23rd to July 29th, 2020.ResultsA total of 1400 participants were recruited through a national, online, opt-in survey. Out of 1194 respondents (41.6% male, 58.4% female) with a median age of 38.5 years, participants who had no testing available in their clinical scenario showed significantly greater intentions to engage in behavior facilitating COVID-19 transmission compared to those who received a positive confirmatory test result scenario (mean absolute difference (SE): 0.14 (0.06), P = 0.016), equating to an 11.1% increase in mean score risky behavior intentions. Intention to engage in behaviors that can spread COVID-19 were also positively associated with male gender, poor health status, and Republican party affiliation.ConclusionTesting availability appears to play an independent role in influencing behaviors facilitating COVID-19 transmission. Such findings shed light on the possible negative externalities of testing unavailability.Trial registrationEffect of Availability of COVID-19 Testing on Choice to Isolate and Socially Distance, NCT04459520, https://clinicaltrials.gov/ct2/show/NCT04459520

Racial Disparities in Potentially Avoidable Hospitalizations During the COVID-19 Pandemic.

IntroductionPotentially avoidable hospitalizations are disproportionately experienced by racial and ethnic minorities and expose these groups to unnecessary iatrogenic harm (including the risk of nosocomial COVID-19) and undue financial burden. In working toward an overarching goal of eliminating racial and ethnic health disparities, it is important to understand whether and to what extent potentially avoidable hospitalizations have changed by race and ethnicity during the COVID-19 pandemic.MethodsThis single-center pre-post study included patients admitted to any UCLA Health hospital for an ambulatory care-sensitive condition between March-August 2019 (prepandemic period) and March-August 2020 (postpandemic period). Investigators measured the change in the number of potentially avoidable hospitalizations (defined per the Agency for Healthcare Research and Quality guidelines) stratified by race and ethnicity and calculated the 95% CIs for these hospitalizations using a cluster bootstrap procedure.ResultsBetween March 1, 2020 and August 31, 2020, 347 of 4,838 hospitalizations (7.2%) were potentially avoidable, compared with 557 of 6,248 (8.9%) during the same 6-month period in 2019. Potentially avoidable hospitalizations decreased by 50.3% (95% CI=41.2, 60.9) among non-Hispanic Whites but only by 8.0% (95% CI= -16.2, 39.9) among African Americans (50.3% vs 8.0%, p=0.015).ConclusionsRacial disparities in potentially avoidable hospitalizations increased during the COVID-19 pandemic at a large urban health system. Given that the prepandemic rates of potentially avoidable hospitalizations were already higher among racial and ethnic minorities, especially among African Americans, this finding should cause alarm and lead to further exploration of the complex factors contributing to these disparities

Accelerated rejection, thrombosis, and graft failure with angiotensin II type 1 receptor antibodies.

BackgroundAngiotensin II type 1 receptor antibodies (AT1R-Abs) have been implicated in renal transplant rejection and failure; however, the mechanism of allograft damage, patterns of clinical presentation, and response to desensitization of AT1R-Abs have not been clearly established.Case diagnosis/treatmentWe present the case of a 7-year-old boy with preformed AT1R-Abs who developed accelerated vascular and cellular rejection and renal allograft thrombosis despite desensitization and treatment with angiotensin receptor blockade. Although an association between AT1R-Abs and microvascular occlusion has been previously described, we are the first to describe an association between AT1R-Abs and renal artery thrombosis, leading to devastating early allograft failure.ConclusionsThis case highlights the risk of allograft thrombosis associated with AT1R-Abs and illustrates that previous treatments utilized for AT1R-Abs may not always be effective. Further studies are needed to better characterize the mechanisms of AT1R-Ab pathogenesis and to establish safe levels of AT1R-Abs both pre- and post-transplantation. Given the outcome of this patient and the evidence of pro-coagulatory effects of AT1R-Abs, we suggest that the presence of AT1R-Ab may be a risk factor for thrombosis. The role of treatment with anti-coagulation and novel immunomodulatory agents such as tocilizumab and bortezomib require further investigation

Association Between In-Person vs Telehealth Follow-up and Rates of Repeated Hospital Visits Among Patients Seen in the Emergency Department

ImportanceFor patients discharged from the emergency department (ED), timely outpatient in-person follow-up is associated with improved mortality, but the effectiveness of telehealth as follow-up modality is unknown.ObjectiveTo evaluate whether the rates of ED return visits and hospitalization differ between patients who obtain in-person vs telehealth encounters for post-ED follow-up care.Design, setting, and participantsThis retrospective cohort study included adult patients who presented to either of 2 in-system EDs of a single integrated urban academic health system from April 1, 2020, to September 30, 2021; were discharged home; and obtained a follow-up appointment with a primary care physician within 14 days of their index ED visit (15 total days).ExposuresIn-person vs telehealth post-ED discharge follow-up within 14 days.Main outcomes and measuresMultivariable logistic regression was used to estimate the odds of ED return visits (primary outcome) or hospitalization (secondary outcome) within 30 days of an ED visit based on the modality of post-ED discharge follow-up. Models were adjusted for age, sex, primary language, race, ethnicity, Social Vulnerability Index, insurance type, distance to the ED, ambulatory billing codes for the index visit, and the time from ED discharge to follow-up.ResultsOverall, 12 848 patients with 16 987 ED encounters (mean [SD] age, 53 [20] years; 9714 [57%] women; 2009 [12%] Black or African American; 3806 [22%] Hispanic or Latinx; and 9858 [58%] White) were included; 11 818 (70%) obtained in-person follow-up, and 5169 (30%) obtained telehealth follow-up. Overall, 2802 initial ED encounters (17%) led to returns to the ED, and 676 (4%) led to subsequent hospitalization. In adjusted analyses, telehealth vs in-person follow-up visits were associated with increased rates of ED returns (28.3 [95% CI, 11.3-45.3] more ED returns per 1000 encounters) and hospitalizations (10.6 [95% CI, 2.9-18.3] more hospitalizations per 1000 encounters).Conclusions and relevanceIn this cohort study of patients in an urban integrated health care system, those with telehealth follow-up visits after an ED encounter were more likely to return to the ED and be hospitalized than patients with in-person follow-up. The use of telehealth warrants further evaluation to examine its effectiveness as a modality for continuing care after an initial ED presentation for acute illness

Embedding research study recruitment within the patient portal preCheck-in.

ObjectivePatient portals are increasingly used to recruit patients in research studies, but communication response rates remain low without tactics such as financial incentives or manual outreach. We evaluated a new method of study enrollment by embedding a study information sheet and HIPAA authorization form (HAF) into the patient portal preCheck-in (where patients report basic information like allergies).Materials and methodsEligible patients who enrolled received an after-visit patient-reported outcomes survey through the patient portal. No additional recruitment/messaging efforts were made.ResultsA total of 386 of 843 patients completed preCheck-in, 308 of whom signed the HAF and enrolled in the study (37% enrollment rate). Of 93 patients who were eligible to receive the after-visit survey, 45 completed it (48% completion rate).ConclusionEnrollment and survey completion rates were higher than what is typically seen with recruitment by patient portal messaging, suggesting that preCheck-in recruitment can enhance research study recruitment and warrants further investigation

Choosing Wisely interventions to reduce antibiotic overuse in the safety net.

ObjectivesPhysician pay-for-performance (P4P) programs frequently target inappropriate antibiotics. Yet little is known about P4P programs' effects on antibiotic prescribing among safety-net populations at risk for unintended harms from reducing care. We evaluated effects of P4P-motivated interventions to reduce antibiotic prescriptions for safety-net patients with acute respiratory tract infections (ARTIs).Study designInterrupted time series.MethodsA nonrandomized intervention (5/28/2015-2/1/2018) was conducted at 2 large academic safety-net hospitals: Los Angeles County+University of Southern California (LAC+USC) and Olive View-UCLA (OV-UCLA). In response to California's 2016 P4P program to reduce antibiotics for acute bronchitis, 5 staggered Choosing Wisely-based interventions were launched in combination: audit and feedback, clinician education, suggested alternatives, procalcitonin, and public commitment. We also assessed 5 unintended effects: reductions in Healthcare Effectiveness Data and Information Set (HEDIS)-appropriate prescribing, diagnosis shifting, substituting antibiotics with steroids, increasing antibiotics for ARTIs not penalized by the P4P program, and inappropriate withholding of antibiotics.ResultsAmong 3583 consecutive patients with ARTIs, mean antibiotic prescribing rates for ARTIs decreased from 35.9% to 22.9% (odds ratio [OR], 0.60; 95% CI, 0.39-0.93) at LAC+USC and from 48.7% to 27.3% (OR, 0.81; 95% CI, 0.70-0.93) at OV-UCLA after the intervention. HEDIS-inappropriate prescribing rates decreased from 28.9% to 19.7% (OR, 0.69; 95% CI, 0.39-1.21) at LAC+USC and from 40.9% to 12.5% (OR, 0.72; 95% CI, 0.59-0.88) at OV-UCLA. There was no evidence of unintended consequences.ConclusionsThese real-world multicomponent interventions responding to P4P incentives were associated with substantial reductions in antibiotic prescriptions for ARTIs in 2 safety-net health systems without unintended harms