Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor.

Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34+ humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies. SIGNIFICANCE: We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach. See related commentary by Capparelli and Aplin, p. 1413. This article is highlighted in the In This Issue feature, p. 1397.

Educational Outcomes of a 4-Year MD-MPH Dual-Degree Program: High Completion Rates and Higher Likelihood of Primary Care Residency.

PURPOSE: In 2007, University of Texas Health Science Center Houston School of Public Health at San Antonio (UTHealth SPH) and UT Health San Antonio Long School of Medicine (LSOM) designed and implemented a 4-year dual MD and Master of Public Health (MPH) program. Dual MD-MPH programs wherein students can receive both degrees within 4 years are unique, and programmatic evaluation may have generalizable implications for accredited MD-MPH programs. METHOD: Demographic information was collected from UTHealth SPH and LSOM student data. The primary outcome variable was MD-MPH program completion in 4 years. Comprehensive Basic Science Examination (CBSE) scores, United States Medical Licensing Examination Step 1 and Step 2 scores, and successful primary care residency match data were compared between MD-MPH and MD-only students. Family medicine, internal medicine, obstetrics-gynecology, and pediatrics were considered primary care residencies, and an analysis excluding obstetrics-gynecology was also conducted. RESULTS: Of 241 MD-MPH students enrolled 2007-2017, 66% were women, 22% Hispanic, and 10% African American. Four-year MD-MPH program completion occurred for 202 (93% of eligible) students; 9 (4.1%) received MD only, 3 (1.4%) received MPH only; and 4 (1.8%) received neither. MD-MPH students' median CBSE score was 2 points lower than for MD-only students (P = .035), but Step 1 and 2 scores did not differ. Primary care residency match was more likely compared with MD-only students, both including and excluding obstetrics-gynecology (odds ratio [OR]: 1.75; 95% confidence interval [CI]: 1.31, 2.33; and OR: 1.36; 95% CI: 1.02, 1.82, respectively). CONCLUSIONS: The 4-year MD-MPH program retains and graduates a socioeconomically and racial/ethnically diverse group of students with a 93% success rate. MD-MPH graduates were more likely to pursue primary care residency than non-dual-degree students, which may have implications for addressing population health disparities.

A Three-Dimensional Print Model of the Pterygopalatine Fossa Significantly Enhances the Learning Experience.

The pterygopalatine fossa (PPF) is a bilateral space deep within the skull that serves as a major neurovascular junction. However, its small volume and poor accessibility make it a difficult space to comprehend using two-dimensional illustrations and cadaveric dissections. A three-dimensional (3D) printed model of the PPF was developed as a visual and kinesthetic learning tool for completely visualizing the fossa, its boundaries, its communicating channels, and its neurovascular structures. The model was evaluated by analyzing student performance on pre- and post-quizzes and a student satisfaction survey based on the five-point Likert scale. The first cohort comprised of 88 students who had never before studied the PPF. The second cohort consisted of 30 students who were previously taught the PPF. Each cohort was randomly divided into a control group who were provided with a half skull and an intervention group that were provided with the 3D printed model. The intervention group performed significantly better on the post-quiz as compared to the control group in cohort I (P = 0.001); while not significant, it also improved learning in cohort II students (P = 0.124). Satisfaction surveys indicated that the intervention group found the 3D printed model to be significantly more useful (P < 0.05) as compared to the half skull used by the control group. Importantly, the effect sizes for cohorts I and II (0.504 and 0.581, respectively) validated the statistical results. Together, this study highlights the importance of 3D printed models as teaching tools in anatomy education.

Clinical Case-Based Image Portfolios in Medical Histopathology.

This descriptive article describes the use of clinical case-based portfolios in histopathology teaching laboratories in conjunction with virtual microscopy not only to integrate histology and pathology disciplines for first and second year medical students but also to stimulate student engagement, promote self-directed and group-based learning and enhance student-to-student interaction in a structured manner. Portfolios consisted of PowerPoint files encompassing four to five clinical case studies relevant to the topics covered that week. Portfolios integrated study materials provided in the module-specific lectures, clinical skill lectures, and online interactive content. Two sets of portfolios, Individual and Group, were used. Individual Portfolios were completed by each student and uploaded prior to the laboratory session. Group Portfolios were completed by students working together in small groups during the laboratory session with minimal faculty assistance. The functional utility and acceptance of Individual and Group Portfolios among first- and second-year medical students was evaluated using electronic surveys and examination performances. Both first- and second-year students agreed that the use of portfolios in conjunction with virtual microscopy promoted understanding and encouraged discussion of the topics covered during the week and that group members worked well together and contributed to the completion of the portfolios. Performances on the Histology and Cell Biology and Pathology sections on the United States Medical Licensing Examination® (USMLE® ) remained consistent and in line with national averages. Overall, use of portfolios promoted peer teaching and contributed towards successful transition to the new system-based integrated curriculum with continued strong performance on the USMLE.

Introduction of Prenatal Oral Health into Medical Students' Obstetrics Training.

The aim of this study was to examine the influence of the Prenatal Oral Health Program (pOHP) at the University of North Carolina at Chapel Hill on medical students' oral health-related knowledge, confidence, attitudes, and dental referral practices. Specifically, the study sought to determine these students' ability to screen, counsel, and refer their patients to a dental home and their overall knowledge regarding the safety of dental treatment for pregnant patients. The study used a pre- and post-intervention survey design with intervention and control groups. Third-year medical students enrolled in an obstetrics and gynecology clerkship were surveyed between 2012 and 2014. The questionnaire assessed students' confidence and behaviors related to prenatal oral health counseling, screening, referral to a dental home, and knowledge about treatment safety during pregnancy. Intervention and control groups were determined by clerkship site. The intervention consisted of a 50-minute seminar on prenatal oral health principles, referral guidelines, and clinical systems changes. A total of 53 intervention and 32 control group students participated (57.4% response rate). The two groups were not significantly different at baseline in age, gender, having children, and residency goals. The results showed that the pOHP positively and significantly influenced students in the intervention group on all clinical constructs except their knowledge about treatment safety during pregnancy. Clinically examining a woman's mouth for signs of dental disease resulted in greater likelihood of making referrals by 26.5 times. These findings suggest that implementing prenatal oral health in a multi-method manner can effectively promote interdisciplinary coordinated care, meet interprofessional education accreditation standards, and aid in implementing practice guidelines in medical school curricula.

Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer.

BACKGROUND: High mitotic activity is associated with the genesis and progression of many cancers. Small molecule inhibitors of mitotic apparatus proteins are now being developed and evaluated clinically as anticancer agents. With clinical trials of several of these experimental compounds underway, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that carry molecular aberrations that confer high mitotic activity, and to develop molecular markers that distinguish which tumors will be most responsive to mitotic apparatus inhibitors. METHODS: We identified a coordinately regulated mitotic apparatus network by analyzing gene expression profiles for 53 malignant and non-malignant human breast cancer cell lines and two separate primary breast tumor datasets. We defined the mitotic network activity index (MNAI) as the sum of the transcriptional levels of the 54 coordinately regulated mitotic apparatus genes. The effect of those genes on cell growth was evaluated by small interfering RNA (siRNA). RESULTS: High MNAI was enriched in basal-like breast tumors and was associated with reduced survival duration and preferential sensitivity to inhibitors of the mitotic apparatus proteins, polo-like kinase, centromere associated protein E and aurora kinase designated GSK462364, GSK923295 and GSK1070916, respectively. Co-amplification of regions of chromosomes 8q24, 10p15-p12, 12p13, and 17q24-q25 was associated with the transcriptional upregulation of this network of 54 mitotic apparatus genes, and we identify transcription factors that localize to these regions and putatively regulate mitotic activity. Knockdown of the mitotic network by siRNA identified 22 genes that might be considered as additional therapeutic targets for this clinically relevant patient subgroup. CONCLUSIONS: We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.

Simultaneous removal of nitrate and arsenic from drinking water sources utilizing a fixed-bed bioreactor system.

A novel bioreactor system, consisting of two biologically active carbon (BAC) reactors in series, was developed for the simultaneous removal of nitrate and arsenic from a synthetic groundwater supplemented with acetic acid. A mixed biofilm microbial community that developed on the BAC was capable of utilizing dissolved oxygen, nitrate, arsenate, and sulfate as the electron acceptors. Nitrate was removed from a concentration of approximately 50 mg/L in the influent to below the detection limit of 0.2 mg/L. Biologically generated sulfides resulted in the precipitation of the iron sulfides mackinawite and greigite, which concomitantly removed arsenic from an influent concentration of approximately 200 ug/L to below 20 ug/L through arsenic sulfide precipitation and surface precipitation on iron sulfides. This study showed for the first time that arsenic and nitrate can be simultaneously removed from drinking water sources utilizing a bioreactor system.