Therapeutic Monoclonal Antibodies against Cancer: Present and Future.

A series of monoclonal antibodies with therapeutic potential against cancer have been generated and developed. Ninety-one are currently used in the clinics, either alone or in combination with chemotherapeutic agents or other antibodies, including immune checkpoint antibodies. These advances helped to coin the term personalized medicine or precision medicine. However, it seems evident that in addition to the current work on the analysis of mechanisms to overcome drug resistance, the use of different classes of antibodies (IgA, IgE, or IgM) instead of IgG, the engineering of the Ig molecules to increase their half-life, the acquisition of additional effector functions, or the advantages associated with the use of agonistic antibodies, to allow a broad prospective usage of precision medicine successfully, a strategy change is required. Here, we discuss our view on how these strategic changes should be implemented and consider their pros and cons using therapeutic antibodies against cancer as a model. The same strategy can be applied to therapeutic antibodies against other diseases, such as infectious or autoimmune diseases.

Diversity Elements on Maternal Fetal Medicine (MFM) Fellowship Websites: Opportunity for Improvement in Recruitment and Representation.

Background: There has been a fundamental shift in recruitment of medical students and trainees into residency and fellowship programs during the Covid 19 pandemic.1 Historically, websites for medical trainees demonstrate a lack of explicit focus on diversity, equity, and inclusion. 2-7 Diversity has positive associations of improving healthcare team performance, patient care, and even financial goals.8 A lack of diversity may negatively impact patient care.9 Directed recruitment of underrepresented in medicine applicants has proven successful to increase diversity within training programs. Department websites have a more prominent role in virtual recruitment since the beginning of the COVID pandemic. Features on these websites may be utilized to attract underrepresented in medicine applicants and increase diversity in a field. Objective: To analyze Maternal Fetal Medicine fellowship websites for presence of diversity elements important to those people who are underrepresented in medicine. Study Design: Fellowship websites were accessed summer of 2021. They were analyzed for presence of twelve website elements that demonstrate commitment to diversity, including: 1) nondiscrimination statement; 2) diversity and inclusion message; 3) diversity specific language; 4) resources for trainees; 5) community demographics; 6-7) personalized biographies of faculty or fellows; 8-9) individual photographs of faculty or fellows; 10) photos or biographies of alumni; 11) diversity publications and; 12) department statistics. Program size, region, and location were collected. Self-reported underrepresented in medicine data on residency programs was extracted from the National Graduate Medical Education Survey from 2019. Programs were dichotomized into 6+ diversity elements. Nonparametric, chi-square and Fisher's exact were used for analysis. Results: Fellowship programs were analyzed (excluding military/fetal surgery, n = 91/94). Websites included a mean of 4.1± 2.5 diversity elements. Most featured fewer than 6 elements (n =75, 82.4%). When dichotomized to 6+ diversity elements, larger faculty size was the only significant factor (p=0.01). The majority of programs had fewer than 12 faculty members (n=54, 59.3%) and only 9.3% of those programs had 6 or more diversity elements. By contrast, among programs with more than 12 faculty, 29.7% had 6 or more diversity elements. Faculty photos, fellow photos, and diversity publications were the most commonly featured items (92.4%, 68.1%, and 49.5%, respectively). Mean rate of underrepresented in medicine was 18.8% ± 11.3% and no significant associations were noted. There was a non-significant difference in diversity elements in the West United States with a mean of 5.3±2.2 diversity elements, compared to 3.7±2 in the South. Conclusion: Fellowship websites convey information for trainees, especially in an era of virtual recruitment. This study highlights opportunities for directed improvements of websites for features which URIM medical trainees have identified as important.

Therapeutic potential of an anti-CCR9 mAb evidenced in xenografts of human CCR9+ tumors.

Relapsed or refractory T acute lymphoblastic leukemia (T-ALL) still carries poor prognosis. Aiming to improve outcomes, the therapeutic potential of an anti-CCR9 monoclonal antibody (mAb 92R), targeting the human chemokine-receptor CCR9 is analyzed on orthotopic xenotransplants. 92R mAb treatment of mice carrying human CCR9+ T-ALL cell lines or primary T cell leukemias inhibits tumor growth and increases survival. The therapeutic effects of 92R are specific and synergize with chemotherapeutic agents increasing survival. Furthermore, 92R decreases size of non-hematopoietic tumors with a forced CCR9 expression and of solid tumors generated by the pancreatic adenocarcinoma cell line AsPC-1. In addition, a humanized version of 92R mAb (Srb1) is also able to inhibit growth of CCR9+ T-ALL tumor cells in vivo, increasing survival 2.66-fold. Finally, 92R mAb prevents liver accumulation of infiltrates and reduces tumor cell numbers in already formed infiltrates. Thus, the humanized version of 92R mAb (Srb1), displays therapeutic potential for CCR9+ tumor treatment and might represent one of the first therapeutic antibodies for precision medicine on T-ALL patients.

Will a mAb-Based Immunotherapy Directed against Cancer Stem Cells Be Feasible?

The cancer stem cell (CSC) hypothesis suggests that within a tumor, there is a small subpopulation of cells with stem cell properties responsible for tumor maintenance and metastasis generation. This hypothesis also implies that new antitumor drugs, rather than targeting the bulk of the tumor mass, would be more effective if they directly targeted the CSC subpopulation. The CSCs from several types of tumors have been identified with mAbs recognizing surface antigens in these cells; however, antigens specifically or exclusively expressed in the CSC population have not yet been identified. Thus, questioning the possibility of using therapeutic antibodies directed against the CSCs. Here, we review the possibilities of using antibodies directly targeting the CSCs as therapeutic agents in the form of naked antibodies, antibodies conjugated to nanoparticles, or antibody cocktails.

Age-Related Changes in the Processing of Emotional Faces in a Dual-Task Paradigm.

UNLABELLED: Background/ Study Context: Age-related changes appear to affect the ability to identify emotional facial expressions in dual-task conditions (i.e., while simultaneously performing a second visual task). The level of interference generated by the secondary task depends on the phase of emotional processing affected by the interference and the nature of the secondary task. The aim of the present study was to investigate the effect of these variables on age-related changes in the processing of emotional faces. METHODS: The identification of emotional facial expressions (EFEs) was assessed in a dual-task paradigm using the following variables: (a) the phase during which interference was applied (encoding vs. retrieval phase); and (b) the nature of the interfering stimulus (visuospatial vs. verbal). The sample population consisted of 24 healthy aged adults (mean age = 75.38) and 40 younger adults (mean age = 26.90). The accuracy of EFE identification was calculated for all experimental conditions. RESULTS: Consistent with our hypothesis, the performance of the older group was poorer than that of the younger group in all experimental conditions. Dual-task performance was poorer when the interference occurred during the encoding phase of emotional face processing and when both tasks were of the same nature (i.e., when the experimental condition was more demanding in terms of attention). CONCLUSIONS: These results provide empirical evidence of age-related deficits in the identification of emotional facial expressions, which may be partially explained by the impairment of cognitive resources specific to this task. These findings may account for the difficulties experienced by the elderly during social interactions that require the concomitant processing of emotional and environmental information.

Influence of the APOE ε4 allele and mild cognitive impairment diagnosis in the disruption of the MEG resting state functional connectivity in sources space.

The apolipoprotein E (APOE) ε4 allele constitutes the major genetic risk for the development of late onset Alzheimer's disease (AD). However, its influence on the neurodegeneration that occurs in early AD remains unresolved. In this study, the resting state magnetoencephalography(MEG) recordings were obtained from 27 aged healthy controls and 36 mild cognitive impairment (MCI) patients. All participants were divided into carriers and non-carriers of the ε4 allele. We have calculated the functional connectivity (FC) in the source space along brain regions estimated using the Harvard-Oxford atlas and in the classical bands. Then, a two way ANOVA analysis (diagnosis and APOE) was performed in each frequency band. The diagnosis effect consisted of a diminished FC within the high frequency bands in the MCI patients, affecting medial temporal and parietal regions. The APOE effect produced a decreased long range FC in delta band in ε4 carriers. Finally, the interaction effect showed that the FC pattern of the right frontal-temporal region could be reflecting a compensatory/disruption process within the ε4 allele carriers. Several of these results correlated with cognitive decline and neuropsychological performance. The present study characterizes how the APOE ε4 allele and MCI status affect the brain's functional organization by analyzing the FC patterns in MEG resting state in the sources space. Therefore a combination of genetic, neuropsychological, and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration.