PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets.

Many cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance.

Traumatic brain injury screening and neuropsychological functioning in women who experience intimate partner violence.

Objective: The potential for traumatic brain injury (TBI) to occur as the result of intimate partner violence (IPV) has received increased interest in recent years. This study sought to investigate the possible occurrence of TBI in a group of women who survived IPV and to measure the specific profile of cognitive deficits using standardized neuropsychological measures. Method: A comprehensive questionnaire about abuse history; neuropsychological measures of attention, memory and executive functioning; and measures of depression, anxiety and post-traumatic stress disorder were given to women who were IPV survivors, women who were sexual assault (SA) survivors, and a comparison group of women who did not experience IPV or SA. Results: Overall, rates of potential TBI, as measured by the HELPS brain injury screening tool, were high and consistent with previous studies. Consistent with potential TBI, lower scores were demonstrated on measures of memory and executive functioning compared to survivors of SA or those not exposed to violence. Importantly, significant differences on measures of memory and executive functioning remained, after controlling for measures of emotion. Of note, cognitive changes were highest among women who experienced non-fatal strangulation (NFS) compared to IPV survivors who did not. Conclusions: Rates of TBI may be high in women who survive IPV, especially those who survive strangulation. Better screening measures and appropriate interventions are needed as well as larger studies that look at social factors associated with IPV.

The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity.

BACKGROUND: Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. METHODS: CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. RESULTS: CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. CONCLUSIONS: CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.

Diverse human VH antibody fragments with bio-therapeutic properties from the Crescendo Mouse.

We describe the 'Crescendo Mouse', a human VH transgenic platform combining an engineered heavy chain locus with diverse human heavy chain V, D and J genes, a modified mouse Cγ1 gene and complete 3' regulatory region, in a triple knock-out (TKO) mouse background devoid of endogenous immunoglobulin expression. The addition of the engineered heavy chain locus to the TKO mouse restored B cell development, giving rise to functional B cells that responded to immunization with a diverse response that comprised entirely 'heavy chain only' antibodies. Heavy chain variable (VH) domain libraries were rapidly mined using phage display technology, yielding diverse high-affinity human VH that had undergone somatic hypermutation, lacked aggregation and showed enhanced expression in E. coli. The Crescendo Mouse produces human VH fragments, or Humabody® VH, with excellent bio-therapeutic potential, as exemplified here by the generation of antagonistic Humabody® VH specific for human IL17A and IL17RA.

Dementia With Lew Body: Impacts of Surgery.

Patients who have dementia with Lewy bodies (DLB) and undergo surgery may develop aggravated postoperative cognitive dysfunction or postoperative delirium. Many patients with DLB respond poorly to surgery and anesthesia, and their conditions may worsen if they have other medical complications along with dementia. They may also face high risk of prolonged hospital stay, increased medical problems and/or mortality, causing significant physical, psychosocial, and financial burdens on individuals, family members, and society. Anesthesia, pain medications, old age, and surgery-related stresses are usually held responsible for the complications; however, the exact causes are still not fully understood. Literature on surgery-related complications for patients with DLB appears to be inadequate, and hence the topic merits detailed and systematic research. This article reviews postoperative complications and various surgery-related risk factors for DLB in light of other dementias such as Alzheimer's disease, as their neuropathologic features overlap with those of DLB.

A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus.

Dengue is a rapidly emerging, mosquito-borne viral infection, with an estimated 400 million infections occurring annually. To gain insight into dengue immunity, we characterized 145 human monoclonal antibodies (mAbs) and identified a previously unknown epitope, the envelope dimer epitope (EDE), that bridges two envelope protein subunits that make up the 90 repeating dimers on the mature virion. The mAbs to EDE were broadly reactive across the dengue serocomplex and fully neutralized virus produced in either insect cells or primary human cells, with 50% neutralization in the low picomolar range. Our results provide a path to a subunit vaccine against dengue virus and have implications for the design and monitoring of future vaccine trials in which the induction of antibody to the EDE should be prioritized.

Efficacy of the Getting Ready Intervention and the Role of Parental Depression.

This study reports the results of a randomized trial of a parent engagement intervention (the Getting Ready Project) on directly observed learning-related social behaviors of children from families of low-income in the context of parent-child interactions. The study explored the moderating effect of parental depression on intervention outcomes. Participants were 204 children and their parents, and 29 Head Start teachers. Semi-structured parent-child interaction tasks were videotaped two times annually over the course of two academic years. Observational codes of child behaviors included agency, persistence, activity level, positive affect, distractibility, and verbalizations. Controlling for gender and disability concerns, relative to children in the control group, those in the treatment condition experienced a significant decline in activity level. Furthermore, compared to children of non-depressed mothers and to control children, those in the experimental condition whose parent reported elevated levels of depression showed greater gains in positive affect and in verbalizations.

Needs assessments of memory disorder patients.

BACKGROUND: Previous research shows that informal caregivers of individuals with a memory disorder experience financial strain, declining physical health, and psychological distress. Various resources and services have been developed to address and/or prevent these potential outcomes, yet caregivers continue to be negatively affected by the demands of caregiving. We hypothesize that better identification and clarification of concrete patient and caregiver needs will aid in the modification and improvement of the available resources. The purpose of this study is to determine the psychosocial needs of the cognitively impaired population and their caregivers. METHODS: A one-page Needs Assessment was created to address areas of potential concern for the individual with a memory disorder and the caregiver. This assessment was administered during visits to an outpatient clinic in Philadelphia. RESULTS: A total of 204 Needs Assessments were collected. The significant needs found in our study cohort include sleep, exercise, clinical trials, education, and assistance with ADLs and IADLs. CONCLUSIONS: This study satisfied the initial identification of caregiver and patient needs; now each must be explored further to determine how to successfully meet such needs. If the primary needs of the patient can be met by a focused service, the caregiver will no longer be the sole provider of meeting the specific need. This will decrease the involved role of the caregiver, maximize patient homecare, minimize caregiver stress, and increase the quality of life for both the patient and caregiver.

High-avidity and potently neutralizing cross-reactive human monoclonal antibodies derived from secondary dengue virus infection.

The envelope (E) protein of dengue virus (DENV) is the major target of neutralizing antibodies (Abs) and vaccine development. Previous studies of human dengue-immune sera reported that a significant proportion of anti-E Abs, known as group-reactive (GR) Abs, were cross-reactive to all four DENV serotypes and to one or more other flaviviruses. Based on studies of mouse anti-E monoclonal antibodies (MAbs), GR MAbs were nonneutralizing or weakly neutralizing compared with type-specific MAbs; a GR response was thus not regarded as important for vaccine strategy. We investigated the epitopes, binding avidities, and neutralization potencies of 32 human GR anti-E MAbs. In addition to fusion loop (FL) residues in E protein domain II, human GR MAbs recognized an epitope involving both FL and bc loop residues in domain II. The neutralization potencies and binding avidities of GR MAbs derived from secondary DENV infection were stronger than those derived from primary infection. GR MAbs derived from primary DENV infection primarily blocked attachment, whereas those derived from secondary infection blocked DENV postattachment. Analysis of the repertoire of anti-E MAbs derived from patients with primary DENV infection revealed that the majority were GR, low-avidity, and weakly neutralizing MAbs, whereas those from secondary infection were primarily GR, high-avidity, and potently neutralizing MAbs. Our findings suggest that the weakly neutralizing GR anti-E Abs generated from primary DENV infection become potently neutralizing MAbs against the four serotypes after secondary infection. The observation that the dengue immune status of the host affects the quality of the cross-reactive Abs generated has implications for new strategies for DENV vaccination.

Potent and broad neutralization of HIV-1 by a llama antibody elicited by immunization.

Llamas (Lama glama) naturally produce heavy chain-only antibodies (Abs) in addition to conventional Abs. The variable regions (VHH) in these heavy chain-only Abs demonstrate comparable affinity and specificity for antigens to conventional immunoglobulins despite their much smaller size. To date, immunizations in humans and animal models have yielded only Abs with limited ability to neutralize HIV-1. In this study, a VHH phagemid library generated from a llama that was multiply immunized with recombinant trimeric HIV-1 envelope proteins (Envs) was screened directly for HIV-1 neutralization. One VHH, L8CJ3 (J3), neutralized 96 of 100 tested HIV-1 strains, encompassing subtypes A, B, C, D, BC, AE, AG, AC, ACD, CD, and G. J3 also potently neutralized chimeric simian-HIV strains with HIV subtypes B and C Env. The sequence of J3 is highly divergent from previous anti-HIV-1 VHH and its own germline sequence. J3 achieves broad and potent neutralization of HIV-1 via interaction with the CD4-binding site of HIV-1 Env. This study may represent a new benchmark for immunogens to be included in B cell-based vaccines and supports the development of VHH as anti-HIV-1 microbicides.

GETTING READY: RESULTS OF A RANDOMIZED TRIAL OF A RELATIONSHIP-FOCUSED INTERVENTION ON THE PARENT-INFANT RELATIONSHIP IN RURAL EARLY HEAD START.

The purpose of this study is to investigate the effects of a relational intervention (the Getting Ready intervention) on parenting behaviors supporting the parent-infant relationship for families enrolled in Early Head Start home-based programming. Two-hundred thirty-four parents and their children participated in the randomized study, with 42% of parents reporting education of less than a high-school diploma. Brief, semistructured parent-child interaction tasks were videotaped every 4 months over a16-month intervention period. Observational codes of parent-infant relationship behaviors included quality of three parental behaviors: warmth and sensitivity, support for learning, and encouragement of autonomy; two appropriateness indicators: support for learning and guidance/directives; and one amount indicator: constructive behaviors. Parents who participated in the Getting Ready intervention demonstrated higher quality interactions with their children that included enhanced quality of warmth and sensitivity, and support for their children's autonomy than did parents in the control group. They also were more likely to use appropriate directives with their children and more likely to demonstrate appropriate supports for their young children's learning. Results indicate an added value of the Getting Ready intervention for Early Head Start home-based programming for families of infants and toddlers.

A randomized trial examining the effects of parent engagement on early language and literacy: the Getting Ready intervention.

Language and literacy skills established during early childhood are critical for later school success. Parental engagement with children has been linked to a number of adaptive characteristics in preschoolers including language and literacy development, and family-school collaboration is an important contributor to school readiness. This study reports the results of a randomized trial of a parent engagement intervention designed to facilitate school readiness among disadvantaged preschool children, with a particular focus on language and literacy development. Participants included 217 children, 211 parents, and 29 Head Start teachers in 21 schools. Statistically significant differences in favor of the treatment group were observed between treatment and control participants in the rate of change over 2 academic years on teacher reports of children's language use (d=1.11), reading (d=1.25), and writing skills (d=0.93). Significant intervention effects on children's direct measures of expressive language were identified for a subgroup of cases where there were concerns about a child's development upon entry into preschool. Additionally, other child and family moderators revealed specific variables that influenced the treatment's effects.

Implementation of a Relationship-Based School Readiness Intervention: A Multidimensional Approach to Fidelity Measurement for Early Childhood.

The implementation efforts of 65 early childhood professionals involved in the Getting Ready project, an integrated, multi-systemic intervention that promotes school readiness through parent engagement for children from birth to age five, were investigated. Digital videotaped records of professionals engaged in home visits with families across both treatment and comparison conditions were coded objectively using a partial-interval recording system to identify and record early childhood professionals' implementation of intervention strategies and their effectiveness in promoting parent engagement and interest in their child. Adherence, quality of intervention delivery, differentiation between groups, and participant responsiveness were assessed as multiple dimensions of fidelity. Early childhood professionals in the treatment group relative to the comparison group demonstrated greater frequency of adherence to some intervention strategies, as well as higher rates of total strategy use. In addition, significant positive relationships were found between years of experience, education and quality of intervention delivery. Quality of intervention delivery was different by program type (Early Head Start versus Head Start). Adherence in the treatment group was correlated with the rate of contact between parent and early childhood professional during the home visit.

Cross-reacting antibodies enhance dengue virus infection in humans.

Dengue virus co-circulates as four serotypes, and sequential infections with more than one serotype are common. One hypothesis for the increased severity seen in secondary infections is antibody-dependent enhancement (ADE) leading to increased replication in Fc receptor-bearing cells. In this study, we have generated a panel of human monoclonal antibodies to dengue virus. Antibodies to the structural precursor-membrane protein (prM) form a major component of the response. These antibodies are highly cross-reactive among the dengue virus serotypes and, even at high concentrations, do not neutralize infection but potently promote ADE. We propose that the partial cleavage of prM from the viral surface reduces the density of antigen available for viral neutralization, leaving dengue viruses susceptible to ADE by antibody to prM, a finding that has implications for future vaccine design.

Parent Engagement and School Readiness: Effects of the Getting Ready Intervention on Preschool Children's Social-Emotional Competencies.

RESEARCH FINDINGS: Parental engagement with children has been linked to a number of adaptive characteristics in preschool children, and relationships between families and professionals are an important contributor to school readiness. Furthermore, social-emotional competence is a key component of young children's school readiness. This study reports the results of a randomized trial of a parent engagement intervention (Getting Ready) designed to facilitate school readiness among disadvantaged preschool children, with a particular focus on social-emotional outcomes. Two hundred and twenty children were involved over the 4-year study period. Statistically significant differences were observed between treatment and control participants in the rate of change over a 2-year period on teacher reports for certain interpersonal competencies (i.e., attachment, initiative, and anxiety/ withdrawal). In contrast, no statistically significant differences between groups over a 2-year period were noted for behavioral concerns (anger/aggression, self-control, or behavioral problems) as a function of the Getting Ready intervention. PRACTICE OR POLICY: The intervention appears to be particularly effective at building social-emotional competencies beyond the effects experienced as a function of participation in Head Start programming alone. Limitations and implications for future research are reviewed.

Professional Development in Early Childhood Programs: Process Issues and Research Needs.

In light of the current policy context, early childhood educators are being asked to have a complex understanding of child development and early education issues and provide rich, meaningful educational experiences for all children and families in their care. Accountability for outcomes is high, and resources for professional support are limited. As such, the early education field needs well-conducted empirical studies on which to base professional development practices. In this paper, we offer research directions associated with the processes underlying professional development, including areas in need of investigation that can inform the early childhood education field in terms of how professional development efforts exert their influence and produce meaningful change in practitioners' skills, behaviors, and dispositions. The paper highlights representative research from the professional development literature on its various forms/approaches and offers an agenda for research on the professional development process. Broad issues associated with the conduct of research on professional development, including considerations of professional development processes, participant characteristics, relationships, and sustainability are discussed.