Soluble immune-checkpoint factors: a potential immunotherapy biomarker.

There is unmet need for additional biomarkers to better select patients with non-small cell lung cancer (NSCLC) that are likely to benefit from immunotherapy in order to improve patient outcomes, reduce patient toxicity, and relieve the growing burden of healthcare costs. In this issue of the JCI, Hayashi and colleagues evaluated soluble forms of the immune checkpoint molecules PD-L1, PD-1, and CTLA-4 in the plasma of patients with advanced NSCLC who had been treated with anti-PD-1/L1 therapy. The findings suggest that these soluble immune-checkpoint factors may provide a complementary biomarker to PD-L1 IHC, although application into the clinic may not be straightforward.

Immune Checkpoint Inhibitors in Geriatric Oncology.

PURPOSE OF REVIEW: This manuscript will update prior reviews of immune checkpoint inhibitors (ICIs) in light of basic science, translational, and clinical discoveries in the field of cancer immunology and aging. RECENT FINDINGS: ICIs have led to significant advancements in the treatment of cancer. Landmark trials of ICIs have cited the efficacy and toxicity experienced by older patients, but most trials are not specifically designed to address outcomes in older patients. Underlying mechanisms of aging, like cellular senescence, affect the immune system and may ultimately alter the host's response to ICIs. Validated tools are currently used to identify older adults who may be at greater risk of developing complications from their cancer treatment. We review changes in the aging immune system that may alter responses to ICIs, report outcomes and toxicities in older adults from recent ICI clinical trials, and discuss clinical tools specific to older patients with cancer.

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D-NKG2DL axis.

The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D-NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants.

ALD-R491 regulates vimentin filament stability and solubility, cell contractile force, cell migration speed and directionality.

Metastasizing cells express the intermediate filament protein vimentin, which is used to diagnose invasive tumors in the clinic. However, the role of vimentin in cell motility, and if the assembly of non-filamentous variants of vimentin into filaments regulates cell migration remains unclear. We observed that the vimentin-targeting drug ALD-R491 increased the stability of vimentin filaments, by reducing filament assembly and/or disassembly. ALD-R491-treatment also resulted in more bundled and disorganized filaments and an increased pool of non-filamentous vimentin. This was accompanied by a reduction in size of cell-matrix adhesions and increased cellular contractile forces. Moreover, during cell migration, cells showed erratic formation of lamellipodia at the cell periphery, loss of coordinated cell movement, reduced cell migration speed, directionality and an elongated cell shape with long thin extensions at the rear that often detached. Taken together, these results indicate that the stability of vimentin filaments and the soluble pool of vimentin regulate the speed and directionality of cell migration and the capacity of cells to migrate in a mechanically cohesive manner. These observations suggest that the stability of vimentin filaments governs the adhesive, physical and migratory properties of cells, and expands our understanding of vimentin functions in health and disease, including cancer metastasis.

B Cell-Intrinsic IRF4 Haploinsufficiency Impairs Affinity Maturation.

The germinal center (GC) reaction is a coordinated and dynamic ensemble of cells and processes that mediate the maturation and selection of high-affinity GC B cells (GCBs) from lower-affinity precursors and ultimately results in plasma cell and memory cell fates that exit the GC. It is of great interest to identify intrinsic and extrinsic factors that control the selection process. The transcription factor IRF4, induced upon BCR and CD40 signaling, is essential for the acquisition of plasma cell and GCB cell fates. We hypothesized that beyond this early requirement, IRF4 continuously operates at later phases of the B cell response. We show that IRF4 is expressed in GCBs at levels greater than seen in resting cells and plays a role in efficient selection of high-affinity GCBs. Halving Irf4 gene copy number in an Ag-specific murine B cell model, we found that Ag presentation, isotype switching, GC formation and zonation, somatic hypermutation rates, and proliferation were comparable with cells with a full Irf4 allelic complement. In contrast, Irf4 haploinsufficient GCBs exhibited impaired generation of high-affinity cells. Mechanistically, we demonstrate suboptimal Blimp-1 regulation among high-affinity Irf4 haploinsufficient GCBs. Furthermore, in cotransfer settings, we observed a marked disadvantage of Irf4 haploinsufficient cells for GC entry, evidential of ineffective recruitment of T cell help. We propose that, analogous to its role in early GC entry, IRF4 continues to function in the late phase of the Ab response to promote productive T follicular helper cell interactions and to activate optimal Blimp-1 expression during GC selection and affinity maturation.

Enhancing T Cell Chemotaxis and Infiltration in Glioblastoma.

Glioblastoma is an immunologically 'cold' tumor, which are characterized by absent or minimal numbers of tumor-infiltrating lymphocytes (TILs). For those tumors that have been invaded by lymphocytes, they are profoundly exhausted and ineffective. While many immunotherapy approaches seek to reinvigorate immune cells at the tumor, this requires TILs to be present. Therefore, to unleash the full potential of immunotherapy in glioblastoma, the trafficking of lymphocytes to the tumor is highly desirable. However, the process of T cell recruitment into the central nervous system (CNS) is tightly regulated. Naïve T cells may undergo an initial licensing process to enter the migratory phenotype necessary to enter the CNS. T cells then must express appropriate integrins and selectin ligands to interact with transmembrane proteins at the blood-brain barrier (BBB). Finally, they must interact with antigen-presenting cells and undergo further licensing to enter the parenchyma. These T cells must then navigate the tumor microenvironment, which is rich in immunosuppressive factors. Altered tumoral metabolism also interferes with T cell motility. In this review, we will describe these processes and their mediators, along with potential therapeutic approaches to enhance trafficking. We also discuss safety considerations for such approaches as well as potential counteragents.

A Synchronous IRF4-Dependent Gene Regulatory Network in B and Helper T Cells Orchestrating the Antibody Response.

Control of diverse pathogens requires an adaptive antibody response, dependent on cellular division of labor to allocate antigen-dependent B- and CD4+ T-cell fates that collaborate to control the quantity and quality of antibody. This is orchestrated by the dynamic action of key transcriptional regulators mediating gene expression programs in response to pathogen-specific environmental inputs. We describe a conserved, likely ancient, gene regulatory network that intriguingly operates contemporaneously in B and CD4+ T cells to control their cell fate dynamics and thus, the character of the antibody response. The remarkable output of this network derives from graded expression, designated by antigen receptor signal strength, of a pivotal transcription factor that regulates alternate cell fate choices.

Evidence for Multiple Classes of Sexually-Violent College Men.

OBJECTIVE: Research on college sexual violence perpetration suggests there are multiple groups of male perpetrators. It is important to understand the distinctions between perpetrator subgroups to determine appropriate prevention strategies, as multiple strategies may be necessary to address multiple types of perpetrators. However, previous studies on subgroups of sexually-violent college men have relied on theoretically based distinctions, and there is currently no consensus on how to best classify perpetrators based on their sexually violent behaviors. The purpose of the current study was to take a data-driven approach to identifying subgroups of sexually-violent college men to help clarify: 1) the number and size of cohesive subgroups of sexually-violent college men, and 2) the types of behaviors that characterize each group. METHODS: 1,982 college men across five universities in the U.S. self-reported their past sexually-violent behaviors, using the Sexual Experiences Survey (SES; Koss et al., 2007). RESULTS: Latent class analysis uncovered evidence for three groups: (1) a group unlikely to perpetrate any SV (88.6%); (2) a group likely to perpetrate SV using coercive tactics (verbal coercion or victim intoxication), but unlikely to use physical force (9.8%); and (3) a group likely to perpetrate the full range of SV (1.5%). Although the coercive tactics group was composed of men unlikely to use forceful tactics, it included the majority who attempted or completed rape based on legal definitions. CONCLUSIONS: Our findings suggest that there are multiple, distinct perpetrator subgroups and signal the need for multiple prevention approaches, including approaches that address campus social norms.

Measuring campus sexual misconduct and its context: The Administrator-Researcher Campus Climate Consortium (ARC3) survey.

OBJECTIVE: In response to The White House Task Force to Protect Students from Sexual Assault's recommendations, the Administrator-Researcher Campus Climate Collaborative (ARC3) has curated an empirically sound, no-cost campus climate survey for U.S. institutions of higher education. The ARC3 survey contains 19 modules that assess a range of Title IX violations, including sexual harassment, dating violence, and sexual misconduct victimization and perpetration; sexual misconduct prevention efforts, resources, and responses; and key predictors and possible outcomes of sexual misconduct. This article describes the ARC3 survey development and pilot test psychometric data. METHOD: A total of 909 students attending one of three U.S. universities responded to the survey; 85% of students who began the survey completed it. Students completed the ARC3 survey in slightly less than 30 min, on average. RESULTS: The majority of measures produced evidence for at least acceptable internal consistency levels (α > .70), with only two short item sets having marginal reliability (α = .65-.70). Correlations among scales matched expectations set by the research literature. Students generally did not find the survey distressing; in fact, students viewed the climate assessment as important and personally meaningful. CONCLUSION: The survey performed sufficiently well in pilot testing to recommend its use with U.S. college populations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

South African Adolescents' Neighborhood Perceptions Predict Longitudinal Change in Youth and Family Functioning.

This study examined South African early adolescent youth (aged 10 to 14) and their female caregivers (N = 99 dyads) participating in an HIV prevention intervention over a period of eight months. We examined youth perceptions of neighborhood cohesion, safety, and collective monitoring as they related to concurrent and longitudinal associations with youth (externalizing behavior and hope about the future) and family (parent-youth relationship quality, parental involvement, and parental responsiveness to sex communication) functioning while controlling for baseline characteristics. Neighborhood perceptions were significantly associated (p < .05) with short- and longer-term outcomes. Gender differences suggested a greater protective association of perceived neighborhood conditions with changes in functioning for boys versus girls. Unexpected associations were also observed, including short-term associations suggesting a link between better neighborhood quality and poorer family functioning. We account for the culture of this South African community when contextualizing our findings and conclude with recommendations for interventions targeting neighborhood contexts.

A Qualitative Analysis of Offenders' Emotional Responses to Perpetrating Sexual Assault.

The purpose of this study was to understand sexual assault perpetrators' emotional responses to perpetration to facilitate treatment development and to better understand processes that may give rise to repeat perpetration. Sixty-one firsthand narratives of sexual assault perpetration, posted on Reddit.com , were analyzed using qualitative text analysis. The analysis revealed four primary emotional responses to perpetrating sexual assault: shame, guilt, depression, and anger. Each emotional response was associated with different contextual features that appeared in the narratives. Shame co-occurred with perpetrator alcohol use and consent confusion, guilt co-occurred with perpetrators' stated self-growth, anger co-occurred with denial of responsibility and hostility toward women, and depressed affect co-occurred with social isolation following perpetration. The findings indicate certain emotional responses may be more adaptive than others for protecting against repeat perpetration. This research has important implications for the treatment of perpetrators and supports the idea that self-image and perceived social context may be important treatment targets.

Mucoadhesive polysaccharides modulate sodium retention, release and taste perception.

The mucoadhesion between polymeric substances and mucosal membranes, widely exploited in the pharmaceutics industry to prolong drug residence, has been investigated as a means of retaining taste or aroma molecules in the oral cavity. This study shows that the mucoadhesive properties of carboxymethyl cellulose, a commonly used polysaccharide in the food and pharmaceutics industry, can modify retention, release and perception of sodium over time. A three-part study was designed coupling in vitro retention using ex vivo porcine tongue, sensory perception with a trained panel and in vivo retention of sodium ions in human volunteers. The findings suggest that although salt perception is stunted in samples containing a random coil, ionic, mucoadhesive thickener, the retention of sodium ions in the mouth is prolonged due to the mucoadhesive nature of the polysaccharide. Not only has this study-investigated mucoadhesion of liquid formulations in the oral cavity but it is also the first to link the mucoadhesive nature of a commonly used polysaccharide to the organoleptic properties of a food.

The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate.

Transcriptional regulation during CD4+ T cell fate decisions enables their differentiation into distinct states, guiding immune responses toward antibody production via Tfh cells or inflammation by Teff cells. Tfh-Teff cell fate commitment is regulated by mutual antagonism between the transcription factors Bcl6 and Blimp-1. Here we examined how T cell receptor (TCR) signals establish and arbitrate Bcl6-Blimp-1 counter-antagonism. We found that the TCR-signal-induced transcription factor Irf4 is essential for the differentiation of Bcl6-expressing Tfh and Blimp-1-expressing Teff cells. Increased TCR signaling raised Irf4 amounts and promoted Teff cell fates at the expense of Tfh ones. Importantly, orthogonal induction of Irf4 expression redirected Tfh cell fate trajectories toward those of Teff. Mechanistically, we linked greater Irf4 abundance with its recruitment toward low-affinity binding sites within Teff cell cis-regulatory elements, including those of Prdm1. We propose that the Irf4 locus functions as the "reader" of TCR signal strength, and in turn, concentration-dependent activity of Irf4 "writes" T helper fate choice.

Parenting and youth sexual risk in context: The role of community factors.

Black South African youth are disproportionately affected by HIV, and risky sexual behaviors increase youths' vulnerability to infection. U.S.-based research has highlighted several contextual influences on sexual risk, but these processes have not been examined in a South African context. In a convenience sample of Black South African caregivers and their 10-14-year-old youth (Mage = 11.7, SD = 1.4; 52.5% female), we examined the relation between parenting and youth sexual risk within the context of community-level processes, including neighborhood quality and maternal social support. Hypotheses were evaluated using structural equation modeling. Results revealed that better neighborhood quality and more social support predicted positive parenting, which in turn predicted less youth sexual risk. There was a significant indirect effect from neighborhood quality to youth sexual risk via parenting. Results highlight the importance of the community context in parenting and youth sexual risk in this understudied sample. HIV prevention-interventions should be informed by these contextual factors.

ActiviTeen: A Protocol for Deployment of a Consumer Wearable Device in an Academic Setting.

BACKGROUND: Regular physical activity (PA) can be an important indicator of health across an individual's life span. Consumer wearables, such as Fitbit or Jawbone, are becoming increasingly popular to track PA. With the increased adoption of activity trackers comes the increased generation of valuable individual-based data. Generated data has the potential to provide detailed insights into the user's behavior and lifestyle. OBJECTIVE: The primary objective of the described study is to evaluate the feasibility of individual data collection from the selected consumer wearable device (the Fitbit Zip). The rate of user attrition and barriers preventing the use of consumer wearable devices will also be evaluated as secondary objectives. METHODS: The pilot study will occur in two stages and employs a long-term review and analysis with a convenience sample of 30 students attending Research Triangle High School. For the first stage, students will initially be asked to wear the Fitbit Zip over the course of 4 weeks. During which time, their activity data and step count will be collected. Students will also be asked to complete a self-administered survey at the beginning and conclusion of the first stage. The second stage will continue to collect students' activity data and step count over an additional 3-month period. RESULTS: We are anticipating results for this study by the end of 2016. CONCLUSION: This study will provide insight into the data collection procedures surrounding consumer wearable devices and could serve as the future foundation for other studies deploying consumer wearable devices in educational settings.

Impact of violence research on participants over time: Helpful, harmful, or neither?

OBJECTIVE: To investigate the impact of answering survey questions about experiences of stressful, stigmatizing, potentially traumatic and sexually violating events on well being, defined as reactions to research, anxiety, and positive and negative affect over two weeks. METHOD: With an ethnically diverse sample of 559 higher education students, we employed a mixed experimental design (with between and within-subjects components) to evaluate changes in positive and negative affect, anxiety, traumatic stress symptoms, and reactions to research. We used multilevel regression models and planned contrasts to determine which, if any, specific characteristics of the survey questions caused changes in well being by comparing the effects of answering a randomly assigned set of survey questions about stressful, stigmatizing, potentially traumatic, or sexually violating life events across a two-week period. RESULTS: Controlling for baseline post-traumatic stress symptoms and levels of the outcome, we identified few statistically significant effects between conditions or across time. Significant effects included a small decrease in positive affect immediately after responding to questions about sexually violating events, which diminished at two weeks; these same participants perceived fewer drawbacks to research participation. Participants who responded to questions about stressful life events reported greater perceptions of benefits. CONCLUSIONS: Our data support the safety of survey research on sexual assault or other stressful, stigmatizing, or potentially traumatic events.

Safety-related moderators of a parent-based HIV prevention intervention in South Africa.

Our study examined factors influencing the effectiveness of a parent-based HIV prevention intervention implemented in Cape Town, South Africa. Caregiver-youth dyads (N = 99) were randomized into intervention or control conditions and assessed longitudinally. The intervention improved a parenting skill associated with youth sexual risk, parent-child communication about sex and HIV. Analyses revealed that over time, intervention participants (female caregivers) who experienced recent intimate partner violence (IPV) or unsafe neighborhoods discussed fewer sex topics with their adolescent children than caregivers in safer neighborhoods or who did not report IPV. Participants with low or moderate decision-making power in their intimate relationships discussed more topics over time only if they received the intervention. The effectiveness of our intervention was challenged by female caregivers' experience with IPV and unsafe neighborhoods, highlighting the importance of safety-related contextual factors when implementing behavioral interventions for women and young people in high-risk environments. Moderation effects did not occur for youth-reported communication outcomes. Implications for cross-cultural adaptations of parent-based HIV prevention interventions are discussed.

Perceived control and communication about sex: a study of South African families.

Caregiver-youth communication about sex protects youth against HIV/AIDS, and caregivers who believe that sex knowledge is important are more likely to talk to their youth about sex. However, caregivers who experience barriers to communication about sex may not talk to their youth about sex even if the caregiver believes that sex education is important. The Theory of Planned Behaviour predicts that an actor has perceived control is necessary for behavioural change. This study therefore hypothesised that caregivers' perceived control moderates the relationship between caregiver attitudes about youth sex knowledge and caregiver-youth communication about sex. Results from a sample of 99 female South African caregivers of adolescent (10-14 year old) youth supported our hypothesis, indicating that caregiver attitudes about providing youth with sex knowledge positively predict communication about sex only when caregivers have perceived control. This finding illustrates the importance of perceived control in predicting caregiver-youth communication, and therefore has implications for family-based interventions aimed at improving caregiver-youth communication about sex.

Caregiver-youth communication about sex in South Africa: the role of maternal child sexual abuse history.

Much of the research on child sexual abuse focuses on negative outcomes. This brief report explores a potentially protective parenting behavior among black South African female caregivers with and without a child sexual abuse history. Using cross-sectional baseline data, we hypothesized that caregiver child sexual abuse history would be positively associated with caregiver-youth sex communication and this relationship would be strongest for girls. Youth whose caregiver experienced child sexual abuse were more likely to report communicating with their caregiver about sex than youth whose caregivers did not experience child sexual abuse; however, this relation did not hold for caregiver reported communication. Child sexual abuse survivors' ability and decision to discuss sex with their youth has the potential to protect youth from sexual risk and demonstrates resilience among a group rarely acknowledged for positive parenting practices.

Perceived Control and Communication about Sex: A Study of South African Families

Caregiver-youth communication about sex protects youth against HIV/AIDS; and caregivers who believe that sex knowledge is important are more likely to talk to their youth about sex. However; caregivers who experience barriers to communication about sex may not talk to their youth about sex even if the caregiver believes that sex education is important. The Theory of Planned Behaviour predicts that an actor has perceived control is necessary for behavioural change. This study therefore hypothesised that caregivers' perceived control moderates the relationship between caregiver attitudes about youth sex knowledge and caregiver-youth communication about sex. Results from a sample of 99 female South African caregivers of adolescent (10-14 year old) youth supported our hypothesis; indicating that caregiver attitudes about providing youth with sex knowledge positively predict communication about sex only when caregivers have perceived control. This finding illustrates the importance of perceived control in predicting caregiver-youth communication; and therefore has implications for family-based interventions aimed at improving caregiver-youth communication about sex