KIR2DS2 Expression Identifies NK Cells With Enhanced Anticancer Activity.

NK cells are promising cellular therapeutics against hematological and solid malignancies. Immunogenetic studies have identified that various activating killer cell Ig-like receptors (KIRs) are associated with cancer outcomes. Specifically, KIR2DS2 has been associated with reduced incidence of relapse following transplant in hematological malignancies and improved outcomes in solid tumors, but the mechanism remains obscure. Therefore, we investigated how KIR2DS2 expression impacts NK cell function. Using a novel flow cytometry panel, we show that human NK cells with high KIR2DS2 expression have enhanced spontaneous activation against malignant B cell lines, liver cancer cell lines, and primary chronic lymphocytic leukemia cells. Surface expression of CD16 was increased on KIR2DS2high NK cells, and, accordingly, KIR2DS2high NK cells had increased activation against lymphoma cells coated with the clinically relevant anti-CD20 Abs rituximab and obinutuzumab. Bulk RNA sequencing revealed that KIR2DS2high NK cells have upregulation of NK-mediated cytotoxicity, translation, and FCGR gene pathways. We developed a novel single-cell RNA-sequencing technique to identify KIR2DS2+ NK cells, and this confirmed that KIR2DS2 is associated with enhanced NK cell-mediated cytotoxicity. This study provides evidence that KIR2DS2 marks a population of NK cells primed for anticancer activity and indicates that KIR2DS2 is an attractive target for NK-based therapeutic strategies.

Preliminary Results of the Use of a Stabilized Hypochlorous Acid Solution in the Management of Ralstonia Pickettii Biofilm on Silicone Breast Implants.

BACKGROUND: Ralstonia Pickettii biofilms are associated with pocket infections following breast implant surgeries. Biofilm protects bacteria most topically applied antimicrobial irrigations. OBJECTIVES: To evaluate the effectiveness of four antimicrobial solutions on the planktonic form and established biofilm of Ralstonia Pickettii grown on 3 different types of silicone breast implants. METHODS: Time kill assays at clinical concentrations of chlorhexidine gluconate, povidone iodine, triple-antibiotic solution, and a 0.025% hypochlorous acid solution stabilized in amber glass were evaluated. Normal saline was the control. Three types of silicone implants, two with a textured surface and one smooth surface, were selected. Planktonic assays were performed after implants were soaked for one, five, 30, and 120 minute time points. Biofilm assays were performed after 5 and 120 minutes of implant soak time. Both tests evaluated cell-forming units (CFU/mL). RESULTS: Triple antibiotic solution had no effect on R. pickettii and was dropped from the study. Remaining solutions showed total kill of planktonic bacteria at one minute. Saline control showed no significant effect on biofilm as anticipated. Stabilized hypochlorous acid was the only solution tested capable of eradicating R. pickettii biofilm on all implant surfaces tested within the first five minute soak time. CONCLUSIONS: Noncytotoxic, 0.025% hypochlorous acid in normal saline, stabilized in amber glass, successfully eradicated Ralstonia pickettii in planktonic and mature biofilm on three types of silicone implants during initial five minute soak time and may be the preferred antimicrobial solution for pocket lavage. This preliminary study requires further investigation. Leaching and implant compatibility testing is currently in progress.

Physical Activity, Air Pollution, and the Risk of Asthma and Chronic Obstructive Pulmonary Disease.

RATIONALE: Physical activity enhances uptake of air pollutants in the lung, possibly augmenting their harmful effects on chronic lung disease during exercise. OBJECTIVES: To examine whether benefits of physical activity with respect to the risk of asthma and chronic obstructive pulmonary disease (COPD) are moderated by exposure to high air pollution levels in an urban setting. METHODS: A total of 53,113 subjects (50-65 yr) from the Danish Diet, Cancer, and Health cohort reported physical activity at recruitment (1993-1997) and were followed until 2013 in the National Patient Register for incident hospitalizations for asthma and COPD. Levels of nitrogen dioxide (NO2) were estimated at subject residences at the time of recruitment. We used Cox regression to associate physical activities and NO2 (high/medium/low) with asthma and COPD, and then introduced an interaction term between each physical activity and NO2. MEASUREMENTS AND MAIN RESULTS: A total of 1,151 subjects were hospitalized for asthma and 3,225 for COPD during 16 years. We found inverse associations of participation in sports (hazard ratio [95% confidence interval]: 0.85 [0.75-0.96]) and cycling (0.85 [0.75-0.96]) with incident asthma, and of participation in sports (0.82 [0.77-0.89]), cycling (0.81 [0.76-0.87]), gardening (0.88 [0.81-0.94]), and walking (0.85 [0.75-0.95]) with incident COPD admissions. We found positive associations between NO2 and incident asthma (1.23 [1.04-1.47]) and COPD (1.15 [1.03-1.27]) hospitalizations (comparing ≥21.0 µg/m3 to <14.3 µg/m3). We found no interaction between associations of any physical activity and NO2 on incident asthma or COPD hospitalizations. CONCLUSIONS: Increased exposure to air pollution during exercise does not outweigh beneficial effects of physical activity on the risk of asthma and COPD.

Gelatinous fibers and variant secondary growth related to stem undulation and contraction in a monkey ladder vine, Bauhinia glabra (Fabaceae).

PREMISE OF THE STUDY: Some of the most striking stem shapes occur in species of Bauhinia (Fabaceae) known as monkey ladder vines. Their mature stems are flattened and develop regular undulations. Although stems have variant (anomalous) secondary growth, the mechanism causing the undulations is unknown. METHODS: We measured stem segments over time (20 mo), described stem development using light microscopy, and correlated the changes in stem shape with anatomy. KEY RESULTS: Growing stems are initially straight and bear tendrils on short axillary branches. The inner secondary xylem has narrow vessels and lignified fibers. As stems age, they become flattened and increasingly undulated with the production of two lobes of outer secondary xylem (OX) with wide vessels and only gelatinous fibers (G-fibers). Similar G-fibers are present in the secondary phloem and the cortical sclerified layer. In transverse sections, the concave side of each undulation has a greater area and quantity of G-fibers than the opposite convex side. Some older stems are not undulated and have less lobing of OX. Undulation causes a shortening of the stem segments: up to 28% of the original length. CONCLUSIONS: Uneven distribution of G-fibers produces tensions that are involved in the protracted development of undulations. While young extending shoots attach by lateral branch tendrils, older stems may maintain their position in the canopy using undulations and persistent branch bases as gripping devices. Flattened and undulated stems with G-fibers produce flexible woody stems.

WHO framework on meaningful engagement: A transformational approach to integrate lived experience in the noncommunicable disease and mental health agenda.

As the global public health community continues to reflect and recover from the COVID-19 pandemic, noncommunicable diseases (NCDs), and mental health and neurological conditions remains one of the largest unmet gaps in progress towards meeting the Sustainable Development Goals (SDG). People living with these health conditions, particularly among those most marginalized, acutely understand the impact of these failures in global action and investment. Integrating lived experience into the NCD and mental health response can act as an accelerator for action. Through a participatory process to co-create the WHO Framework on Meaningful Engagement on NCDs, and Mental Health and Neurological Conditions, we conducted a mixed methods and semi-structured approach, including informal consultations, focus groups, in-depth interviews, online surveys, and a short film series, that captured the perspectives of 700 individuals from 111 countries, including 386 individuals with lived experience. Working alongside lived experience communities and other relevant stakeholders, we have established and co-created a set of principles, enablers and actions for operationalizing meaningful engagement, related to dignity and respect, power and equity, inclusivity and intersectionality, commitment and transparency, and institutionalization and contextualization. People with lived experience have a right to be equitably included in all levels of policy-setting, design and implementation of programs, and to have a central role in reforming and reorienting the structures and systems intended to address the complex multifactorial challenges that they face. WHO is committed to leveraging its role in global health to further operationalize meaningful engagement within WHO and its Member States.

KIR2DS2+ NK cells in cancer patients demonstrate high activation in response to tumour-targeting antibodies.

Strategies to mobilise natural killer (NK) cells against cancer include tumour-targeting antibodies, NK cell engagers (NKCEs) and the adoptive transfer of ex vivo expanded healthy donor-derived NK cells. Genetic and functional studies have revealed that expression of the activating killer immunoglobulin-like receptor KIR2DS2 is associated with enhanced function in NK cells from healthy donors and improved outcome in several different malignancies. The optimal strategy to leverage KIR2DS2+ NK cells therapeutically is however currently unclear. In this study, we therefore evaluated the response of KIR2DS2-expressing NK cells to activation against cancer with clinically relevant tumour-targeting antibodies and following ex vivo expansion. We identified that KIR2DS2high NK cells from patients with chronic lymphocytic leukaemia and hepatocellular carcinoma had enhanced activation in response to tumour-targeting antibodies compared to KIR2DS2- NK cells. However, the superior function of healthy donor derived KIR2DS2high NK cells was lost following ex vivo expansion which is required for adoptive transfer-based therapeutic strategies. These data provide evidence that targeting KIR2DS2 directly in cancer patients may allow for the utilisation of their enhanced effector function, however such activity may be lost following their ex vivo expansion.

Why do patients seek revisionary breast surgery?

BACKGROUND: Patient motivations for revisionary breast surgery following breast augmentation, mastopexy-augmentation, and breast reduction are often overlooked. Most patients presenting for a revision do so because they desire a subsequent improvement in their appearance or wish to correct a problem resulting from the primary operation. OBJECTIVE: We present and analyze the clinical indications for revisionary breast surgery in a series of 134 consecutive cases. METHODS: We retrospectively reviewed the charts of 134 patients who underwent revisionary breast surgery in a single clinic from 1994 to 2009. Patients were grouped based on operative procedure: augmentation (n = 110), mastopexy-augmentation (n = 10), bilateral breast reduction (n = 15), breast malformation correction (n = 1). Three categories were also specified according to the cause for secondary surgery: (1) the surgeon's operative plan was flawed and/or involved a technical error, (2) an independent factor occurred such as ptosis or capsular contracture, or (3) there was a combination of both factors. RESULTS: The most frequent reasons for revisionary surgery among aesthetic implant patients were the development of ptosis (42%), capsular contracture (29%), and lower-pole deformities (19%). Twenty-six percent of patients had a combination of problems. Revision among breast reduction patients was due to volume loss from overresection (40%), nipple-areola loss (27%), and breast asymmetry (27%). The average time between the first surgery and reoperation was 8.9 years for augmentation, 4.3 years for mastopexy-augmentation, and 2.9 years for reduction. In implant patients, the biggest problem leading to revisionary surgery was natural progression (66% augmentation, 90% mastopexy-augmentation). However, among breast reduction patients, 73% of revision requests were a result of problems with surgeon judgment or technique. CONCLUSIONS: Our study demonstrates that although the rate of surgeon-specific problems was high in reduction patients, overall, independent factors were the primary reason patients sought revisionary breast surgery. This may be contrary to commonly held beliefs that attribute poor results and revision requests to incorrect surgical technique and erroneous surgical decision making.

Targeting KIR as a novel approach to improve CAR-NK cell function.

Chimeric antigen receptor (CAR) NK cells are demonstrating promising activity in clinical trials and possess a favorable safety profile compared to CAR-T cells. The Killer cell Immunoglobulin-like Receptors (KIR) have a critical role in the control of NK cell function, and recently, this family of activating and inhibitory receptors have been targeted to improve CAR-NK function. These strategies include the utilisation of inhibitory KIR to reduce trogocytosis-associated NK cell fratricide, the downregulation of inhibitory KIR on CAR-NK cells to alleviate HLA mediated suppression, the selection of CAR-NK cell donors enriched for activating KIR, and the use of activating KIR intracellular domains within novel CAR constructs. These pre-clinical studies demonstrate the potential utility of targeting the KIR to improve CAR-NK cell efficacy and patient outcomes.

XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression.

The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL.

Disruption of the NKG2A:HLA-E Immune Checkpoint Axis to Enhance NK Cell Activation against Cancer.

Ligation of the inhibitory receptor NKG2A by its ligand HLA-E negatively regulates the activation of natural killer (NK) cells, as well as subsets of CD8+ T cells and innate T cell populations. NKG2A has recently become a novel immune checkpoint target for the treatment of cancer and direct antibody mediated blockade of NKG2A function is currently under assessment in two phase 3 clinical trials. In addition to direct targeting, the NKG2A:HLA-E axis can also be disrupted indirectly via multiple different targeted cancer agents that were not previously recognised to possess immunomodulatory properties. Increased understanding of immune cell modulation by targeted cancer therapies will allow for the design of rational and more efficacious drug combination strategies to improve cancer patient outcomes. In this review, we summarise and discuss the various strategies currently in development which either directly or indirectly disrupt the NKG2A:HLA-E interaction to enhance NK cell activation against cancer.