Around a third of children perceive and process their environment more deeply and are more impacted by its quality. To obtain a more comprehensive and objective measure of this Environmental ...Sensitivity (ES) in primary school children, we developed a semi-structured, multi-informant interview. Study 1 captures the item development while Study 2 covers the psychometric analysis and initial validation of the interview in a small pilot sample of 61 parents, their 60 children, and nine teachers, recruited from a longitudinal study involving 7–9-year-old second-graders in Swiss primary schools. Method: Interviews were conducted by trained psychologists with expertise in ES. Questionnaire data was collected from parents, children, and teachers. Findings: Parent and child interviews had good internal consistency (α = 0.83, α = 0.79, respectively) and correlated highly with each other (r = 0.535). Parent-interview correlated well with the validated sensitivity questionnaire (r = 0.514). Teacher interviews diverged from parent and child views and may inform about differences in how sensitivity is reflected across contexts. Conclusions: The new Highly Sensitive Child Interview (HSC – I) is a promising tool for a comprehensive and reliable assessment of sensitivity in primary school children and will be of value to educational psychologists following larger-scale validation.
Declarations of Interest: None.
•Highly sensitive children process their environment more deeply.•We present a new multi-informant interview of children's environmental sensitivity.•Parent and child interviews are characterized by good psychometric properties.•Parent and child interviews have a strong agreement between them.•The interview correlates with existing sensitivity measures.
Social interactions can be stressful, especially if they involve provocation or ambiguity. At the same time, such interactions necessitate social cognition. The question thus arises how stress ...affects social cognition and how personality attributes modulate this effect. The aim of the current study was to investigate the link between emotional reactivity, physical exercise, and social cognition under stress. As a measure of social cognition, we used spontaneous perspective taking, i.e., the degree to which participants represented the mental state of another agent. Studying young female participants, we investigated how physiological regulation, measured through resting heart-rate variability, is related to spontaneous social perspective taking under stress, and to predicted anger in an ambiguous social scenario. When controlling for resting heart rate, vagally mediated heart-rate variability was negatively correlated with the effect of stress on perspective taking, indicating that good physiological regulation supports social cognition under stress. Further, participants who reported to exercise at least once a week showed higher perspective taking under stress than less active participants. Finally, we found tentative evidence for participants who exercised regularly to show reduced predicted anger in response to an ambiguous provocation. Our findings suggest that good physiological regulation and regular physical exercise support social cognition under stress.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Bone metastases are prevalent in many common cancers such as breast, prostate, and lung cancers, and novel therapies for treating bone metastases are needed. Human immune system-engrafted models are ...used in immuno-oncology (IO) studies for subcutaneous cancer cell or patient-derived xenograft implantations that mimic primary tumor growth. Novel efficacy models for IO compounds on bone metastases need to be established. The study was performed using CIEA NOG (NOG) mice engrafted with human CD34+ hematopoietic stem cells (huNOG) and age-matched immunodeficient NOG mice. Bone phenotyping was performed to evaluate baseline differences. BT-474 human breast cancer cells were inoculated into the tibia bone marrow, and cancer-induced bone changes were monitored by X-ray imaging. Bone content and volume were analyzed by dual X-ray absorptiometry and microcomputed tomography. Tumor-infiltrating lymphocytes (TILs) and the expression of immune checkpoint markers were analyzed by immunohistochemistry. Bone phenotyping showed no differences in bone architecture or volume of the healthy bones in huNOG and NOG mice, but the bone marrow fat was absent in huNOG mice. Fibrotic areas were observed in the bone marrow of some huNOG mice. BT-474 tumors induced osteoblastic bone growth. Bone lesions appeared earlier and were larger, and bone mineral density was higher in huNOG mice. huNOG mice had a high number of human CD3-, CD4-, and CD8-positive T cells and CD20-positive B cells in immune-related organs. A low number of TILs and PD-1-positive cells and low PD-L1 expression were observed in the BT-474 tumors at the endpoint. This study reports characterization of the first breast cancer bone growth model in huNOG mice. BT-474 tumors represent a “cold” tumor with a low number of TILs. This model can be used for evaluating the efficacy of combination treatments of IO therapies with immune-stimulatory compounds or therapeutic approaches on bone metastatic breast cancer.
A growing body of literature suggests that specific markers of relationship quality are meaningfully linked to health outcomes. We tested whether relational self‐expansion potential might be one of ...these markers in cross‐sectional samples of individuals and romantic couples. Study 1 found that greater self‐expansion potential was linked to better perceived physical health via both higher positive affect (PA) and lower negative affect (NA). Study 2 replicated these findings for PA (but not NA) and revealed both actor and partner effects of self‐expansion potential. Results remained robust when statistically accounting for gender, age, body mass index, agreeableness, neuroticism, and perceived partner responsiveness. These findings identify a new relationship‐level “active ingredient” associated with health and have implications for future physical health studies.
Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive cancer with treatment options limited to standard-of-care chemotherapy. TNBC patients develop metastases in high incidence, ...and almost all patients have bone metastases at end-stage disease. Bone metastases are mainly osteolytic, causing severe bone loss that can be prevented by bone-targeted agents. Currently, there is no efficient cure for bone metastases. Activation of the patient’s own immune system by immunotherapies is widely studied in various cancers, but their efficacy on bone metastases is not well established. In this study, we aimed to evaluate the efficacy of immunotherapies in comparison to standard-of-care compounds in a preclinical TNBC bone metastasis model. Materials and methods: Mouse 4T1-GFP TNBC cells were inoculated intracardially to immunocompetent female Balb/c mice to model bone metastasis. Treatment of single agents of chemotherapy (cyclophosphamide, 100 mg/kg), bone-targeting agent (zoledronic acid, 0.1 mg/kg), and immunotherapies programmed cell death 1 antibody (mouse anti-PD-1, 10 mg/kg) and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor (epacadostat, 100 mg/kg), and the combination of anti-PD-1 and epacadostat were started on the day following the cancer cell inoculations. The study was terminated 12-13 days after the inoculations. Tumor burden was evaluated by GFP imaging and tumor-induced bone loss by X-ray imaging at sacrifice. Tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemical stainings of CD3+, CD4+ and CD8+ T cells. Results: Cyclophosphamide decreased skeletal tumor burden and the area of tumor-induced osteolytic bone lesions. Zoledronic acid decreased the area of osteolytic lesions but had no effect on skeletal tumor burden. Anti-PD-1, epacadostat and their combination had no effect on skeletal tumor burden or in the development of osteolytic lesions. Low number or no TILs were observed in the tumors growing in bone obtained from vehicle-treated mice. Conclusions: Immunotherapies did not prevent tumor growth in bone or tumor-induced bone changes in the syngeneic TNBC model. This is probably caused by the low number of TILs in the tumors growing in bone. Further studies are needed to evaluate the effects of treatment combinations and to increase the responsiveness to immunotherapies especially in bone metastases.
Citation Format: Tiina E Kähkönen, Mari I Suominen, Jenni HE Mäki-Jouppila, Jussi M Halleen, Jenni Bernoulli. Lack of immunotherapy efficacy in a syngeneic bone metastasis model of triple-negative breast cancer abstract. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B144. doi:10.1158/1535-7163.TARG-19-B144
Abstract
Background: Programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) expression is typically low in primary prostate cancer but increases at advanced stages. However, targeting ...PD-1 or PD-L1 has not proven efficacy in prostate cancer patients, and recent clinical trials are directed to combination therapies. About 85% of advanced prostate cancer patients develop skeletal metastases, and the focus in this context should be addressed to the treatment of these metastases. These efforts have been hindered by the lack of relevant preclinical bone metastasis models in immunocompetent mice. We aimed to establish a prostate cancer bone metastasis model in humanized mice and to assess pembrolizumab efficacy in the established model. Materials and methods: Two million LNCaP human prostate cancer cells were inoculated into tibia bone marrow of male CIEA NOG® mice engrafted with human CD34+ hematopoietic stem cells to generate humanized mice. Serum prostate-specific antigen (PSA) levels were measured at 4 weeks, and the mice were allocated to receive either pembrolizumab (anti-PD-1, Keytruda®, 5 mg/kg, Q5D) or human IgG4 isotype control for 6 weeks. Tumor growth was monitored by measuring serum PSA levels. Tumor-induced bone changes were monitored by measuring serum levels of the bone formation marker N-terminal propeptide of type I procollagen (PINP), and by X-ray imaging of tibia. Changes in quantity of circulating T cells was monitored by flow cytometry. At study termination, tissue samples were collected for histological and immunohistochemical evaluation of tumor-infiltrating lymphocytes (TILs). Results: A tumor take of 90% was observed in the humanized mice evaluated by serum PSA levels at endpoint. No significant differences were observed in serum PSA levels, but in a few mice treated with pembrolizumab, only modest tumor growth was observed. Intratibial LNCaP tumors induced osteoblastic-mixed lesions as evaluated by X-ray imaging. No differences were observed in the bone lesion area or in serum PINP levels between the isotype control and pembrolizumab groups. No changes in circulating levels of CD4+, CD8+, or CD4+CD8+ cells were observed. Histology will be performed to confirm tumor morphology and overall tumor viability, and immunohistochemical analysis will reveal the quantity and location of TILs in the tumor. Conclusions: A novel preclinical model of bone metastasis in humanized mice was established. Intratibial prostate cancer tumors induced osteoblastic mixed bone lesions and increased serum PSA levels, mimicking the clinical situation in patients. Resembling recent clinical findings, no or modest responses with pembrolizumab as monotherapy were observed.
Citation Format: Tiina E Kähkönen, Mari I Suominen, Jenni HE Mäki-Jouppila, Azusa Tanaka, Philip Dube, Jussi M Halleen, Jenni Bernoulli. Establishment of a novel prostate cancer bone metastasis model in humanized mice and early efficacy results of pembrolizumab abstract. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A01. doi:10.1158/1535-7163.TARG-19-LB-A01
Abstract
Background: Immunotherapy is an emerging treatment option for different subtypes of breast cancer. Pembrolizumab (Keytruda®) targets PD-1 expressing T cells in tumors and mediates anti-tumor ...effects. Targeting PD-1 has shown promising results in advanced breast cancer and is being evaluated in clinical trials in triple-negative breast cancer (TNBC) and in estrogen receptor positive, human epidermal growth factor 2 negative (ER+/HER2-) breast cancer patients. Immunotherapy is not yet an established treatment option for early breast cancer. The aim of this study was to establish preclinical primary tumor models for TNBC and ER+/HER2- in humanized mice, and to evaluate efficacy of pembrolizumab in the models. Materials and methods: Immunodeficient CIEA NOG female mice engrafted with human CD34+ hematopoietic stem cells (huNOG mice) were inoculated orthotopically into mammary fat pad with either MDA-MB-231(SA) (TNBC) or MCF-7 (ER+/HER2-) human breast cancer cells. The mice receiving MCF-7 cells were implanted with estradiol (E2) releasing pellets before cancer cell inoculation to support tumor growth. The mice were treated with pembrolizumab (5 mg/kg) or isotype control in a Q5D schedule. The treatments were started 3 or 14 days after cancer cell inoculation in the TNBC and ER+/HER2- models, respectively. Tumor growth was monitored by caliper measurements, and the study was terminated at 3 weeks (TNBC model) or 7 weeks (ER+/HER2- model). Tumors were collected and analyzed immunohistochemically for tumor-infiltrating lymphocytes (TILs), and hematological analysis was performed from the mice in the ER+/HER2- model. Results: Tumors responded to pembrolizumab treatment in the TNBC model. Three out of eight mice responded to the treatment and one of them had a tumor rejection. Pembrolizumab treatment was associated with decrease in CD8+ TILs and granzyme B+ cells in the tumor. In the ER+/HER2- model, E2 supplementation was essential for tumor growth. However, E2 caused a decrease in the clinical condition, including decrease in white and red blood cells, leading to early sacrifices. Only modest responses for pembrolizumab were observed in a few mice and the results did not reach statistical significance. No major changes were observed in TILs due to pembrolizumab treatment. Conclusions: In the established breast cancer models in humanized mice, pembrolizumab decreased tumor growth in the TNBC model but induced only minor tumor responses in the ER+/HER2- model. Estrogen was essential for ER+/HER2- tumor growth but induced severe anemia and had immunomodulatory effects potentially influencing the lack of pembrolizumab efficacy in the model.
Citation Format: Tiina E Kähkönen, Mari I Suominen, Jenni HE Mäki-Jouppila, Azusa Tanaka, Philip Dube, Michael Seiler, Jussi M Halleen, Jenni Bernoulli. Establishment of primary tumor models of TNBC and ER+/HER2- breast cancer in humanized mice and validation of pembrolizumab efficacy abstract. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B143. doi:10.1158/1535-7163.TARG-19-B143
Bone is among the main sites of metastasis in breast, prostate and other major cancers. Bone metastases remain incurable causing high mortality, severe skeletal-related effects and decreased quality ...of life. Despite the success of immunotherapies in oncology, no immunotherapies are approved for bone metastasis and no clear benefit has been observed with approved immunotherapies in treatment of bone metastatic disease. Therefore, it is crucial to consider unique features of tumor microenvironment in bone metastasis when developing novel therapies. The vicious cycle of bone metastasis, referring to crosstalk between tumor and bone cells that enables the tumor cells to grow in the bone microenvironment, is a well-established concept. Very recently, a novel osteoimmuno-oncology (OIO) concept was introduced to the scientific community. OIO emphasizes the significance of interactions between tumor, immune and bone cells in promoting tumor growth in bone metastasis, and it can be used to reveal the most promising targets for bone metastasis. In order to provide an insight into the current immuno-oncology drug development landscape, we used 1stOncology database, a cancer drug development resource to identify novel immunotherapies in preclinical or clinical development for breast and prostate cancer bone metastasis. Based on the database search, 24 immunotherapies were identified in preclinical or clinical development that included evaluation of effects on bone metastasis. This review provides an insight to novel immuno-oncology drug development in the context of bone metastasis. Bone metastases can be approached using different modalities, and tumor microenvironment in bone provides many potential targets for bone metastasis. Noting current increasing interest in the field of OIO, more therapeutic opportunities that primarily target bone metastasis are expected in the future.
Abstract
Bone metastases are a significant cause of mortality in many major cancers. They are difficult to treat and their response rate to standard-of-care therapies is low. Immunotherapies have ...been approved as stand-alone therapies or in combination with other therapies for the treatment of advanced or metastatic breast, prostate and lung cancer and melanoma patients. It is unclear if approved immunotherapies affect bone metastases.
In this study, relevant scientific publications were evaluated for feasibility to perform a meta-analysis about immunotherapy efficacy on bone metastases. A PubMed search for approved immunotherapies for each of the above-mentioned cancer indications on September 21, 2020 resulted in 561 relevant scientific publications. From these, the criteria for the selection of publications for this study were: 1) patients had detectable bone metastases, 2) patients received at least one immunotherapy treatment, 3) therapy effects for bone metastases was followed, 4) the study was published between 2010-2020. Based on these criteria only six eligible studies were identified.
Treatment with atezolizumab and nab-paclitaxel increased median overall survival in PD-L1+ bone metastatic tripe-negative breast cancer patients compared to nab-paclitaxel treatment only (Schmid et al., 2020). In metastatic castration-resistant prostate cancer patients with bone-predominant disease, pembrolizumab increased disease control rate and median overall survival compared to patients without bone metastases (Antonarakis et al., 2019). In non-small cell lung cancer patients, long-term survivors (LTS, over 24 months) had fewer bone metastases than non-LTS (Pawel et al., 2019). Upon progression, LTS treated with atezolizumab had less cases with liver and bone metastases compared to non-LTS, whereas the incidence was similar in patients treated with docetaxel. In melanoma, complete radiographic responses in bone metastatic patients were not observed when the patients were treated with pembrolizumab (Lee et al., 2017), progressive disease was observed with ipilimumab in combination with radiation therapy (Sundahl et al., 2018), and patients progressed at bone and other metastatic sites with ipilimumab in combination with Bacillicus Calmette-Guérin (Da Gama Duarte et al., 2018).
Only about 1% (6/561) of publications with approved immunotherapies in breast, prostate and lung cancer and melanoma patients reported results on bone metastases. No conclusion can be drawn about the efficacy due to the limited number of eligible studies. Clinical trials with immunotherapies specifying effects on bone metastases are warranted as they would allow to better understand metastasis-specific responses, improve patient selection in future clinical studies, and ultimately help in providing more effective treatments for patients with life-threatening bone metastases.
Citation Format: Tiina E. Kähkönen, Jussi M. Halleen, Jenni Bernoulli. Limited data from clinical trials assessing immunotherapy effects on bone metastases abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2870.
Immunotherapies provide a potential treatment option for currently incurable bone metastases. Bone marrow is an important secondary lymphoid organ with a unique immune contexture. Even at non-disease ...state immune cells and bone cells interact with each other, bone cells supporting the development of immune cells and immune cells regulating bone turnover. In cancer, tumor cells interfere with this homeostatic process starting from formation of pre-metastatic niche and later supporting growth of bone metastases. In this review, we introduce a novel concept osteoimmuno-oncology (OIO), which refers to interactions between bone, immune and tumor cells in bone metastatic microenvironment. We also discuss therapeutic opportunities of targeting immune cells in bone metastases, and associated efficacy and safety concerns.
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