Introduction: Cabozantinib (cabo) is an inhibitor of tyrosine kinases including MET, VEGFR2, RET, and the TAM family kinases TYRO3, AXL, and MER. Cabo has shown clinical activity in patients with ...castration-resistant prostate cancer and other solid tumors with bone metastases. Multiple myeloma (MM) is the second most common hematologic malignancy, and represents ~2% of all cancer deaths. MM is a monoclonal B-cell (plasma cell) neoplasia with clinical hallmarks of multiple osteolytic lesions causing bone pain, pathologic fractures, and hypercalcemia. Circulating levels of HGF and VEGF are upregulated in MM patients, and regulation of plasma cell-osteoblast communication by the HGF-MET signaling pathway has been implicated in the development of lytic bone disease in these patients. Thus, the primary objectives of this research were to A): determine the activity of cabo on bone lesions and tumor burden in the syngeneic 5TGM1 mouse MM model (study 1), and B): investigate the impact of cabo on overall survival of these mice when dosed alone or in combination with bortezomib (btz) (study 2).
Methods: Female C57BL/KaLwRij mice were allocated to treatment groups (n=15-16 per group) with equivalent average body weights. Four experimental groups were utilized in each of 2 studies: a vehicle control group, and groups receiving single agent btz (0.5 mg/kg ip twice a week) or cabo (10 mg/kg, PO QD). Study 1 also included a higher dose cabo group (30 mg/kg, PO QD), and study 2 included a combination group: btz (0.5 mg/kg ip twice a week) plus cabo (10 mg/kg, PO QD). In study 2, each single agent group also received the vehicle from the alternate single-agent group via the appropriate route and schedule.
On day 0, animals were inoculated with 5TGM1 mouse myeloma cells by IV administration. Dosing began on day 1 and continued daily until euthanasia at day 35 (study 1) or day 70 (study 2). Body weights were determined twice a week and blood samples were collected on days -1, 15, 22, and 34 for analysis of paraprotein (IgG2b) and TRACP 5b. In study 1 the development of osteolytic lesions was detected by radiography at the end of the study. Some animals were euthanized before the end of the experiment due to paraplegia. Animals euthanized within four days of the end of the experiment in study 1 were included in the analyses.
Results: In study 1, btz reduced serum IgG2b levels, and decreased the frequency of soft tissue lesions, but did not show bone protective properties. Cabo exhibited bone protective effects: mean and total area of osteolytic lesions were reduced at the 30 mg/kg dose, and serum TRACP 5b values and osteoclast counts at the tumor-bone interface were reduced at both the 10 and 30 mg/kg doses. Relative bone area did not differ from control according to histomorphometry. The rise in serum IgG2b started earlier than vehicle control in both cabo-treated groups, but a significant difference was not observed in relative IgG2b at sacrifice. Cabo dose dependently increased the necrotic tumor area in bone, indicating the possibility that the rise in IgG2b may have been due to lysis of plasma cells. Both doses of cabo decreased the frequency of soft tissue lesions.
In study 2, the median survival times were 36 d (vehicle), 43 d (btz), 48 d (cabo), and 55 d (cabo+btz). The prolongation of OS compared to vehicle was statistically significant for the cabo group but not for the btz group. Prolongation of OS in the combination group was significant compared to btz alone, but not when compared to cabo alone.
Conclusions: Cabo showed both bone-protective and anti-tumor effects in this murine model of MM. In addition, statistically-significant prolongation of overall survival was observed with the combination of cabo+btz compared to btz alone, and with single-agent cabo compared to vehicle. Based on these results, further investigation of cabozantinib alone or in combination with other agents in multiple myeloma is warranted.
Aftab:Exelixis: Employment, Equity Ownership. Suominen:Pharmatest: Employment; Exelixis: Research Funding. Clary:Exelixis: Employment, Equity Ownership. Käkönen:Pharmatest: Employment; Exelixis: Research Funding. Fagerlund:Pharmatest: Employment; Exelixis: Research Funding. Alhoniemi:Pharmatest: Employment; Exelixis: Research Funding. Rissanen:Pharmatest: Employment; Exelixis: Research Funding. Halleen:Pharmatest: Employment; Exelixis: Research Funding.
Autonomy has been recognised as a key principle in healthcare, but we still need to develop a consistent understanding of older people’s perceived autonomy in residential care. This study aimed to ...identify, describe and synthesise previous studies on the perceived autonomy of older people in residential care. Ethical approval was not required, as this was a review of published literature. We carried out an integrative review to synthesise previous knowledge published in peer-review journals in English up to September 2019. Electronic and manual searches were conducted using the CINAHL, Philosopher’s Index, PubMed, SocINDEX, Scopus and Web of Science databases. The data were analysed using the constant comparison method. The review identified 46 studies. Perceived autonomy referred to the opportunities that older people had to make their own choices about their daily life in residential care, and achieving autonomy promoted both health and quality of life. Autonomy was linked to older people’s individual capacities, including their level of independence, physical and mental competence, personal characteristics, and whether relatives shared and supported their perceived autonomy. Professionals could facilitate or hinder older peoples’ autonomy in a number of ways, including providing opportunities for autonomy, how daily care needs and activities were managed, and controlling older people’s choices. Professionals’ characteristics, such as education and attitudes, and the older people’s living environments were also associated with their perceived autonomy and included organisational characteristics and physical and social care facilitators. Older people’s perceived autonomy promoted health and quality of life in residential care. However, their autonomy was associated with a number of protective and restrictive individual and environmental factors, which influenced whether autonomy was achieved.
BackgroundThe recent KEYNOTE-199 trial raises hope for new treatment options for prostate cancer patients with the encouraging results of checkpoint inhibitor activity in a subset of prostate cancer ...patients, also including patients with bone-predominant disease. However, the patient subset that benefited from the treatment was small, needing identification predictive biomarkers1. Proper preclinical models can help in the biomarker quest as well as in the search and selection of the best possible combination partners for further clinical trials.MethodsIn this study the bone-metastatic disease was modeled by intratibial inoculation of LNCaP human prostate cancer cells to male CIEA NOG® (NOG) mice and NOG mice engrafted with human CD34+ hematopoietic stem cells (huNOG, Taconic Biosciences). Tumor growth was followed by serum PSA measurements and tumor-induced bone changes by X-ray images. At study week 4, the PSA positive mice were stratified to two groups (n=10) treated with IgG4 isotype control or pembrolizumab (5 mg/kg, i.p., Q5D) until the end of the study. Tumor-induced bone changes were followed by X-ray 4, 8 and 10 weeks after inoculation. The study was terminated 10 weeks after inoculation and tumors were processed for histological and immunohistochemical (IHC) analysis of tumor infiltrating lymphocytes (TILs). Changes in blood cell counts were assessed by flow cytometry and hematology (n=5/group).ResultsAt sacrifice, tumor-induced bone changes were observed in all mice, and there was no difference between the groups. Even though the PSA was not significantly lower in the pembrolizumab-treated group, the average histological tumorous surface was lower. In flow cytometry of peripheral blood, increases in the portions of CD3+ leukocytes and double positive CD4+CD8+ cells were observed, but no differences were found in CD4+ nor CD8+ T-cells. However, CD8+ T-cells were radically increased within the tumor as analyzed by IHC.ConclusionsThe model successfully mimicked the prevalent clinical situation, where clear responses in PSA or target lesions are not observed. However, a dramatic increase of cytotoxic T-cells in the tumor was observed, revealing the effects of pembrolizumab in a model of prostate cancer growth in bone of huNOG mice. The model presents a suitable platform for studying combination partners with pembrolizumab, that would boost or unlock the anti-tumor activity of the increased TILs.Ethics ApprovalThis study was approved by the National Animal Experiment Board in Finland; license number ESAVI-2331-04 10 07-2017.ReferenceAntonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol 2020;38:395–405.
Only few studies exist on the phenotype distribution of peripheral blood lymphocytes concerning persistent oral HPV infection. T-lymphocyte subsets were phenotyped in women who had persistent genital ...or oral HPV16 infection, using HPV-negative women as a reference group. A subset of 42 mothers and their children (
= 28), were stratified into two groups according to the mothers' HPV status. PBMCs from previously cryopreserved venous samples were immunophenotyped by flow cytometry. Proportions of the CD4
or CD8
lymphocytes by their immunophenotype subsets were compared between HPV-positive and -negative mothers and their children. The mean rank distribution of CD8
memory cells was significantly higher among mothers with persistent genital HPV16 infection. The median levels of both the antigen-presenting CD4
cells and activated CD8
cells were significantly lower in mothers with persistent oral HPV16 infection. When oral and genital HPV16-persistors were analyzed as a group, a marker of terminal effector cells was significantly increased as compared to HPV-negative women. Significantly higher levels of activated CD4
, CD8
and circulating CD8
memory cells were found among children whose mothers had persistent oral HPV16 infection. Persistent HPV16 infections are associated with changes in peripheral blood T-lymphocyte subsets. The mother's persistent oral HPV16 infection possibly results in immune alterations in her offspring.
Induced pluripotent stem cell (iPSC) technology enables differentiation of human hepatocytes or hepatocyte-like cells (iPSC-HLCs). Advances in 3D culturing platforms enable the development of more in ...vivo-like liver models that recapitulate the complex liver architecture and functionality better than traditional 2D monocultures. Moreover, within the liver, non-parenchymal cells (NPCs) are critically involved in the regulation and maintenance of hepatocyte metabolic function. Thus, models combining 3D culture and co-culturing of various cell types potentially create more functional in vitro liver models than 2D monocultures. Here, we report the establishment of 3D cultures of iPSC-HLCs alone and in co-culture with human umbilical vein endothelial cells (HUVECs) and adipose tissue-derived mesenchymal stem/stromal cells (hASCs). The 3D cultures were performed as spheroids or on microfluidic chips utilizing various biomaterials. Our results show that both 3D spheroid and on-chip culture enhance the expression of mature liver marker genes and proteins compared to 2D. Among the spheroid models, we saw the best functionality in iPSC-HLC monoculture spheroids. On the contrary, in the chip system, the multilineage model outperformed the monoculture chip model. Additionally, the optical projection tomography (OPT) and electrical impedance tomography (EIT) system revealed changes in spheroid size and electrical conductivity during spheroid culture, suggesting changes in cell–cell connections. Altogether, the present study demonstrates that iPSC-HLCs can successfully be cultured in 3D as spheroids and on microfluidic chips, and co-culturing iPSC-HLCs with NPCs enhances their functionality. These 3D in vitro liver systems are promising human-derived platforms usable in various liver-related studies, specifically when using patient-specific iPSCs.
The health, well-being and safety of the general population are important goals for society, but forecasting outcomes and weighing up the costs and benefits of effective promotional programmes is ...challenging. This study aimed to identify and describe the cost-effectiveness calculators that analyze interventions that promote health, well-being and safety.
Our systematic review used the CINAHL, PsycINFO, SocINDEX, EconLit, PubMed and Scopus databases to identify peer-reviewed studies published in English between January 2010 and April 2020. The data were analyzed with narrative synthesis.
The searches identified 6880 papers and nine met our eligibility and quality criteria. All nine calculators focussed on interventions that promoted health and well-being, but no safety promotion tools were identified. Five calculators were targeted at group-level initiatives, two at regional levels and two at national levels. The calculators combined different data sources, in addition to data inputted by users. This included empirical research and previous literature. The calculators created baseline estimates and assessed the cost-effectiveness of the interventions before or after they were implemented. The calculators were heterogeneous in terms of outcomes, the interventions they evaluated and the data and methods used.
This review identified nine calculators that assessed the cost-effectiveness of health and well-being interventions and supported decision-making and resource allocations at local, regional and national levels, but none focussed on safety. Producing calculators that work accurately in different contexts might be challenging. Further research should identify how to assess sustainable evaluation of health, well-being and safety strategies.
We investigated whether certain bacterial species and their combinations in saliva can be used as markers for periodontitis. In 1,198 subjects, the detection of multiple species, rather than the ...presence of a certain pathogen, in saliva was associated with periodontitis as determined by the number of teeth with deepened periodontal pockets.
The improvement of energy efficiency is seen as one of the most promising measures for reducing global CO2 emissions. However, the emission reduction potential may seem different from the industrial ...plant and policy-maker's perspectives. This paper evaluates the influences of process heat conservation on CHP electricity production, primary energy consumption and CO2 emissions from both the mill site and national perspectives. The results indicate that heat conservation in an industrial process may lead to varying results in primary energy consumption and CO2 emissions, depending on the form of marginal heat production used at the mill site. In the CHP process, reduction of the heat load lowers electricity production, and this reduction may have to be compensated for at the national level. Therefore, the energy conservation potential in industry has to be evaluated by taking into account the connections to the outside society, which means that a wider system boundary than a mill site has to be used. This study demonstrates by theoretical analysis and case mill studies the magnitude of the effects of system boundary definition when evaluating the contribution of an individual energy efficiency investment towards fulfilling the commitment to reduce CO2 emissions at the national level.
Large, general population-based data on carriage rates of periodontal pathogens hardly exist in the current literature. The objectives of the present study were to examine the salivary detection of ...Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, Campylobacter rectus, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythensis, and Treponema denticola in a representative sample of the adult population living in southern Finland and to clarify which determinants are associated with the presence of these pathogens in saliva. 16S rRNA-based PCR methods with species-specific primers were employed to determine the presence of the six target bacteria in stimulated saliva samples, which were available from 1,294 subjects aged >=30 years. The age group, gender, level of education, marital status, smoking history, number of teeth, and number of teeth with deepened pockets were included in the statistical analysis. In general, the carriage of periodontal pathogens was common, since at least one of the examined pathogens was found in 88.2% of the subjects. In descending order, the total detection rates were 56.9%, 38.2%, 35.4%, 31.3%, 20.0%, and 13.9% for T. forsythensis, T. denticola, P. gingivalis, C. rectus, A. actinomycetemcomitans, and P. intermedia, respectively. Age per se was strongly associated with the carriage of P. gingivalis (P = 0.000), and the level of education with that of T. denticola (P = 0.000). There was an association between the number of teeth with deepened pockets and carriage of P. gingivalis (P = 0.000), P. intermedia (P = 0.000), T. denticola (P = 0.000), and A. actinomycetemcomitans (P = 0.004). The data suggest that distinct species have a different carriage profile, depending on variables such as age, educational level, and periodontal status.
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