Browsing by Subject "COMBINATION"

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  • Sanwald, Corinna; Robciuc, Alexandra; Ruokonen, Suvi-Katriina; Wiedmer, Susanne K.; Lammerhofer, Michael (2019)
    This work presents the development and validation of a quantitative HILIC UHPLC-ESI-QTOF-MS/MS method for amino acids combined with untargeted metabolic profiling of human corneal epithelial (HCE) cells after treatment with ionic liquids. The work included a preliminary metabotoxicity screening of 14 different ionic liquids, of which 9 carefully selected ionic liquids were chosen for a metabolomics study. This study is focused on the correlation between the toxicity of the ionic liquids and their metabolic profiles. The method development included the comparison of different MS/MS acquisition modes. A sequential window acquisition of all theoretical fragment ion mass spectra (SWATH) method with variable Q1 window widths and narrow Q1 target windows of 5 Da for most of the amino acids was selected as the optimal acquisition mode. Due to the absence of a true blank matrix, C-13,N-15-isotopically labelled amino acids were utilized as surrogate calibrants, instead of proteinogenic amino acids. Partial least squares (PLS) analysis of the median effective concentrations (EC50) of 9 selected ionic liquids showed a correlation with their metabolic profile measured by the untargeted screening.
  • Jousi, Mikko O.; Erkkilä, Jukka; Varjonen, Mari; Soiva, Martti; Hukkinen, Katja; Sequeiros, Roberto Blanco (2019)
    Background Digital breast tomosynthesis (DBT) is gaining popularity in breast imaging. There are several different technical approaches for conducting DBT imaging. Purpose To determine optimal imaging parameters, test patient friendliness, evaluate the initial diagnostic performance, and describe diagnostic advances possible with the new Continuous Sync-and-Shoot method. Material and Methods Thirty-six surgical breast specimens were imaged with digital mammography (DM) and a prototype of a DBT system (Planmed Oy, Helsinki, Finland). We tested the patient friendliness of the sync-and-shoot movement without radiation exposure in eight volunteers. Different imaging parameters were tested with 20 specimens to identify the optimal combination: angular range 30 degrees, 40 degrees, and 60 degrees; pixel binning; Rhodium (Rh) and Silver (Ag) filtrations; and different kV and mAs values. Two breast radiologists evaluated 16 DM and DBT image pairs and rated six different image properties. Imaging modalities were compared with paired t-test. Results The Continuous Sync-and-Shoot method produced diagnostically valid images. Five out of eight volunteers felt no/minimal discomfort, three experienced mild discomfort from the tilting movement of the detector, with the motion being barely recognized. The combination of 30 degrees, Ag filtering, and 2 x 2 pixel binning produced the best image quality at an acceptable dose level. DBT was significantly better in all six evaluated properties (P <0.05). Mean Dose(DBT)/Dose(DM) ratio was 1.22 (SD = 0.42). Conclusion The evaluated imaging method is feasible for imaging and analysing surgical breast specimens and DBT is significantly better than DM in image evaluation.
  • NORD STAR Study Grp; Hetland, Merete Lund; Haavardsholm, Espen A.; Rudin, Anna; Nordström, Dan; van Vollenhoven, Ronald (2020)
    OBJECTIVE To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. DESIGN Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. SETTING Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. PARTICIPANTS Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. INTERVENTIONS Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intraarticular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. MAIN OUTCOME MEASURES The primary outcome was adjusted clinical disease activity index remission (CDAI RESULTS 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. CONCLUSIONS All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.
  • Cervera-Carrascon, Victor; Quixabeira, Dafne C. A.; Santos, Joao M.; Havunen, Riikka; Milenova, Ioanna; Verhoeff, Jan; Heinio, Camilla; Zafar, Sadia; Garcia-Vallejo, Juan J.; van Beusechem, Victor W.; de Gruijl, Tanja D.; Kalervo, Aino; Sorsa, Suvi; Kanerva, Anna; Hemminki, Akseli (2021)
    Immune checkpoint inhibitors such as anti-PD-1 have revolutionized the field of oncology over the past decade. Nevertheless, the majority of patients do not benefit from them. Virotherapy is a flexible tool that can be used to stimulate and/or recruit different immune populations. T-cell enabling virotherapy could enhance the efficacy of immune checkpoint inhibitors, even in tumors resistant to these inhibitors. The T-cell potentiating virotherapy used here consisted of adenoviruses engineered to express tumor necrosis factor alpha and interleukin-2 in the tumor microenvironment. To study virus efficacy in checkpoint-inhibitor resistant tumors, we developed an anti-PD-1 resistant melanoma model in vivo. In resistant tumors, adding virotherapy to an anti-PD-1 regimen resulted in increased survival (p=0.0009), when compared to anti-PD-1 monotherapy. Some of the animals receiving virotherapy displayed complete responses, which did not occur in the immune checkpoint-inhibitor monotherapy group. When adenoviruses were delivered into resistant tumors, there were signs of increased CD8 T-cell infiltration and activation, which - together with a reduced presence of M2 macrophages and myeloid-derived suppressor cells - could explain those results. T-cell enabling virotherapy appeared as a valuable tool to counter resistance to immune checkpoint inhibitors. The clinical translation of this approach could increase the number of cancer patients benefiting from immunotherapies.
  • EFSA Panel Dietetic Prod Nutr All (2018)
    Following an application from Unilever NV, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Ireland, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to black tea and improvement of attention. The scope of the application was proposed to fall under a health claim based on newly developed scientific evidence. The food proposed by the applicant as the subject of the health claim is black tea. The Panel considers that black tea characterised by its content of tea solids, caffeine and L-theanine, which is the subject of the health claim, is sufficiently characterised in relation to the claimed effect. The claimed effect proposed by the applicant is 'improves attention'. The Panel considers that improvement of attention is a beneficial physiological effect. Three human intervention studies provided by the applicant show an effect of black tea on attention under the conditions of used proposed by the applicant. The applicant proposed that the claimed effect depends on the concerted action of two substances, caffeine and L-theanine, both of which are present in black tea. The Panel considers that the effect of black tea on attention observed in the three human intervention studies provided by the applicant can be explained by its caffeine content. The Panel concludes that a cause and effect relationship has been established between the consumption of black tea and improvement of attention. The Panel considers that the effect of black tea on attention can be explained by its caffeine content. The following wording reflects the scientific evidence: 'Owing to its caffeine content, black tea improves attention'. In order to obtain the claimed effect, 2-3 servings of black tea providing at least 75 mg of caffeine in total should be consumed within 90 min. (C) 2018 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.
  • Choueiri, Toni K.; Escudier, Bernard; Powles, Thomas; Tannir, Nizar M.; Mainwaring, Paul N.; Rini, Brian I.; Hammers, Hans J.; Donskov, Frede; Roth, Bruce J.; Peltola, Katriina; Lee, Jae Lyun; Heng, Daniel Y. C.; Schmidinger, Manuela; Agarwal, Neeraj; Sternberg, Cora N.; McDermott, David F.; Aftab, Dana T.; Hessel, Colin; Old, Christian Scheff; Schwab, Gisela; Hutson, Thomas E.; Pal, Sumanta; Motzer, Robert J.; METEOR Investigators (2016)
    Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with, number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18.7 months (IQR 16.1-21.1) in the cabozantinib group and 18.8 months (16.0-21.2) in the everolimus group. Median overall survival was 21.4 months (95% CI 18.7-not estimable) with cabozantinib and 16.5 months (14.7-18.8) with everolimus (hazard ratio [HR] 0.66 [95% CI 0.53-0.83]; p=0.00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0.51 [95% CI 0.41-0.62]; p Interpretation Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications.
  • Einwaller, Joy; Painer, Johanna; Raekallio, Marja; Gasch, Kristina; Restitutti, Flavia; Auer, Ulrike; Stalder, Gabrielle L. (2020)
    Objective To determine the effect of intravenous vatinoxan administration on bradycardia, hypertension and level of anaesthesia induced by medetomidine-tiletamine-zolazepam in red deer (Cervus elaphus). Study design and animals A total of 10 healthy red deer were enrolled in a randomized, controlled, experimental, crossover study. Methods Deer were administered a combination of 0.1 mg kg-1 medetomidine hydrochloride and 2.5 mg kg-1 tiletamine-zolazepam intramuscularly, followed by 0.1 mg kg-1 vatinoxan hydrochloride or equivalent volume of saline intravenously (IV) 35 minutes after anaesthetic induction. Heart rate (HR), mean arterial blood pressure (MAP), respiration rate (fR), end-tidal CO2 (PE′CO2), arterial oxygen saturation (SpO2), rectal temperature (RT) and level of anaesthesia were assessed before saline/vatinoxan administration (baseline) and at intervals for 25 minutes thereafter. Differences within treatments (change from baseline) and between treatments were analysed with linear mixed effect models (p <0.05). Results Maximal (81 ± 10 beats minute-1) HR occurred 90 seconds after vatinoxan injection and remained significantly above baseline (42 ± 4 beats minute-1) for 15 minutes. MAP significantly decreased from baseline (122 ± 10 mmHg) to a minimum MAP of 83 ± 6 mmHg 60 seconds after vatinoxan and remained below baseline until end of anaesthesia. HR remained unchanged from baseline (43 ± 5 beats minute-1) with the saline treatment, while MAP decreased significantly (112 ± 16 mmHg) from baseline after 20 minutes. PE′CO2, fR, and SpO2 showed no significant differences between treatments, while RT decreased significantly 25 minutes after vatinoxan. Level of anaesthesia was not significantly influenced by vatinoxan. Conclusion and clinical relevance Vatinoxan reversed hypertension and bradycardia induced by medetomidine without causing hypotension or affecting the level of anaesthesia in red deer. However, the effect on HR subsided 15 minutes after vatinoxan IV administration. Vatinoxan has the potential to reduce anaesthetic side effects in non-domestic ruminants immobilized with medetomidine-tiletamine-zolazepam.
  • Lauper, Kim; Mongin, Denis; Iannone, Florenzo; Kristianslund, Eirik Klami; Kvien, Tore K.; Nordström, Dan; Pavelka, Karel; Pombo-Suarez, Manuel; Rotar, Ziga; Santos, Maria Jose; Codreanu, Catalin; Lukina, Galina; Courvoisier, Delphine S.; Gabay, Cem (2018)
    Objective To compare the real-word effectiveness of subcutaneous tocilizumab (TCZ-SC) and intravenous tocilizumab (TCZ-IV) in rheumatoid arthritis (RA). Methods Patients with RA with TCZ from eight European registries were included. Drug retention was compared using unadjusted Kaplan-Meier and Cox models adjusted for baseline patient, disease and treatment characteristics, using a strata term for year of treatment initiation and country of registry. The proportions of patients achieving Clinical Disease Activity Index (CDAI) remission and low disease activity (LDA) at 1 year were compared using samples matched on the same covariates and corrected for attrition using LUNDEX. Results 3448 patients were retrieved, 2414 with TCZ-IV and 1034 with TCZ-SC. Crude median retention was 3.52 years (95% CI 3.22 to 3.85) for TCZ-IV and 2.12 years for TCZ-SC (95% CI 1.88 to 2.38). In a country-stratified and year of treatment initiation-stratified, covariate-adjusted analysis, hazards of discontinuation were similar between TCZ-SC and TCZ-IV treated patients (HR 0.93, 95% CI 0.80 to 1.09). The average adjusted CDAI change at 1 year was similar in both groups (-6.08). After matching, with 560 patients in each group, CDAI remission corrected for attrition at 1 year was also similar between TCZ-SC and TCZ-IV (10.4% in TCZ-IV vs 12.8% in TCZ-SC (difference: 2.4%, bootstrap 95% CI -2.1% to 7.6%)), but CDAI LDA was lower in TCZ-IV patients: 41.0% in TCZ-IV versus 49.1% in TCZ-SC (difference: 8.0 %; bootstrap 95% CI 2.4% to 12.4%). Conclusion With similar retention and effectiveness, TCZ-SC is an adequate alternative to TCZ-IV for RA. When possible, considering the costs of the TCZ-IV route, TCZ-SC should be the preferred mode of administration.
  • Cervera-Carrascon, Victor; Quixabeira, Dafne C.A.; Havunen, Riikka; Santos, Joao M.; Kutvonen, Emma; Clubb, James H.A.; Siurala, Mikko; Heiniö, Camilla; Zafar, Sadia; Koivula, Teija; Lumen, Dave; Vaha, Marjo; Garcia-Horsman, Arturo; Airaksinen, Anu J.; Sorsa, Suvi; Anttila, Marjukka; Hukkanen, Veijo; Kanerva, Anna; Hemminki, Akseli (2020)
    Despite some promising results, the majority of patients do not benefit from T-cell therapies, as tumors prevent T-cells from entering the tumor, shut down their activity, or downregulate key antigens. Due to their nature and mechanism of action, oncolytic viruses have features that can help overcome many of the barriers currently facing T-cell therapies of solid tumors. This study aims to understand how four different oncolytic viruses (adenovirus, vaccinia virus, herpes simplex virus and reovirus) perform in that task. For that purpose, an immunocompetent in vivo tumor model featuring adoptive tumor-infiltrating lymphocyte (TIL) therapy was used. Tumor growth control (p
  • Salla, Kati Maria; Lepajoe, Jaan; Candido, Marcus Vinicius; Spillmann, Thomas; Casoni, Daniela (2020)
    Objective To evaluate the feasibility of gastroduodenoscopy in dogs premedicated with acepromazine in combination with butorphanol or methadone. Study design Prospective, randomized, double-blinded clinical trial. Animals A group of 40 client-owned dogs. Methods Dogs were randomly allocated to one of two groups and give intramuscular acepromazine 0.02 mg kg(-1) combined with either butorphanol 0.3 mg kg(-1) (group ACEBUT) or methadone 0.2 mg kg(-1) (group ACEMET). General anaesthesia was induced with propofol and ketamine and maintained with sevoflurane (2.3%) in oxygen. Cardiopulmonary variables were recorded at 5 minute intervals during anaesthesia. Feasibility of the entire gastroduodenoscopy was evaluated with a visual analogue scale (VAS) from 0 (best) to 100 (worst) (primary outcome of the study). Lower oesophageal sphincter dilatation and duodenal intubation were scored. Pylorus diameter was measured with standard endoscopic inflatable balloons. Overall cardiovascular stability was assessed during anaesthesia, using a VAS (0-100), as was the presence of fluid in the oesophagus, regurgitation, need for mechanical ventilation, and intraoperative and postoperative rescue analgesia (secondary outcomes of the study). Differences between treatments were analysed with Mann-Whitney U, Student t test, Fisher exact test or mixed model analysis of variance as appropriate. Subsequently, feasibility VAS of the gastroduodenoscopy was assessed for noninferiority between groups. The noninferiority margin was set as -10. Results All gastroduodenoscopies were successfully completed in both groups using an endoscope tip diameter of 12.8 mm in all but one dog. Feasibility of gastroduodenoscopy was evaluated as 2.9 +/- 5.6 in group ACEBUT and 5.1 +/- 5.8 in group ACEMET. No significant differences between groups were detected in any measured or assessed variables, and noninferiority was confirmed. Conclusion and clinical relevance In our study population, the effects of methadone and butorphanol when combined with acepromazine were comparable.
  • Toutah, Krimo; Nawar, Nabanita; Timonen, Sanna; Sorger, Helena; Raouf, Yasir S.; Bukhari, Shazreh; von Jan, Jana; Ianevski, Aleksandr; Gawel, Justyna M.; Olaoye, Olasunkanmi O.; Geletu, Mulu; Abdeldayem, Ayah; Israelian, Johan; Radu, Tudor B.; Sedighi, Abootaleb; Bhatti, Muzaffar N.; Hassan, Muhammad Murtaza; Manaswiyoungkul, Pimyupa; Shouksmith, Andrew E.; Neubauer, Heidi A.; de Araujo, Elvin D.; Aittokallio, Tero; Kraemer, Oliver H.; Moriggl, Richard; Mustjoki, Satu; Herling, Marco; Gunning, Patrick T. (2021)
    Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as standalone or in combination with targeted drugs.
  • Narvi, Elli; Vaparanta, Katri; Karrila, Anna; Chakroborty, Deepankar; Knuutila, Sakari; Pulliainen, Arto; Sundvall, Maria; Elenius, Klaus (2018)
    Therapeutic protocols including EGFR antibodies in the context of oxaliplatin-based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in vitro and in vivo. Cetuximab reduced the efficacy of oxaliplatin when administered before oxaliplatin but provided additive effect when administered after oxaliplatin regardless of the KRAS or BRAF mutation status of the cells. Systemic gene expression and protein phosphorylation screens revealed alternatively activated pathways regulating apoptosis, cell cycle and DNA damage response. Functional assays indicated that cetuximab-induced arrest of the cells into the G1 phase of the cell cycle was associated with reduced responsiveness of the cells to subsequent treatment with oxaliplatin. In contrast, oxaliplatin-enhanced responsiveness to subsequent treatment with cetuximab was associated with increased apoptosis, inhibition of STAT3 activity and increased EGFR down-regulation. This preclinical study indicates that optimizing the sequence of administration may enhance the antitumor effect of combination therapy with EGFR antibodies and oxaliplatin.
  • Joensuu, Heikki; Fraser, Judith; Wildiers, Hans; Huovinen, Riikka; Auvinen, Päivi; Utriainen, Meri; Nyandoto, Paul; Villman, Kenneth K.; Halonen, Päivi; Granstam-Björneklett, Helena; Lundgren, Lotta; Sailas, Liisa; Turpeenniemi-Hujanen, Taina; Tanner, Minna; Yachnin, Jeffrey; Ritchie, Diana; Johansson, Oskar; Huttunen, Teppo; Neven, Patrick; Canney, Peter; Harvey, Vernon J.; Kellokumpu-Lehtinen, Pirkko-Liisa; Lindman, Henrik (2018)
    IMPORTANCE Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear. OBJECTIVE To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab. DESIGN, SETTING, AND PARTICIPANTS Open-label, randomized (1: 1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m(2)) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries. INTERVENTION Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year. MAIN OUTCOMES AND MEASURES The primary objectivewas DFS; secondary objectives included distant disease-free survival, overall survival, cardiac DFS, and safety. RESULTS In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease-free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m(2) had inferior and those treated with 100 mg/m(2) had similar DFS as patients in the 1-year group. CONCLUSIONS AND RELEVANCE Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study.
  • Turunen, Heta; Raekallio, Marja; Honkavaara, Juhana; Jaakkola, Johanna; Scheinin, Mika; Männikkö, Sofia; Hautajärvi, Heidi; Bennett, Rachel; Vainio, Outi (2020)
    Objective To investigate the impact of intramuscular (IM) co-administration of the peripheral alpha(2)-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonary and anaesthetic effects in dogs, followed by atipamezole reversal. Study design Randomized, masked crossover study. Animals A total of eight purpose-bred Beagle dogs aged 3 years. Methods Each dog was instrumented and administered two treatments 2 weeks apart: medetomidine (20 mu g kg(-1)) and butorphanol (100 mu g kg(-1)) premedication with vatinoxan (500 mu g kg(-1); treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg(-1)). Atipamezole (100 mu g kg(-1)) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured; cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analysed with repeated measures analysis of covariance models. A p-value Results At most time points, HR and CI were significantly higher, and SVRI and CVP significantly lower with MVB than with MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than with MB; mild hypotension (57-59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB. Conclusions and clinical relevance Haemodynamic performance was improved by vatinoxan co-administration with medetomidine-butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this study. Vatinoxan shortened the duration of anaesthesia.
  • Konig, Walter; Konig, Emilia; Elo, Kari; Vanhatalo, Aila; Jaakkola, Seija (2019)
    Legumes are particularly susceptible to clostridial fermentation when ensiled because of their high buffering capacity and water-soluble carbohydrate contents. The aim of the study was to investigate if a sodium nitrite treatment (900 g t(-1) herbage in fresh matter [FM]) impairs butyric acid fermentation of red clover-timothy-meadow fescue silage compared with formic acid-treated (4 l t(-1) FM) and untreated silage. The sward was harvested after wilting at low dry matter (DM) (LDM, 194 g kg(-1)) and high DM (HDM, 314 g kg(-1)) concentrations and half of the herbage batches were inoculated with Clostridium tyrobutyricum spores before additive treatments. No butyric acid fermentation was observed in HDM silages probably because of the relatively high DM and nitrate contents of the herbage mixture. In LDM silage butyric acid was detected only in formic acid-treated silage, and the number of clostridia copies was higher in formic acid-treated than in sodium nitrite treated silage. Sodium nitrite treatment was superior to FA treatment in suppressing clostridial fermentation in the LDM silages.
  • Kankare, Ville; Joensuu, Marianna; Vauhkonen, Jari; Holopainen, Markus; Tanhuanpaa, Topi; Vastaranta, Mikko; Hyyppa, Juha; Hyyppa, Hannu; Alho, Petteri; Rikala, Juha; Sipi, Marketta (2014)
  • Tanhuanpää, Topi; Saarinen, Ninni; Kankare, Ville; Nurminen, Kimmo; Vastaranta, Mikko; Honkavaara, Eija; Karjalainen, Mika; Yu, Xiaowei; Holopainen, Markus; Hyyppä, Juha (2016)
    Height models based on high-altitude aerial images provide a low-cost means of generating detailed 3D models of the forest canopy. In this study, the performance of these height models in the detection of individual trees was evaluated in a commercially managed boreal forest. Airborne digital stereo imagery (DSI) was captured from a flight altitude of 5 km with a ground sample distance of 50 cm and corresponds to regular national topographic airborne data capture programs operated in many countries. Tree tops were detected from smoothed canopy height models (CHM) using watershed segmentation. The relative amount of detected trees varied between 26% and 140%, and the RMSE of plot-level arithmetic mean height between 2.2 m and 3.1 m. Both the dominant tree species and the filter used for smoothing affected the results. Even though the spatial resolution of DSI-based CHM was sufficient, detecting individual trees from the data proved to be demanding because of the shading effect of the dominant trees and the limited amount of data from lower canopy levels and near the ground.
  • Tuomainen, Katja; Hyytiäinen, Aini; Al-Samadi, Ahmed; Ianevski, Philipp; Ianevski, Aleksandr; Potdar, Swapnil; Turunen, Laura; Saarela, Jani; Kuznetsov, Sergey; Wahbi, Wafa; Risteli, Maija; Mäkitie, Antti; Monni, Outi; Salo, Tuula (2021)
    Conventional chemotherapeutic agents are nonselective, often resulting in severe side effects and the development of resistance. Therefore, new molecular-targeted therapies are urgently needed to be integrated into existing treatment regimens. Here, we performed a high-throughput compound screen to identify a synergistic interaction between ionizing radiation and 396 anticancer compounds. The assay was run using five human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) cell lines cultured on the human tumor-derived matrix Myogel. Our screen identified several compounds with strong synergistic and antagonistic effects, which we further investigated using multiple irradiation doses. Navitoclax, which emerged as the most promising radiosensitizer, exhibited synergy with irradiation regardless of the p53 mutation status in all 13 HNSCC cell lines. We performed a live cell apoptosis assay for two representative HNSCC cell lines to examine the effects of navitoclax and irradiation. As a single agent, navitoclax reduced proliferation and induced apoptosis in a dose-dependent manner, whereas the navitoclax-irradiation combination arrested cell cycle progression and resulted in substantially elevated apoptosis. Overall, we demonstrated that combining navitoclax with irradiation resulted in synergistic in vitro antitumor effects in HNSCC cell lines, possibly indicating the therapeutic potential for HNSCC patients.
  • Majumder, Muntasir Mamun; Silvennoinen, Raija; Anttila, Pekka; Tamborero, David; Eldfors, Samuli; Yadav, Bhagwan; Karjalainen, Riikka; Kuusanmaki, Heikki; Lievonen, Juha; Parsons, Alun; Suvela, Minna; Jantunen, Esa; Porkka, Kimmo; Heckman, Caroline A. (2017)
    Novel agents have increased survival of multiple myeloma (MM) patients, however high-risk and relapsed/refractory patients remain challenging to treat and their outcome is poor. To identify novel therapies and aid treatment selection for MM, we assessed the ex vivo sensitivity of 50 MM patient samples to 308 approved and investigational drugs. With the results we i) classified patients based on their ex vivo drug response profile; ii) identified and matched potential drug candidates to recurrent cytogenetic alterations; and iii) correlated ex vivo drug sensitivity to patient outcome. Based on their drug sensitivity profiles, MM patients were stratified into four distinct subgroups with varied survival outcomes. Patients with progressive disease and poor survival clustered in a drug response group exhibiting high sensitivity to signal transduction inhibitors. Del(17p) positive samples were resistant to most drugs tested with the exception of histone deacetylase and BCL2 inhibitors. Samples positive for t(4; 14) were highly sensitive to immunomodulatory drugs, proteasome inhibitors and several targeted drugs. Three patients treated based on the ex vivo results showed good response to the selected treatments. Our results demonstrate that ex vivo drug testing may potentially be applied to optimize treatment selection and achieve therapeutic benefit for relapsed/refractory MM.
  • Huuhtanen, Jani; Ilander, Mette; Yadav, Bhagwan; Dufva, Olli M. J.; Lähteenmäki, Hanna; Kasanen, Tiina; Klievink, Jay; Olsson-Strömberg, Ulla; Stentoft, Jesper; Richter, Johan; Koskenvesa, Perttu; Hoglund, Martin; Söderlund, Stina; Dreimane, Arta; Porkka, Kimmo; Gedde-Dahl, Tobias; Gjertsen, Bjorn T.; Stenke, Leif; Myhr-Eriksson, Kristina; Markevarn, Berit; Lubking, Anna; Dimitrijevic, Andreja; Udby, Lene; Bjerrum, Ole Weis; Hjorth-Hansen, Henrik; Mustjoki, Satu (2022)
    In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-alpha is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-alpha in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCR beta sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8(+) recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-alpha reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-alpha had costimulatory effects on TCR signaling. Our work supports the combination of IFN-alpha with TKI therapy, as IFN-alpha broadens the immune repertoire and restores immunological function.