Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study

Background Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. Methods In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0–2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Findings Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60–72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61–72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0–8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2–5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64–0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4–22·8) in the melflufen group and 16·3 months (10·1–23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1–25·6) at a median follow-up of 19·8 months (IQR 12·0–25·0) in the melflufen group and 25·0 months (95% CI 18·1–31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8–23·7; HR 1·10 [95% CI 0·85–1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). Interpretation Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.Oncopeptides ABPeer reviewe

Household economies of scale, food consumption and intra-household allocation of time

textThis thesis presents and empirically tests three utility theoretic models of the household behavior. Larger households economize money and time by sharing expenses and specializing labor within and outside of the home. A “paradox” arises when the budget share of food declines with household size in the consumer expenditure survey data contradicting the Barten model prediction that per capita food consumption should increase with household size. I test the Barten model in the expenditure data from the U.S., South Africa and Russia, and show that the share of food increases relative to a more public good and decreases relative to a more private good. This suggests food is less private than the composite of all other goods in the household budget; the likely public component of food being food preparation time. Extending the model to incorporate time, I explain the food consumption paradox: larger households choose more time intensive meals, thus per capita expenditures on food decline with household size while food consumption does not. In the data from Russia, doubling the size of household reduces per capita food expenditure by over 30% and per capita preparation time by about 75% in households with two and more people. Single men spend over three times more hours in food-related activities than men from two-person households spend. Single women enjoy smaller time saving for a similar transition, but married women enjoy no time saving at all. The quality of meals is unaffected by changes in household size. Finally, I study the effect of labor market shocks on the allocation of non-market time in transitional Russia. The model of a two-sector labor market with restricted hours of work in the state sector of employment and high fixed costs of entry in the private sector implies that earnings are a better approximation of worker’s well- being than wages. Cross-sectional and panel data analysis shows the population enjoyed more leisure during transition than before and movement to and from employment took place mostly at the expense of leisure hours. In response to higher earning opportunities employed men reduced leisure while employed women also cut down on childcare and housework.Economic

Integration of Russian speaking students at HAAGA-HELIA, case Porvoo Campus

The aim of the study was to find out the level of academic and social integration of Russian-speaking students studying on Porvoo Campus. We wanted to find out why they had chosen Finland and Porvoo Campus for their place of study, what they thought about their lives and studies in Porvoo, how they interacted with Finnish stu-dents, what they thought about stereotypes and whether they believed they would stay in Finland after graduation. To make our research more reliable, we also included Finnish students’ and teachers’ opinions. This topic is quite important nowadays, since the number of Russian-speaking people visiting Finland is increasing all the time. Finnish Universities need more specialists with knowledge of Russia. That is why it is important to survey experiences of Russian-speaking students already studying in Finland. The theoretical framework of the thesis is based on literature on key concepts related to the subject: immigration, adaptation to new cultures, acculturation, integration, ste-reotypes, cultural differences between Russians and Finns, Russians in Finland, current Finnish-Russian relations, education systems in Finland and Russia, and the differences between these. The research method applied in this thesis is qualitative based on semi-structured in-depth interviews. The main reason for choosing this method was because we wanted to have the respondents’ own experiences on the topic. The target group of our re-search consists of ten Russian-speaking students, ten Finnish students and five teachers who studying and teaching on Porvoo Campus. In general, Russian-speaking respondents were very satisfied with living in Finland and studying on Porvoo Campus. They would like to communicate more with Finnish stu-dents and Finns feel the same way. Students wish teachers to be more active and mix groups more. Tandem courses and a will to leave stereotypes and prejudices behind were also recommended means for further improving interaction between Russian-speaking and Finnish students.Tämän tutkimuksen tarkoituksena oli selvittää, miten venäjänkieliset opiskelijat ovat integroituneet Haaga- Heliaan, Porvoon yksikköön. Tutkimus käsittelee Porvoo Cam-puksella venäjänkielisten tutkinto-opiskelijoiden kokemuksia opiskelusta ja opiskelu-ympäristöstä sekä heidän sosiaalista asemaansa ja tulevaisuuden suunnitelmiaan. Työmme aihe on hyvin ajankohtainen, sillä tällä hetkellä venäjänkielisten matkustelijoi-den määrä on suuressa kasvussa ja Suomi tarvitsee lisää Venäjä-osaajia. Korkeakoulut tarvitsevat entistä enemmän venäjänkielisiä tutkinto-opiskelijoita. Sen takia on erityisen tärkeätä kartoittaa jo opiskelevien venäjänkielisten opiskelijoiden viihtyvyyttä Suomes-sa. Tutkimuksemme teoreettinen viitekehys perustui kirjallisuuteen kulttuurisesta sopeu-tumisesta, Venäjän ja Suomen kulttuurien käyttäytymisistä sekä Venäjän ja Suomen opiskelujärjestelmien eroista. Tutkimuksemme lähestymistapana käytettiin kvalitatiivista menetelmää. Aineistoa ke-rättiin teemahaastatteluiden avulla vuosina 2011–2012. Haastattelimme yhteensä 10 venäjänkielistä ja 10 suomenkielistä opiskelijaa sekä 5 opettajaa. Kohteiden määrä koet-tiin riittäväksi määräksi haastatteluista kertyvän aineiston määrän arvioinnin jälkeen. Työssämme selvisi, että venäjänkieliset opiskelijat ovat tyytyväisiä Suomeen ja opiske-luun Porvoon Campuksella. He haluaisivat kommunikoida enemmän suomalaisten kanssa ja suomalais-opiskelijoista tuntuu samalta. Opiskelijat toivovat opettajia olla ak-tiivisempia ja sekoittaa ryhmiä useimmiten. Tandem-kurssia sekä stereotyyppiöiden pois jättämistä kehotettiin myös venäjänkielisten ja suomalaisten opiskelijoiden vuoro-vaikutuksen parantamiseksi

BRITISH CONSULATES IN PORT CITIES OF THE NORTHERN BLACK SEA AND AZOV REGION OF THE SECOND HALF OF THE 19TH - EARLY 20TH CENTURIES

Summary. The purpose of the research is to study the history of British consular offices in port cities of the Southern Ukraine at the times of the Russian Empire. The research methodology is based on search and comprehensive study of representative complexes of primarily sources on the history of the British consulates in the region, in particular, the annual consular reports to London. The scientific novelty: changes in the network of consulates of the British Empire and in the configuration of British consular districts in the region have been tracked; lists of consular representatives in each consular office have been composed; the specifics of the consuls’ status, functions and working conditions have been researched. Сonclusions. The development of the network of British consular offices in port cities of the Northern Black Sea and Azov region, which took place after the end of the Crimean War, unambiguously demonstrated the understanding by official London prospects of the deployment of economic ties with the region. During the second half of the 19th - early 20th centuries the consular district of Odessa turned into the largest British consular district on the territory of the Russian Empire in number of consular offices. Forming the consular staff, the British Empire for a long time preferred appointing «non-trading» consuls, or «consul de carriere», which required considerably more money, but allowed consuls to focus on their professional duties, while the majority of consular representatives of other countries in the region were engaged in business. On the other hand, approaches of official London to the formation of the consular staff, financing consuls and the regulation of their activities had a number of disadvantages, which ultimately led to a revision of these approaches. However, the dynamics of development of economic relations between ports of the Northern Black Sea and Azov region and the British Empire was affected by a wide range of factors, and, despite the efforts of the British consuls, this dynamics was not always positive. So, the consuls only had to report about such a state of affairs, recalling with nostalgia «better times» of British trade in the region

Research Institute of Urban History

The review is dedicated to activities of Research Institute of Urban History. The main attention turns to directions of the work of the Research Institute: 1. Multifaceted studying of urban history (continuation of individual Institute’s member's studies on various components of the urban past; realization of joint research projects connected with urbanization; organization of conferences and meetings dedicated to urban issues; cooperation with other research in­stitutions and associations involved in studying urban past); 2. Developing a website of the Institute, which should become a platform for communica­tion scholars and the public involved and interested in urban history as well as for publishing articles and archival collections of the Research Institute; 3. Work as editorial board and authors of historical-cultural anthology “Frontiers of the city”. 4. Conducting oral historical research on urban history with the formation of an archive of oral historical narrative (theoretical and practical training for interviewers; preparing and conducting expeditions; systematization, processing the collected materials; preparation of materials for publication); 5. Development and maintenance of the archive of film doc­uments related to urban history (heuristic work in archives; identifying and copying film documents from private collections; participation in creation on the basis of these film documents documentaries and popular science films on the history of cities); 6. Development and maintenance of the depositary of photographs related to the history of “urban space”; 7. Creating in the structure of the Research Institute the Museum of Berdyansk State Pedagog­ical University, which is a broader context may be considered as a museum of the history of education in an urban area; 8. Public activities aimed at popularization of urban history and at the interaction of researchers with society (organization of exhibitions, competitions, etc.; initiation and implementation of public projects)

URBAN PROJECT “WHAT IS YOUR HISTORY?”

The report is dedicated to the project "What is your history?", which is been implementing by Zaporizhzhia scientific society named after Yakiv Novytskyi with the support of the U.S. Agency for International Development. The project is focused on promoting the history of three Ukrainian cities (Zaporizhzhia, Berdyansk and Melitopol)

Nano-TiO2 penetration of oral mucosa: in vitro analysis using 3D organotypic human buccal mucosa models

BACKGROUND: Oral cavity is a doorway for a variety of products containing titanium dioxide (TiO2) nanoparticles (NPs) (nano-TiO2) such as food additives, oral healthcare products and dental materials. Their potential to penetrate and affect normal human oral mucosa is not yet determined. OBJECTIVES: To evaluate the ability of nano-TiO2 to penetrate the in vitro reconstructed normal human buccal mucosa (RNHBM). METHODS: RNHBM was generated from primary normal human oral keratinocytes and fibroblasts isolated from buccal oral mucosa of healthy patients (n = 6). The reconstructed tissues were exposed after 10 days to clinically relevant concentrations of spherical or spindle rutile nano-TiO2 in suspension for short (20 min) and longer time (24 h). Ultrahigh-resolution imaging (URI) microscopy (CytoVivaTM, Auburn, AL, USA) was used to assess the depth of penetration into reconstructed tissues. RESULTS: Ultrahigh-resolution imaging microscopy demonstrated the presence of nano-TiO2 mostly in the epithelium of RNHBM at both 20 min and 24-h exposure, and this was shape and doze dependent at 24 h of exposure. The depth of penetration diminished in time at higher concentrations. The exposed epithelium showed increased desquamation but preserved thickness. CONCLUSION: Nano-TiO2 is able to penetrate RNHBM and to activate its barrier function in a doze- and timedependent manner

Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression

<b>Rationale:</b> Whether idiopathic, familial, or secondary to another disease, pulmonary arterial hypertension (PAH) is characterized by increased vascular tone, neointimal hyperplasia, medial hypertrophy, and adventitial fibrosis. Imatinib, a potent receptor tyrosine kinase inhibitor, reverses pulmonary remodeling in animal models of PAH and improves hemodynamics and exercise capacity in selected patients with PAH. <p></p> <b>Objectives:</b> Here we use both imatinib and knockout animals to determine the relationship between platelet-derived growth factor receptor (PDGFR) and serotonin signaling and investigate the PAH pathologies each mediates. <p></p> <b>Methods:</b> We investigated the effects of imatinib (100 mg/kg) on hemodynamics, vascular remodeling, and downstream molecular signatures in the chronic hypoxia/SU5416 murine model of PAH. <p></p> <b>Measurements and Main Results:</b> Treatment with imatinib reduced all measures of PAH pathology observed in hypoxia/SU5416 mice. In addition, 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase 1 (Tph1) expression were reduced compared with the normoxia/SU5416 control group. Imatinib attenuated hypoxia-induced increases in Tph1 expression in pulmonary endothelial cells in vitro via inhibition of the PDGFR-β pathway. To better understand the consequences of this novel mode of action for imatinib, we examined the development of PAH after hypoxic/SU5416 exposure in Tph1-deficient mice (Tph1−/−). The extensive changes in pulmonary vascular remodeling and hemodynamics in response to hypoxia/SU5416 were attenuated in Tph1−/− mice and further decreased after imatinib treatment. However, imatinib did not significantly further impact collagen deposition and collagen 3a1 expression in hypoxic Tph1−/− mice. Post hoc subgroup analysis suggests that patients with PAH with greater hemodynamic impairment showed significantly reduced 5-HT plasma levels after imatinib treatment compared with placebo. <p></p> <b>Conclusions:</b> We report a novel mode of action for imatinib, demonstrating TPH1 down-regulation via inhibition of PDGFR-β signaling. Our data reveal interplay between PDGF and 5-HT pathways within PAH, demonstrating TPH1-dependent imatinib efficacy in collagen-mediated mechanisms of fibrosis. <p></p&gt

Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study

Background: Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. Methods: In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0–2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Findings: Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60–72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61–72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0–8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2–5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64–0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4–22·8) in the melflufen group and 16·3 months (10·1–23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1–25·6) at a median follow-up of 19·8 months (IQR 12·0–25·0) in the melflufen group and 25·0 months (95% CI 18·1–31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8–23·7; HR 1·10 [95% CI 0·85–1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). Interpretation: Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma