bluuebunny/crossref_metadata_2025 huggingface dataset:
International students, immigration and earnings growth: the effect of a pre-immigration host-country university education
Authors: Hou Feng , Lu Yuqian
Published: June 2017

While destination-country education provides many potential advantages for immigrants, empirical studies in Australia, Canada and the USA have produced mixed results on the labour outcomes of immigrants who are former international students. This study uses large national longitudinal datasets to examine cross-cohort trends and within-cohort changes in earnings among three groups of young university graduates: immigrants who are former international students in Canada (Canadian-educated immigrants), foreign-educated immigrants who had a university degree before immigrating to Canada and the Canadian-born population. The results show that Canadian-educated immigrants on average had much lower earnings than the Canadian-born population but higher earnings than foreign-educated immigrants both in the short run and in the long run. However, Canadian-educated immigrants are a highly heterogeneous group, and the key factor differentiating their post-immigration earnings from the earnings of the Canadian-born population and foreign-educated immigrants is whether they held a well-paid job in Canada before becoming permanent residents. Furthermore, an extra year of Canadian work experience or an extra year of Canadian education experience before immigration added only a small or no earnings gain after immigration for Canadian-educated immigrants.

JEL Classification: J15, J24, J61
Lamination of microfibrous PLGA fabric by electrospinning a layer of collagen-hydroxyapatite composite nanofibers for bone tissue engineering
Authors: Kwon Gi-Wan , Gupta Kailash Chandra , Jung Kyung-Hye , Kang Inn-Kyu
Published: June 2017

Background

To mimic the muscle inspired cells adhesion through proteins secretion, the lamination of collagen–hydroxyapatite nanorod (nHA) composite nanofibers has been carried out successfully on polydopamine (PDA)-coated microfibrous polylactide-co-glycolide (PLGA) fabrics. The lamination of collagen-hydroxyapatite composite nanofibers on polydopamine-coated microfibrous PLGA fabrics was carried through electrospinning the solution of collagen containing L-glutamic acid-grafted hydroxyapatite nanorods (nHA-GA) at a flow rate of 1.5 mL/h and an applied voltage of 15 kV.

Results

In comparison to pristine PLGA, dopamine-coated PLGA and collagen-hydroxyapatite composite nanofiber lamination has produced more wettable surfaces and surface wettability is found to higher with dopamine-coated PLGA fabrics then pristine PLGA. The SEM micrographs have clearly indicated that the lamination of polydopamine-coated PLGA fabric with collagen-hydroxyapatite composite nanofibers has shown increased adhesion of MC3T3E1 cells in comparison to pristine PLGA fabrics.

Conclusion

The results of these studies have clearly demonstrated that collagen-nHA composites fibers may be used to create bioactive 3D scaffolds using PLGA as an architectural support agent.
Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1–Selected Advanced Non–Small-Cell Lung Cancer (BIRCH)
Authors: Peters Solange , Gettinger Scott , Johnson Melissa L. , Jänne Pasi A. , Garassino Marina C. , Christoph Daniel , Toh Chee Keong , Rizvi Naiyer A. , Chaft Jamie E. , Carcereny Costa Enric , Patel Jyoti D. , Chow Laura Q.M. , Koczywas Marianna , Ho Cheryl , Früh Martin , van den Heuvel Michel , Rothenstein Jeffrey , Reck Martin , Paz-Ares Luis , Shepherd Frances A. , Kurata Takayasu , Li Zhengrong , Qiu Jiaheng , Kowanetz Marcin , Mocci Simonetta , Shankar Geetha , Sandler Alan , Felip Enriqueta
Published: June 2017

Purpose

BIRCH was designed to examine the efficacy of atezolizumab, a humanized anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non–small-cell lung cancer (NSCLC) across lines of therapy. Patients were selected on the basis of PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC).

Patients and Methods

Eligible patients had advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior chemotherapy. Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5% of TC or IC (TC2/3 or IC2/3 [TC or IC ≥ 5% PD-L1–expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659) comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n = 268); and third line or higher (cohort 3; n = 252). The primary end point was independent review facility–assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points included median duration of response, progression-free survival, and overall survival (OS).

Results

BIRCH met its primary objective of demonstrating a significant ORR versus historical controls. With a minimum of 12 months of follow-up, the independent review facility–assessed ORR was 18% to 22% for the three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The median OS from an updated survival analysis (minimum of 20 month follow up) for cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials.

Conclusion

BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1–selected advanced NSCLC, with good tolerability. PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab.
Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.
Authors: Shi Qian , Sobrero Alberto F. , Shields Anthony Frank , Yoshino Takayuki , Paul James , Taieb Julien , Sougklakos Ioannis , Kerr Rachel , Labianca Roberto , Meyerhardt Jeffrey A. , Bonnetain Franck , Watanabe Toshiaki , Boukovinas Ioannis , Renfro Lindsay A. , Grothey Axel , Niedzwiecki Donna , Torri Valter , Andre Thierry , Sargent Daniel J. , Iveson Timothy
Published: June 2017

LBA1

Background: Since 2004, 6 months (m) of oxaliplatin (oxali)-based treatment has been the standard of care as adjuvant therapy for stage III CC. Since oxali is associated with cumulative neurotoxicity, shorter duration of adjuv therapy could spare pts toxicity and lead to substantial saving in health expenditures. Methods: A prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials (SCOT, TOSCA, Alliance/SWOG 80702, IDEA France (GERCOR/PRODIGE), ACHIEVE, HORG) was performed to evaluate the non-inferiority (NI) of 3m compared with 6m (ref) of adjuv FOLFOX/XELOX. The primary endpoint was disease-free survival (DFS), defined as time from enrolment to relapse, 2nd CRC, and death (all causes). NI was to be declared if the 2-sided 95% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.12. NI was examined within regimen and stage subgroups as pre-planned. Results: The analysis included 12,834 pts from 12 countries, accrued from 6/07 to 12/15. Stage distribution: 13% T1-2, 66% T3, 21% T4; 28% N2; 40% received XELOX. G3+ neurotoxicity was higher in the 6m v 3m arm (16 v 3% FOLFOX, 9 v 3% XELOX, p<0.0001). With a median follow-up of 39 mos, 3263 DFS events were observed. Overall, the 3 year DFS rate was 74.6% (3m) and 75.5% (6m), with estimated DFS HR of 1.07 (95%CI, 1.00-1.15). The 3m v 6m DFS HRs were 1.16 (95%CI, 1.06-1.26) and 0.95 (95% CI, 0.85-1.06) for FOLFOX and XELOX treated pts, respectively. The 3m v 6m DFS HRs were 1.01 (95%CI, 0.90-1.12) in T1-3 N1, and 1.12 (95%CI, 1.03-1.23) for T4 or N2 pts. Conclusions: While NI was not established for the overall cohort, NI of 3m v 6m oxali-based adjuv therapy was supported for XELOX. As each IDEA trial treated varying proportions of pts with XELOX (0 to 75%), the regimen interaction likely produced the differential outcomes observed between individual studies. Certain substages (T1-3 N1) also showed NI for 3m v 6m. These data provide a framework for discussions on risks and benefits of individualized adjuv therapy approaches. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180835, INCA, PHRC2009, EME 09/800/34, HTA 14/140/84, CRUK C1348/A15960, JFMC. Clinical trial information: NCT01150045.
Web-based stress management for newly diagnosed cancer patients (STREAM): A randomized, wait-list controlled intervention study.
Authors: Hess Viviane , Grossert Astrid , Alder Judith , Scherer Sandra , Handschin Barbara , Borislavova Borislava , Degen Sven , Faessler Alexandra , Hartung Jennifer , Schibli Sarah , Werndli Celine , Gaab Jens , Berger Thomas , Zumbrunn Thomas , Urech Corinne
Published: June 2017

LBA10002

Background: Being diagnosed with cancer causes major distress, yet the majority of newly diagnosed cancer patients (pts) lack psychological support. Internet interventions overcome many barriers for seeking support. We assess efficacy and feasibility of a web-based minimal-contact stress management intervention (STREAM) for newly diagnosed cancer pts. Methods: In a prospective, wait-list controlled trial, newly diagnosed cancer pts were randomized within 12 weeks of starting anti-cancer treatment to an immediate or delayed (control group) 8-week, web-based intervention. The intervention consisted of 8 modules with weekly written feedback by a psychologist (“minimal-contact”) based on well-established stress management manuals. The aim of this study was to evaluate efficacy in terms of improvement in QoL (FACIT-F), decrease in distress (DT), anxiety/depression (HADS), as compared to pts in the wait-list group. 120 pts were needed to show (80% power, 2-sided α of 0.05) a clinically meaningful difference of ≥ 9 in FACT score after the immediate intervention (week 8 = T2). Results: 225 pts applied online. 128 pts were randomized. Median age was 52 (22-77)y. 108 (84%) were female. The majority of pts were treated in the curative setting (117pts; 91%), with chemotherapy (74 pts; 58%), for breast cancer (91pts; 71%). Self-reported distress at baseline ( = stratification factor) was above 4 on a 10-point scale (DT) with 96 pts (75%). At T2, QoL (FACIT-F) was sign. increased (p = 0.044; ANCOVA adjusted for baseline-distress) and distress sign. lowered (p = 0.032) in the intervention group as compared to the wait-list control. Median score (lower/upper quartile) for FACIT-F at baseline/T2 was 101.0(80.8/120)/119.0(98.0/132) and 108.3(87.8/124.0) /109.5(97.2/121.0); of DT at baseline/T2 was 6(5/8)/4(3/6) and 6(5/8)/6(4/7) for the intervention and control group, respectively. Decrease in HADS was not sign. different between the groups (p = 0.273). Conclusions: With STREAM, we open the field of minimal-contact online interventions to newly diagnosed cancer pts and show that an 8-week web-based stress management program is feasible and effective in improving QoL and distress. Clinical trial information: NCT02289014.
Adverse health outcomes in relationship to hypogonadism (HG) after platinum-based chemotherapy: A multicenter study of North American testicular cancer survivors (TCS).
Authors: Abu Zaid Mohammad Issam , Menendez Alvaro G. , El Charif Omar , Fung Chunkit , Monahan Patrick O. , Feldman Darren R. , Hamilton Robert James , Vaughn David J. , Beard Clair , Cook Ryan , Althouse Sandra K. , Sesso Howard D. , Ardeshirrouhanifard Shirin , Dinh Paul C , Einhorn Lawrence , Fosså Sophie , Travis Lois B. ,   For the Platinum Study Group
Published: June 2017

LBA10012

Background: HG affects a substantial percentage of TCS and can contribute to significant morbidity, but few studies have examined the relationship between HG and adverse health outcomes (AHO), taking into account genetic variation. Methods: Eligible TCS were < 55 y at diagnosis and treated with only first line chemotherapy after 1990. TCS underwent physical exams and genotyping, and completed questionnaires regarding 16 AHO and health behaviors. HG was defined as serum testosterone ≤ 3.0 ng/mL or the use of testosterone replacement therapy. Results: We evaluated 491 TCS. Median age at evaluation was 38 y (range 19-68). 38.5% had HG. Two SNPs in the sex-hormone-binding globulin ( SHBG) locus previously implicated in increased HG risk in the general population (Ohlsson et al, PLOS Genetics 2011) displayed effect sizes consistent with prior reports (rs6258, OR = 1.3; rs12150660, OR = 0.79), but were not statistically significant. However, TCS with ≥ 2 risk alleles for the two SNPs in the SHBG locus vs no risk alleles had 2-fold increased risk for HG (OR = 2.2, P = .12). Multivariate analysis identified risk factors for HG including: age (OR = 1.4 per 10 year increase, P = .007), and BMI ≥ 25 kg/m2 (OR = 2.2, P = .003). Vigorous-intensity physical activity appeared protective (OR = 0.6, P = .06). Type of chemotherapy regimen and socioeconomic factors did not correlate with HG. Only 35% of TCS with HG vs 49% of those without HG reported none or 1 AHO ( P = .003). TCS with HG were more likely to take medications for dyslipidemia (20% vs 6%, P < .001), hypertension (19% vs 11%, P = .01), erectile dysfunction (ED) (20% vs 12%, P = .02), diabetes (6% vs 3%, P = .07), or anxiety/depression (15% vs 10%, P = 0.06) compared to TCS with normal levels, and also to have peripheral neuropathy (PN) (31% vs 23%, P = .04). HG status did not correlate with oto- or renal toxicity. Conclusions: Over a third of TCS have HG at a relatively young age. HG was associated with increased cardiovascular disease risk factors, ED, and PN. SHBG polymorphisms appear important in TCS, but our study was underpowered to confirm an association. Providers should screen TCS for HG and treat those who are symptomatic.
Temporal trends in chronic disease among survivors of childhood cancer diagnosed across three decades: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Gibson Todd M. , Mostoufi-Moab Sogol , Stratton Kayla , Barnea Dana , Chow Eric Jessen , Donaldson Sarah S. , Howell Rebecca M. , Hudson Melissa M. , Leisenring Wendy M. , Mahajan Anita , Nathan Paul C. , Ness Kirsten K. , Sklar Charles A. , Tonorezos Emily S. , Weldon Christopher Bertero , Wells Elizabeth M. , Yasui Yutaka , Armstrong Gregory T. , Robison Leslie L. , Oeffinger Kevin C.
Published: June 2017

LBA10500

Background: Modifications in childhood cancer treatments in recent decades have contributed to reductions in late mortality among 5-year survivors. We used the recently expanded CCSS cohort to investigate whether these changes have also reduced the incidence of chronic disease. Methods: We evaluated the incidence of severe, disabling/life-threatening, or fatal chronic health conditions (Common Terminology Criteria for Adverse Events, CTCAE grades 3-5) among 5-year survivors diagnosed prior to age 21 years from 1970 through 1999. We calculated the 15-year cumulative incidence of chronic health conditions by decade of cancer diagnosis and compared risk across decades using Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 23,601 survivors, median age 28 years (range 5-63), 21 years from diagnosis (5-43), the 15-year cumulative incidence of grade 3-5 conditions decreased from 12.7% in survivors diagnosed in the 1970s to 10.1% and 8.8% in those diagnosed in the 1980s and 1990s (per 10 years, HR 0.84 [95% CI = 0.80-0.89]). The association with diagnosis decade was attenuated (HR 0.92 [0.85-1.00]) when detailed treatment data were included in the model, indicating that treatment reductions mediated risk. Adjusted for sex and attained age, significant reduction in risk over time was found among survivors of Wilms tumor (HR 0.57 [0.46-0.70]), Hodgkin lymphoma (HR 0.75 [0.65-0.85]), astrocytoma (HR 0.77 [0.64-0.92]), non-Hodgkin lymphoma (HR 0.79 [0.63-0.99]), and acute lymphoblastic leukemia (HR 0.86 [0.76-0.98]). Decreases were largely driven by a reduced incidence of endocrine conditions (1970s: 4.0% v. 1990s:1.6%; HR 0.66 [0.59-0.73]) and subsequent malignant neoplasms (1970s: 2.4% v. 1990s: 1.6%; HR 0.85 [0.76-0.96]). Significant reductions were also found for gastrointestinal (HR 0.80 [0.66-0.97]) and neurological conditions (HR 0.77 [0.65-0.91]), but not cardiac or pulmonary conditions. Conclusions: Changes in childhood cancer treatment protocols have not only extended lifespan for many survivors, but have also reduced the incidence of serious chronic morbidity in this population.
LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer.
Authors: Fizazi Karim , Tran Namphuong , Fein Luis Enrique , Matsubara Nobuaki , Rodríguez Antolín Alfredo , Alekseev Boris Y. , Ozguroglu Mustafa , Ye Dingwei , Feyerabend Susan , Protheroe Andrew , De Porre Peter , Kheoh Thian , Park Youn C. , Todd Mary Beth , Chi Kim N. ,   On Behalf of the LATITUDE Investigators
Published: June 2017

LBA3

Background: Pts with newly diagnosed mHNPC, particularly with high-risk characteristics, have a poor prognosis. ADT+docetaxel showed improved outcomes in mHNPC, but many pts are not candidates for docetaxel and may benefit from alternative therapy. AA+P is indicated for metastatic castration-resistant prostate cancer pts. LATITUDE evaluates clinical benefit of early intervention with AA+P added to ADT in newly diagnosed, high-risk mHNPC pts. Methods: 1199 pts with newly diagnosed (≤ 3 mos prior to randomization) mHNPC (ECOG PS 0-2) with ≥ 2 of 3 risk factors (Gleason ≥ 8, ≥ 3 bone lesions, measurable visceral metastases) were randomized 1:1 to ADT+AA (1 g QD) + P (5 mg QD) or ADT+PBOs of AA and P. Co-primary end points were overall survival (OS) and radiographic progression-free survival (rPFS). One rPFS (~565 events), 2 interim, and 1 final OS analyses (~426, ~554, and ~852 events) were planned. Results: At this first interim analysis (median follow-up of 30.4 mos; 406 deaths [48%]; 593 rPFS events), OS, rPFS, and all secondary end points significantly favored ADT+AA+P (Table). The IDMC unanimously recommended unblinding the study and crossing pts to ADT+AA+P. Grade 3/4 adverse events (ADT+AA+P vs ADT+PBOs) (%): hypertension (20.3 vs 10.0); hypokalemia (10.4 vs 1.3); increased ALT (5.5 vs 1.3) or AST (4.4 vs 1.5). Conclusions: Early use of AA+P added to ADT in pts with high-risk mHNPC yielded significantly improved OS, rPFS, and all secondary end points vs ADT+PBOs alone. ADT+AA+P had a favorable risk/benefit ratio and supports early intervention with AA+P in newly diagnosed, high-risk mHNPC. Clinical trial information: NCT01715285. [Table: see text]
Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma.
Authors: Fan Frank (Xiaohu) , Zhao Wanhong , Liu Jie , He Aili , Chen Yinxia , Cao Xingmei , Yang Nan , Wang Baiyan , Zhang Pengyu , Zhang Yilin , Wang Fangxia , Lei Bo , Gu Liufang , Wang Xugeng , Zhuang Qiuchuan , Zhang Wanggang
Published: June 2017

LBA3001

Background: Chimeric antigen receptor engineered T cell (CAR-T) is a novel immunotherapeutic approach for cancer treatment and has been clinically validated in the treatment of acute lymphoblastic leukemia (ALL). Here we report an encouraging breakthrough of treating multiple myeloma (MM) using a CAR-T designated LCAR-B38M CAR-T, which targets principally BCMA. Methods: A single arm clinical trial was conducted to assess safety and efficacy of this approach. A total of 19 patients with refractory/relapsed multiple myeloma were included in the trial. The median number of infused cells was 4.7 (0.6 ~ 7.0) × 10e6/ kg. The median follow-up times was 208 (62 ~ 321) days. Results: Among the 19 patients who completed the infusion, 7 patients were monitored for a period of more than 6 months. Six out of the 7 achieved complete remission (CR) and minimal residual disease (MRD)-negative status. The 12 patients who were followed up for less than 6 months met near CR criteria of modified EBMT criteria for various degrees of positive immunofixation. All these effects were observed with a progressive decrease of M-protein and thus expected to eventually meet CR criteria. In the most recent follow-up examination, all 18 survived patients were determined to be free of myeloma-related biochemical and hematologic abnormalities. One of the most common adverse event of CAR-T therapy is acute cytokine release syndrome (CRS). This was observed in 14 (74%) patients who received treatment. Among these 14 patients there were 9 cases of grade 1, 2 cases of grade 2, 1 case of grade 3, and 1 case of grade 4 patient who recovered after treatments. Conclusions: A 100% objective response rate (ORR) to LCAR-B38M CAR-T cells was observed in refractory/relapsed myeloma patients. 18 out of 19 (95%) patients reached CR or near CR status without a single event of relapse in a median follow-up of 6 months. The majority (14) of the patients experienced mild or manageable CRS, and the rest (5) were even free of diagnosable CRS. Based on the encouraging safety and efficacy outcomes, we believe that our LCAR-B38M CAR-T cell therapy is an innovative and highly effective treatment for multiple myeloma.
OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm).
Authors: Robson Mark E. , Im Seock-Ah , Senkus Elżbieta , Xu Binghe , Domchek Susan M. , Masuda Norikazu , Delaloge Suzette , Li Wei , Tung Nadine M. , Armstrong Anne , Wu Wenting , Goessl Carsten Dietrich , Runswick Sarah , Conte Pier Franco
Published: June 2017

LBA4

Background: Olaparib is an oral PARP inhibitor with anti-tumor activity in HER2-negative mBC with a g BRCAm (NCT00494234). OlympiAD (NCT02000622) was a randomized, open-label, phase III study that assessed efficacy and safety of olaparib vs standard single agent chemotherapy treatment of physician’s choice (TPC) in pts with HER2-negative mBC and a g BRCAm. Methods: Pts aged ≥18 y with HER2-negative mBC (hormone receptor positive or triple negative [TN]) and a g BRCAm, who had received ≤2 chemotherapy lines for mBC, were randomized (2:1) to olaparib tablets (300 mg po bid) or TPC (21-day cycles of either capecitabine [2500 mg/m2 po days 1–14], vinorelbine [30 mg/m2 IV days 1 and 8] or eribulin [1.4 mg/m2IV days 1 and 8]). Treatment was continued until objective disease progression (RECIST v1.1) or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR). Results: 302 pts were randomized (median age 44 y; 50% TN; 71% prior chemotherapy for mBC; 28% prior platinum) of whom 205 received olaparib and 91 received TPC (6 TPC pts were not treated). At 77% data maturity, PFS by BICR was significantly longer in pts treated with olaparib vs TPC (HR 0.58; 95% CI 0.43, 0.80; P=0.0009; 7.0 vs 4.2 months, respectively). Time to second progression (investigator-assessed) was also longer in the olaparib arm (HR 0.57; 95% CI 0.40, 0.83). Objective response rate was 59.9 and 28.8% in olaparib and TPC arms, respectively. Grade ≥3 adverse events (AE) occurred in 36.6 and 50.5% of olaparib and TPC pts, with AEs leading to discontinuation in 4.9 and 7.7% of pts, respectively. Mean change from baseline in global health-related quality of life (HRQoL, EORTC-QLQ-C30) across all timepoints favored olaparib (difference vs TPC 7.5; 95% CI 2.48, 12.44; P=0.0035). Conclusions: Olaparib tablet monotherapy provided a statistically significant and clinically meaningful PFS benefit to HER2-negative mBC pts with a g BRCAm, compared to standard TPC. The safety profile of olaparib was consistent with prior studies. The efficacy benefit was seen beyond the first progression and HRQoL also improved. Clinical trial information: NCT02000622.
Alectinib versus crizotinib in treatment-naive advanced ALK-positive non-small cell lung cancer (NSCLC): Primary results of the global phase III ALEX study.
Authors: Shaw Alice Tsang , Peters Solange , Mok Tony , Gadgeel Shirish M. , Ahn Jin Seok , Ou Sai-Hong Ignatius , Perol Maurice , Dziadziuszko Rafal , Kim Dong-Wan , Rosell Rafael , Zeaiter Ali Hassan , Liu Ting , Golding Sophie , Balas Bogdana , Noé Johannes , Morcos Peter N. , Camidge D. Ross
Published: June 2017

LBA9008

Background: Alectinib, a TKI targeting ALK, has shown robust efficacy in crizotinib-naïve/resistant ALK+ NSCLC. J-ALEX showed superiority of alectinib 300mg BID vs crizotinib in Japanese pts with crizotinib-naïve ALK+ NSCLC (progression-free survival [PFS] HR 0.34, p<0.0001). We report primary results from the ALEX study of first-line alectinib 600mg BID vs crizotinib in advanced ALK+ NSCLC (NCT02075840). Methods: This open-label randomized multicenter phase III study enrolled pts with stage IIIB/IV ALK+ NSCLC, determined by central IHC testing. Eligible pts had ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC. Pts with asymptomatic CNS metastases were allowed. Pts (n=303) were randomized 1:1 to receive alectinib 600mg or crizotinib 250mg BID. Primary endpoint: Investigator (Inv)-assessed PFS (RECIST v1.1), with systematic CNS imaging in all pts. Secondary endpoints included independent review committee (IRC)-assessed PFS, IRC-assessed time to CNS progression (TTP), objective response rate (ORR), overall survival (OS) and safety. Results: At the primary data cut-off (9 Feb 2017), alectinib demonstrated statistically significant superiority vs crizotinib, reducing risk of progression/death by 53% (HR 0.47, 95% CI 0.34–0.65, p<0.0001); alectinib median PFS was not reached (95% CI 17.7–NE) vs crizotinib 11.1 months (95% CI 9.1–13.1). Key secondary endpoints showed superiority for alectinib vs crizotinib, respectively: IRC PFS, HR 0.50 (95% CI 0.36–0.70; p<0.0001); median PFS 25.7 months (95% CI 19.9–NE) vs 10.4 months (95% CI 7.7–14.6); CNS TTP, cause-specific HR of CNS progression 0.16 (95% CI 0.10–0.28; p<0.0001); ORR (Inv) 83% (95% CI 76–89) vs 76% (95% CI 68–82), p=0.09; OS, based on 25% events, HR 0.76 (95% CI 0.48–1.20; p=0.24). Grade 3/4 AEs were less frequent with alectinib, 41%, vs 50% with crizotinib; fatal AEs occurred in 3% vs 5%, respectively. Rates of AEs leading to discontinuation, dose reduction and interruption were lower with alectinib. Conclusions: Alectinib showed superior efficacy and favorable tolerability compared with crizotinib. ALEX results support alectinib as a new standard of care for treatment-naïve ALK+ NSCLC. Funding: F. Hoffmann-La Roche Clinical trial information: NCT02075840.
Magic Mirror, On the Wall—Which Is the Right Study Design of Them All?—Part II
Authors: Vetter Thomas R.
Published: June 2017

The assessment of a new or existing treatment or other intervention typically answers 1 of 3 central research-related questions: (1) “Can it work?” (efficacy); (2) “Does it work?” (effectiveness); or (3) “Is it worth it?” (efficiency or cost-effectiveness). There are a number of study designs that, on a situational basis, are appropriate to apply in conducting research. These study designs are generally classified as experimental, quasiexperimental, or observational, with observational studies being further divided into descriptive and analytic categories. This second of a 2-part statistical tutorial reviews these 3 salient research questions and describes a subset of the most common types of observational study designs. Attention is focused on the strengths and weaknesses of each study design to assist in choosing which is appropriate for a given study objective and hypothesis as well as the particular study setting and available resources and data. Specific studies and papers are highlighted as examples of a well-chosen, clearly stated, and properly executed study design type.
Notch2 and Notch3 suppress the proliferation and mediate invasion of trophoblast cell lines
Authors: Zhao Wei-Xiu , Wu Zhen-Ming , Liu Wei , Lin Jian-Hua
Published: June 2017

Notch signaling pathways play important roles in cell fate and many diseases, including preeclampsia, the dysregulation of which may be the main cause of maternal mortality. This study aimed to investigate the roles of Notch2 and Notch3 in proliferation and invasion in trophoblast cell lines (BeWo and JAR). Small hairpin RNAs targeting Notch2/Notch3 and Notch2/Notch3-overexpression vectors were designed, constructed and transfected into BeWo and JAR cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were then used to detect Notch2 and Notch3 mRNA and protein levels, and confirm the efficiency of silence and overexpression. Flow cytometry assays were conducted to evaluate the cell cycle of the two cell lines, and transwell assays were used to detect migration and invasion. Western blot analysis was also performed to show the alteration of the cell lines' physiological activities at protein level.

When Notch2 was downregulated in BeWo cells, proliferation was dramatically promoted, while migration and invasion were significantly inhibited. When Notch2 was upregulated in JAR cells, proliferation was inhibited, but migration and invasion were promoted. After overexpression of Notch3 in BeWo cells, proliferation was downregulated, but migration and invasion were both upregulated. By contrast, the silencing of Notch3 expression in JAR cells significantly enhanced proliferation, but suppressed migration and invasion. These data indicated that Notch2 and Notch3 mediate the invasion and migration of BeWo and JAR cells, and may play a potential role in early onset severe preeclampsia.
Cell lineage of timed cohorts ofTbx6-expressing cells in wild type andTbx6mutant embryos
Authors: Concepcion Daniel , Washkowitz Andrew J. , DeSantis Akiko , Ogea Phillip , Yang Jason I. , Douglas Nataki C. , Papaioannou Virginia E.
Published: June 2017

Tbx6 is a T-box transcription factor with multiple roles in embryonic development as evidenced by dramatic effects on mesoderm cell fate determination, left/right axis determination, and somite segmentation in mutant mice. The expression of Tbx6 is restricted to the primitive streak and presomitic mesoderm, but some of the phenotypic features of mutants are not easily explained by this expression pattern. We have used genetically-inducible fate mapping to trace the fate of Tbx6-expressing cells in wild type and mutant embryos to explain some of the puzzling features of the mutant phenotype. We created an inducible Tbx6-creERT2 transgenic mouse in which cre expression closely recapitulates endogenous Tbx6 expression both temporally and spatially. Using a lacZ-based Cre reporter and timed tamoxifen injections, we followed temporally overlapping cohorts of cells that had expressed Tbx6 and found contributions to virtually all mesodermally-derived embryonic structures as well as the extraembryonic allantois. Contribution to the endothelium of major blood vessels may account for the embryonic death of homozygous mutant embryos. In mutant embryos, Tbx6-creERT2-traced cells contributed to the abnormally segmented anterior somites and formed the characteristic ectopic neural tubes. Retention of cells in the mutant tail bud indicates a deficiency in migratory behavior of the mutant cells and the presence of Tbx6-creERT2-traced cells in the notochord, a node derivative provides a possible explanation for the heterotaxia seen in mutant embryos.
Carotenoids buffer the acute phase response on fever, sickness behavior, and rapid bill color change in zebra finches
Authors: Broughton Deanna R. , Schneider Brent C. , McGraw Kevin J. , Ardia Daniel R.
Published: June 2017

Carotenoids are finite resources that animals can allocate to self-maintenance, attractiveness, or reproduction. Here we test how carotenoids affect the acute phase response (APR), an intense rapid systemic response characterized by fever, sickness behavior, and production of acute phase proteins, which serves to reduce pathogen persistence. We conducted a 2x2 factorial design experiment in captive adult male and female zebra finches (Taeniopygia guttata) to determine the effects of carotenoid supplementation on the intensity of the APR. We measured changes in feeding rate, activity level, and body temperature of the birds. We found that, relative to unsupplemented controls, carotenoid-supplemented birds exhibited less severe reductions in feeding and activity, smaller increases in body temperature, and lower circulating levels of haptoglobin (an acute phase protein) 24 h after inducing an APR. Among supplemented individuals, those with higher blood carotenoid levels exhibited a lower reduction in activity rate after 24 h. Forty-eight hours after APR induction, birds exhibited a significant decrease in plasma carotenoid levels and a decrease in bill hue, with less reduction in hue in carotenoid-supplemented individuals. These results demonstrate that carotenoids can alleviate several important behavioral and physiological effects of an APR and that bill color can change rapidly following induction of the costly APR immune defense. In particular, immune activation may have caused birds to preferentially draw down carotenoids from the bloodstream, ostensibly for use in health. Rapid bill color changes over a 48-hr period support growing evidence that bills may serve as short-term signals of health and condition.
Role of the terminator hairpin in the biogenesis of functional Hfq-binding sRNAs
Authors: Morita Teppei , Nishino Ryo , Aiba Hiroji
Published: June 2017

Rho-independent transcription terminators of the genes encoding bacterial Hfq-binding sRNAs possess a set of seven or more T residues at the 3′ end, as noted in previous studies. Here, we have studied the role of the terminator hairpin in the biogenesis of sRNAs focusing on SgrS and RyhB in Escherichia coli. We constructed variant sRNA genes in which the GC-rich inverted repeat sequences are extended to stabilize the terminator hairpins. We demonstrate that the extension of the hairpin stem leads to generation of heterogeneous transcripts in which the poly(U) tail is shortened. The transcripts with shortened poly(U) tails no longer bind to Hfq and lose the ability to repress the target mRNAs. The shortened transcripts are generated in an in vitro transcription system with purified RNA polymerase, indicating that the generation of shortened transcripts is caused by premature transcription termination. We conclude that the terminator structure of sRNA genes is optimized to generate functional sRNAs. Thus, the Rho-independent terminators of sRNA genes possess two common features: a long T residue stretch that is a prerequisite for generation of functional sRNAs and a moderate strength of hairpin structure that ensures the termination at the seventh or longer position within the consecutive T stretch. The modulation of the termination position at the Rho-independent terminators is critical for biosynthesis of functional sRNAs.
DECENTRALIZATION OF PUBLIC ADMINISTRATION: A COMPARATIVE ANALYSIS OF THE EXPERIENCE OF THE REPUBLIC OF UZBEKISTAN AND FOREIGN COUNTRIES (BY THE EXAMPLE OF FRANCE AND THE FEDERAL REPUBLIC OF GERMANY)
Authors: Алимухамедов Сухроб , Alimuhamedov Suhrob
Published: June 2017

The article provides a comparative analysis of the experience of the Republic of Uzbekistan in the sphere of decentralization of public administration, and developed countries such as France and Germany. The issues concerning organizational and legal support of decentralization of public administration in these countries were analyzed as well. The author has analyzed the stages of decentralization of public administration in France and its peculiarities; the administrative-territorial entities of the French Republic and their relations with the central authorities are also considered in present article. The powers of the Federation and the German federal land, as well as their relationships are considered. The article also studied the powers of the communities in Germany, as well as their relationships with each other, with the federal states and the federation. Moreover, the Institute of Federal enforcement in Germany as a means of control by the Federation is considered as well. The article contains the stages of the decentralization of public administration in the Republic of Uzbekistan, issues on the differentiation of powers between the central government and state authorities in the local areas. There are disclosed the powers of the authoritative local bodies, the issues of organizational and legal support to their activities, as well as their relationship with the central bodies of state administration. The article also shows the role and nature of self-government bodies in the process of decentralization of public administration in the Republic of Uzbekistan.
REFORM OF LEGISLATIVE REGULATION OF PROTECTION OF THE ADULT PERSONS’ RIGHTS IN SWITZERLAND
Authors: Петурова Наталья , Peturova Natal'ya
Published: June 2017

The article shows the evolution of the Swiss civil legislation in the sphere of guardianship over an adults in Switzerland, presents the principles which are the basis of the system of measures for protection of these persons at present, analyzes the approaches to the reform 2012 of the Swiss Civil Code, embodied the concept of the protection of the fundamental rights and freedoms. The author paid attention on a specific reform measures of protection and the procedure of their adoption. Also the attention paid to new concepts, laid the basis for the reform, such as respect for human dignity, promoting self-determination of individuals, strengthening the solidarity of the family, reducing the degree of state intervention in private life of a person, differentiational approach to the application of safeguards, the non-evaluative terminology, and disclosure of information on application of protection measures.
The article discusses the current legislative regulation of Switzerland (order in case of loss of ability to reason intelligently, accommodation in an institution for assistance, the representation of the spouse or registered partner and the four kinds of guardianship: guardianship by the guardianship cooperation, guardianship representation and custody of the common actions).
The theme of the article is relevant considering the need for the further revision of the Russian legislation in the part of protection and promotion of the interests of persons with mental disabilities. Foreign experience is extremely useful, as important changes of the Civil code of the Russian Federation (2012) and the Civil Procedural Code of the Russian Federation (2013), prepared under pressure of the European Court of Human Rights and the Constitutional Court of the Russian Federation, are not sufficient and the reform in Russia should be continued.
PRE-CONTRACTUAL RELATIONS IN INTERNATIONAL COMMERCIAL TURNOVER: SPECIFICITY AND TENDENCIES OF LEGAL REGULATION
Authors: Муратова Ольга , Muratova Olga
Published: June 2017

The article is devoted to analysis of specifics and trends of legal regulation of pre-contractual relations in international commercial turnover. The emergence of disputes arising from pre-contractual relations, the recognition of the doctrine of culpa in contrahendo, which appeared in the late nineteenth century and helped to establish the Institute that meets the needs of the international commercial turnover in the XXI century. The determining factor in the formation of the new Institute of pre-contractual relations of the Russian civil law are the successes of the foreign national codifications of private law and the unification of international private law in the European Union in the framework of non-governmental organizations: International Institute for the Unification of Private Law (UNIDROIT), the Hague conference on private international law, etc. These achievements prefaced the inclusion in the civil code provisions on pre-contractual relations by putting the question of formal recognition of their existence as an independent Institute of the civil law on the legal consequences occurring as the result of unfair behavior at the pre-contractual stage. The author also draws attention to the complexity of the recognition of those or other actions of potential contractors of the existence of pre-contractual relations, which raises the question of whether their formalization through written fixation. In addition, the author considers the problem of implementation in the Russian legislation the principle of autonomy of will of parties to select the law applicable to pre-contractual relations. At the end the author comes to a conclusion that the most suited to modern commercial reality is an approach, according to which the principle of autonomy of will of the parties is a fundamental criterion for determining the law applicable to pre-contractual relations. The choice of such rights must be granted to the parties pre-contractual relations, as the conclusion of the main contract or after its conclusion (for example, if you have any pre-contractual dispute).
CRIMINALLY-LEGAL MAINTENANCE OF OPERATIONAL-INVESTIGATIVE ACTIVITY IN AUSTRALIA AND THE UNITED STATES: THE EXPERIENCE FOR THE RUSSIAN LEGISLATOR
Authors: Шкабин Геннадий , Shkabin Gennadiy
Published: June 2017

For a relatively long time there is consideration of criminal law maintenance for secrecy activity of law enforcement agencies in order to combat crime in the legislation, judicial practice and jurisprudence of some foreign countries. In many states this process has undergone numerous changes. The article presents the experience of legal regulation of causing harm during performance of activities, which is called operational-investigative in Russia. The provisions of legal acts and court decisions of Australia and the United States as the countries with the most developed regulatory and scientific basis for solving these problems are analyzed. It is noted that in both countries the root cause of the formation of the regulatory framework dedicated to harm causing during covert operations were specific criminal cases. The legislation of Australia, which establishes the procedure for controlled operations causing harm to the objects of criminal law protection, is considered. The conditions of the legitimacy of the controlled behavior are described. Attention is paid to the border admissibility of acts as well as the release of the Australian legislator since 2010, the so-called auxiliary crime during a controlled operation. Legal maintenance for acts of secret FBI employees in USA, conditions of their lawful conduct and the limits of harm causing are described. The author comes to a conclusion that the representatives of US law enforcement-enforcement agencies have extremely broad powers during operational implementation. Based on the review conclusions, including and recommendations for the improvement of the Russian legislation are drawn.
THE DEVELOPMENT OF THE USA LEGISLATION ON THE FIGHT AGAINST TERRORISM AFTER 11 SEPTEMBER 2001
Authors: Ефремов Андрей , Efremov Andrey
Published: June 2017

The article is devoted to development of the USA legislation on the fight against terrorism. The author considered the objectives and tasks of the state in a particular historical period; analyzed the laws passed by the USA Congress aimed at combating home and international terrorism; identifies the main directions of the state policy of the USA in the field of counter-terrorism. The article covers the events after 11 September 2001 to the present. The author gives a brief overview of the events of 11 September 2001, discusses the Patriot Act and other laws, aimed at combating terrorism. The Patriot Act allows the Federal Bureau of Investigation to intercept telephone, verbally and electronic communications relating to terrorism, computer and mail fraud; introduces special measures to combat money-laundering; expands immigration rules, in particular, mandatory requirement of detention of persons suspected of terrorism appeared; reveals the procedure of multilateral cooperation to combat terrorism, strengthening measures to investigate terrorist crimes; established rewards for information on terrorism; introduces the procedure of identification of DNA of persons charged for committing terrorist crimes or any violent crime; introduced the concept of domestic terrorism and Federal crimes of terrorism, the prohibition on harboring terrorists and material support; there is a new crime — terrorist and other acts of violence against public transportation systems. The law abolished for the statute of limitations for crimes of terrorist orientation. In 2002 5 laws wer adopted: “Homeland Security Act of 2002”, “Maritime Transportation Security Act of 2002”, “Aviation and Transportation Security Act“, “Public Health Security and Bioterrorism Preparedness and Response Act of 2002”, “Terrorism Risk Insurance Act of 2002”. The Palestinian Anti-Terrorism Act was adopted in 2006. This law restricted the financial assistance to the Palestinian national authority; Haqqani Network Terrorist Designation Act of 2012 included the Haqqani Network in the list of international terrorist organizations; the political act of refusal of admission to the United States representative to the United Nations, because he was accused of the occupation of the espionage or terrorist activities against the United States and poses a threat to the national security interests of the United States.
JURIDICAL FRAMEWORK OF IMPLEMENTATION OF UN CONVENTIONS ON BIOLOGICAL DIVERSITY (CBD) IN AZERBAIJAN REPUBLIC
Authors: Гусейнов Тургай Имамгулу оглы , Guseynov Turgay Imamgulu ogly
Published: June 2017

The article deals with the study of the issues over the implementation of the provisions of the Convention on Biological Diversity, 1992 in the Azerbaijan Republic. National regulations and legal acts, aimed at realization of the mentioned Convention hereupon, are analyzed. The gaps existed in the legislation of the republic are identified. The intended measures on the provision of biological diversity to be fulfilled within the National strategy plans asserted by the Decree of the President of the Azerbaijan Republic are analyzed as well. Biodiversity conservation is not to be limited to the territory of individual states. It is necessary to proceed from the protected area, which sometimes may cover the territory of several states. These elements should be taken into account when forming the national legal framework and the implementation of the provisions of international agreements in the field of biodiversity conservation. The importance of active participation of each State in the preservation of biodiversity and, thus, protection of the environment as a whole. Naturally invaluable role here, and the public, and each one of us. All this requires improved national legal framework and institutional arrangements in this area. The fight for the preservation of biodiversity is achieved not only by the struggle with the consequences, by the application of administrative and criminal sanctions, but preventive actions to prevent them. An important role will be played by the National Plan, providing for comprehensive measures for the conservation of biodiversity.