bluuebunny/crossref_metadata_2025_split huggingface dataset:
An open-label, phase II study of rucaparib, a PARP inhibitor, in HER2- metastatic breast cancer patients with high genomic loss of heterozygosity: RUBY.
Authors: Patsouris Anne , Vicier Cecile , Campion Loic , Gouraud Wilfried , Jimenez Marta , Pezzella Veronica , Loehr Andrea , Raponi Mitch , Bieche Ivan , Callens Celine , Andre Fabrice 
Published: September 2018

TPS1117 Background: BRCA1 and/or BRCA2 mutations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). In addition to BRCA1/2, alterations of other genes (PALB2, RAD51C….) implicated in homologous recombination repair (HRR) pathways leads to a BRCAness phenotype that is also associated with PARPi sensitivity. Rucaparib, a potent oral PARP-1, -2 and -3 inhibitor, has shown activity in a phase 1 study of patients (pts) with homologous recombination deficient (HRD) breast cancer (Kristeleit, RS. J Clin Oncol 32:5s, 2014 [suppl; abstr 2573]). This single arm, open-label, multicenter phase II study (NCT02505048) is evaluating the efficacy and safety of rucaparib in pts with HER2- metastatic breast cancer (MBC) associated with a BRCAness phenotype determined by “high tumor genomic LOH” score and/or a somatic BRCAmutation. Methods: Pts with HER2- MBC exhibiting a BRCAness phenotype will receive oral rucaparib 600 mg BID continuously in 21-day cycles until disease progression. The primary endpoint is clinical benefit rate (CBR), defined by complete and partial response and stable disease lasting for at least 16 weeks and, if CBR is significant, the objective response rate (ORR). Secondary endpoints include progression-free survival, overall survival, safety, and the prognostic value of the BRCAness signature. Targeted enrollment is 41 pts using a Simon two-stage design. Eligibility: Women with HER2- MBC with a BRCAness phenotype who received 1-4 prior chemotherapy regimens are eligible. ECOG PS 0-1 and adequate organ function is required. The BRCAness phenotype is defined by high tumor genomic LOH (LOH cutoff of 18%) that can identify HRD tumors, including both known BRCA1 methylation and unknown genetic/epigenetic mechanisms and somatic BRCA1/2 mutations. Pts with a known BRCA1 and/or BRCA2 germline mutation are excluded. “high tumor genomic LOH” score will be generated from the CytoScan HD SNP array, which is available from the SAFIR02 protocol or other molecular programs. To date, 13 pts have been enrolled, with enrollment ongoing. This trial design is intended to establish proof-of-concept that rucaparib can improve ORR in HER2- MBC with HRD. Clinical trial information: NCT02505048.
A phase I study of oral SRA737 (formerly CCT245737) given in combination with gemcitabine plus cisplatin or gemcitabine alone in patients with advanced cancer.
Authors: Ingles Garces Alvaro Henrique , Chenard-Poirier Maxime , Jones Robert Hugh , Quinton Amy , Plummer Elizabeth R. , Drew Yvette , Kowalski Mark Marion , Klencke Barbara J. , Banerji Udai 
Published: September 2018

TPS2613 Background: SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key cell cycle checkpoint and central regulator of the DNA Damage Response (DDR) network. In cancer cells, replication stress induced by genomic alterations in oncogenes (eg, MYC and RAS) combined with loss of function in tumor suppressors (eg, TP53 and ATM) results in persistent DNA damage and genomic instability. Targeted inhibition of components of the DDR network such as Chk1 by SRA737 may be synthetically lethal to cancer cells. Chk1 is also believed to facilitate tumor cell resistance to chemotherapy or radiation-induced DNA damage and the combination of SRA737 with these standards-of-care may provide synergistic antitumor activity. SRA737 is being investigated in two Phase 1 trials in patients with advanced cancer. We now describe the Phase 1 multicenter, dose-escalation study of SRA737 in combination with gemcitabine/cisplatin (GC) or gemcitabine (G) alone (NCT02797977). Methods: Up to 70 patients will receive escalating doses of SRA737+GC in Stage 1 or SRA737+G in Stage 2 until a recommended Phase 2 dose (RP2D) is established, followed by expansion cohorts. Patients will receive a single SRA737 PK run-in dose followed by Gem on D1 and 8, Cis on D1, SRA737 on D2, 3, 9 and 10 of each 21-d cycle or Gem on D1, 8 and 15, SRA737 on D2, 3, 9, 10, 16, 17 of each 28-d cycle. Eligibility criteria include WHO performance status of 0-1 and ≤ 3 prior lines of cytotoxic chemotherapy for metastatic disease. Primary objectives are to assess the safety profile of SRA737 combination therapy and to establish a RP2D. The PK profile and PD biomarkers (eg, phosphorylation of Chk1 at Ser296, Ser345 and γH2AX foci in PBMCs and tumor tissue) will be explored. The study was opened to enrollment in mid-2016. An amendment, which includes the addition of an indication specific expansion cohort of subjects with genetically-defined tumors known to have Chk1-sensitizing aberrations (eg, gene mutations and amplifications/deletions), has been submitted and is pending regulatory review while enrollment continues. At the Annual Meeting, the amended design will be described. Clinical trial information: NCT02797977.
A phase I study of the bispecific antibody T-cell engager GBR 1302 in subjects with HER2-positive cancers.
Authors: Wermke Martin , Schmidt Helmuth , Nolte Hildegard , Ochsenreither Sebastian , Back Jonathan , Salhi Yacine , Bayever Eliel 
Published: September 2018

TPS3091 Background: GBR 1302, a bispecific antibody based on Glenmark’s BEAT platform, is designed to recruit cytotoxic T-cells (independent of their specificity) to HER2-positive cancer cells where they are activated by the CD3e-specific domain of the molecule. Preclinically, GBR 1302 has demonstrated potent killing of HER2-positive human cancer cells (HER2 3+ or 2+ by IHC HercepTest), as well as growth suppression of the trastuzumab-resistant cell line JIMT-1. In contrast, the GBR 1302 concentration required to kill primary cardiomyocytes with normal HER2 levels was up to 1000 times greater than the concentration needed to kill HER2 3+ tumor cell lines. This study will determine safety and tolerability of GBR 1302 monotherapy in subjects with HER2-positive cancers. Methods: Part 1 (dose-finding) of this ongoing phase 1 study (NCT02829372) is enrolling adults with progressing HER2-positive solid tumors for which no standard treatment is available. Intravenous GBR 1302 is given every 2 weeks in 28-day cycles at escalating doses (Table). Each of the first 4 cohorts includes a single subject; subsequent cohorts enroll subjects using a standard 3+3 design. Primary endpoints are: maximum tolerated dose (MTD) of GBR 1302; and relationship of GBR 1302 with the incidence, nature, and intensity of adverse events. After Cycle 1, subjects continue GBR 1302 treatment until disease progression or unacceptable toxicity. Part 2 (expansion) will treat subjects at the MTD to further evaluate anti-tumor activity, as well as safety and pharmacokinetics. Due to the known cardiotoxic potential of classic HER2-targeting strategies, this study incorporates a rigorous serological and echocardiographic surveillance schedule. The effects of GBR 1302 on the adaptive immune system will also be studied at cellular and serological levels in translational research. Clinical trial information: NCT02829372. [Table: see text]
Phase 1b/2 keynote-365 trial: Pembrolizumab (pembro) combination therapy in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Yu Evan Y. , Wu Haiyan , Schloss Charles 
Published: September 2018

TPS5089 Background: Approved treatments for mCRPC (eg, enzalutamide and docetaxel) may increase programmed death ligand 1 (PD-L1) expression and facilitate neoantigen release. In phase 1b and 1/2 trials, pembro, an anti–PD-1 antibody, has produced antitumor responses in previously treated mCRPC as monotherapy and in combination with enzalutamide. Olaparib, a PARP inhibitor, has shown activity in mCRPC with DNA-repair defects. The nonrandomized, multicohort, open-label KEYNOTE-365 study (NCT02861573) will evaluate the safety and efficacy of pembro with olaparib (cohort A), docetaxel + prednisone (cohort B), or enzalutamide (cohort C) in mCRPC. Methods: Cohort allocation depends upon prior treatment: cohort A requires prior docetaxel (treatment with 1 other chemotherapy and ≤2 second-generation hormonal manipulations is allowed); cohort B requires prior abiraterone acetate or enzalutamide (but not both); cohort C requires prior abiraterone acetate. Additional eligibility criteria include confirmed prostate adenocarcinoma, disease progression (PD) ≤6 months before screening, ongoing androgen deprivation (serum testosterone < 50 ng/dL), and provision of nonirradiated tumor sample. Pembro 200 mg will be given every 3 weeks (Q3W) with either olaparib 400 mg twice daily (cohort A), docetaxel 75 mg/m2 Q3W + prednisone 5 mg twice daily (cohort B), or enzalutamide 160 mg once daily (cohort C). Pembro treatment will continue for up to 35 cycles or until PD or unacceptable adverse events (AEs). Patients in cohort B may receive a maximum of 10 cycles of docetaxel + prednisone. Patients who discontinue 1 of 2 drugs in a combination because of a treatment-related AE may continue to receive the other drug until PD. Response will be evaluated by prostate-specific antigen (PSA) levels Q3W and by imaging Q9W for the first year and Q12W thereafter. Primary end points are safety and PSA response rate (decline of ≥50% from baseline twice ≥3 weeks apart). Secondary end points include time to PSA progression, progression-free survival, overall survival, and overall response rate. Enrollment will continue until 70 patients are enrolled for each cohort. Clinical trial information: NCT02861573.
KI intolerance study: A phase 2 study to assess the safety and efficacy of TGR-1202 in pts with chronic lymphocytic leukemia (CLL) who are intolerant to prior BTK or PI3K-delta inhibitor therapy.
Authors: Dorsey Colleen , Paskalis Dana , Brander Danielle M. , Lansigan Frederick , Barr Paul M. , Lamanna Nicole , Cheson Bruce D. , Pu Jeffrey J. , Schreeder Marshall T. , Pagel John M. , Sportelli Peter , Fanning Molly J , Miskin Hari P. , Zimmer Tracey , Walsh Kristy , Schuster Stephen J. , Luning-Prak Eline T. , Wileyto E. Paul , Weiss Michael S. , Mato Anthony R. 
Published: September 2018

TPS7569 Background: Although kinase inhibitor (KI) therapies, such as ibrutinib, are generally well tolerated, intolerance is the most common reason for discontinuation (d/c) in practice (~50%, Mato et al, Blood 2016). Additionally KI interruptions (≥ 8 days) can shorten OS (Barr et al, ASCO 2015). Fortunately, data suggest that KIs have non-overlapping toxicity profiles. Therefore, pts who d/c KI due to intolerance, with ongoing CLL response, represent an unmet need. TGR-1202 is a next generation, highly-specific PI3K-delta inhibitor with nanomolar inhibitory potency. TGR-1202 is well-tolerated with a d/c rate due to AEs of 8% as demonstrated in an integrated safety analysis of 165 treated pts (Burris et al, ASCO 2016). Methods: A phase 2 investigator initiated study is being conducted to assess the safety and activity of TGR-1202 in CLL pts who are KI intolerant. KI Intolerance is defined as ≥ 1 Gr 3 or ≥ 2 Gr 2 non-heme toxicities, ≥ 1 Gr 3 neutropenia with infection or fever, and/or ≥ 1 Gr 4 heme toxicity leading to KI (BTK and/or PI3K inhibitor) d/c (Table). Toxicities must resolve to ≤ Gr 1 prior to TGR-1202 dosing. Prior KI must be d/c for ≥ 14 days without progression (PD). All eligible pts are treated with TGR-1202 (800mg oral daily) until PD, toxicity or study conclusion. Primary study endpoint is PFS. Secondary endpoints include ORR, duration of response, time to treatment failure and TGR-1202 safety profile. Peripheral blood samples are collected prior to TGR-1202, after 28 days and at PD for correlative analyses to identify markers associated with KI intolerance. The trial commenced 10/1/2016. 55 eligible pts will be enrolled in approximately 12 months with 24 months follow-up. As of 1/2017, 10 study sites are enrolling pts with 10 more to be activated. To date, 10 pts have been enrolled and treated with TGR-1202. Clinical trial information: NCT02742090. [Table: see text]
Multicenter phase 2 study to identify the optimal neo-adjuvant combination scheme of ipilimumab (IPI) and nivolumab (NIVO) (OpACIN-neo).
Authors: Rozeman Elisa A. , Van Akkooi Alexander Christopher Jonathan , Routier Emilie , Menzies Alexander M. , Eriksson Hanna , Smith Myles , Scolyer Richard A. , Hoeller Christoph , Hansson Johan , Robert Caroline , Larkin James M. G. , Long Georgina V. , Blank Christian U. 
Published: September 2018

TPS9600 Background: The outcome of high risk stage IIIb and IIIc melanoma patients is poor, with a 5 year overall survival (OS) rate of < 50%. Adjuvant high dose IPI significantly improves 5 year progression free survival (PFS) and OS. In stage IV patients the combination of IPI and NIVO improves response rates (RR) and PFS compared to monotherapy, but at cost of higher toxicity. Neo-adjuvant treatment may be a favorable approach as immune checkpoint inhibition (ICI) is of greatest value at the moment of TCR triggering and therefore dependent on the amount of antigen present. The phase Ib OpACIN study comparing neo-adjuvant and adjuvant IPI and NIVO showed that neo-adjuvant treatment is feasible as all patients underwent surgery on time. The neo-adjuvant pathological RR was 80%, although 18/20 patients (90%) stopped early due to ≥1 grade 3 or 4 immune-related adverse events (irAEs). To date (median follow-up 45 wks), none of the 8 responders in the neo-adjuvant arm have relapsed. This raises the question whether the neo-adjuvant IPI and NIVO schedule can be adjusted to reduce toxicity but preserve efficacy. Methods: The aim of the multi-center phase 2 OpACIN-neo trial is to identify an optimal neo-adjuvant combination scheme of IPI and NIVO. 90 patients with resectable stage III melanoma will be randomized 1:1:1 between three combination schemes of IPI and NIVO. Patients in arm A will receive 2 courses standard regimen IPI 3mg/kg + NIVO 1mg/kg q3wks, in arm B IPI 1mg/kg + NIVO 3mg/kg q3wks, and in arm C 2 courses of IPI 3mg/kg q3wks directly followed (2-24hr) by 2 courses NIVO 3mg/kg q2wks. All patients will undergo surgery at week 6. The primary endpoints are rate of grade 3/4 irAEs, pathological RR, and radiologic RECIST 1.1. An interim analysis is planned after 13 patients have been accrued to each arm (according to the Simon 2-stage design). Major inclusion criteria are: ≥1 measurable lymph node metastases (according to RECIST 1.1) that can be biopsied, no history of in-transit metastases in the last 6 months, and naïve for ICI. Baseline biopsies and blood samples (week 0, 6, 12) will be taken for translational research. The first center started inclusion in December 2016, until now 2 patients have been enrolled. Clinical trial information: NCT02977052.
Robotic tilt table exercises versus conventional exercises in rehabilitation of hemiplegic patients
Authors: Yadav Ramakant , Kuma Suraj , Aafreen  , Yadav Sandeep 
Published: September 2018

Background/Aims: Early mobilisation in people with stroke has the potential to affect a number of health-related areas, such as power, coordination, reflex activity, joint range of motion and wellbeing. The aim of this study was to determine the efficacy of a 1-month exercise programme using a robotic tilt table over conventional physiotherapy treatment in the rehabilitation of patients with hemiplegia following stroke. Methods: A total of30 patients with acute stroke were included in the study and randomised equally into two groups (15 in each group), using the lottery method. Group A underwent conventional physiotherapy and Group B had robotic tilt table therapy. Patients were reassessed after 30 days. Outcome measures used were the Quality of Life scale and muscle strength. Findings: Both the groups improved in Quality of Life scores and motor power, but Group B improved significantly more than the conventional physiotherapy group. Conclusions: Robotic tilt table exercises were found to be beneficial in hemiplegic patients in improving quality of life and muscle strength.
Effects of lumbar stabilisation and treadmill exercise on function in patients with chronic mechanical low back pain
Authors: Bello Bashir , Adeniyi Ade Fatai 
Published: September 2018

Background/Aims: Multifidus muscle is an important contributor to low back pain as it atrophies and is inhibited during the first episode of low back pain. This study aims to compare the effectiveness of lumbar stabilisation exercise with treadmill walking on multifidus muscle activation, pain intensity and functional disability among people with chronic mechanical low back pain. Methods: Individuals with chronic mechanical low back pain were randomised into two groups: Group 1 (n=25) performed lumbar stabilisation exercises following the McGill protocol; and Group 2 (n=25) followed the modified Bruce treadmill walking protocol. Participants walked or exercised three times a week for 8 weeks. Pain intensity (measured using a visual analogue scale), functional disability (using the Oswestry Disability Index Questionnaire) and amplitude of multifidus muscle activation (using a surface electromyography machine) were assessed at baseline and at the end of week 8. Data were analysed using descriptive statistics, paired and independent t-tests at α≤0.05. Findings: There were no significant differences between the groups' anthropometric and clinical characteristics at baseline. Both groups demonstrated significant reductions in pain intensity and functional disability and increases in multifidus muscle activation at the end of the study (all P<0.05). Group 1 had lower pain intensity (2.60 ± 0.48 vs 4.50 ± 0.12) and functional disability (24.20 ± 4.06 vs 40.00 ± 10.56) and significantly higher multifidus muscle activation levels (40.00 ± 4.16 vs 26.95 ± 4.04; P<0.05) than Group 2 at the end of week 8. Conclusions: Lumbar stabilisation exercises are more effective than treadmill walking exercises in activating the multifidus muscle, reducing pain intensity and functional disability in individuals with chronic mechanical low back pain.
LA PENA CON RESTRICCIÓN DE LA LIBERTAD EN EL ACUERDO DE PAZ: VISIÓN GEOPOLÍTICA DEL TRATADO FIRMADO ENTRE EL GOBIERNO DE COLOMBIA Y LA FUERZA ARMADA DE REVOLUCIÓN DE COLOMBIA
Authors: Garcete Juan Marcelino González 
Published: September 2018

La fuerza armada de revolución colombiana es un grupo al margen de la ley en Colombia que ha cometido delitos que violan los derechos humanos. Actualmente este grupo ilegal se encuentra en diálogos con el gobierno colombiano con el fin de llegar a un acuerdo de paz motivo por el cual en este trabajo tenemos que remitirnos a los pactos y convenciones internacionales para verificar si lo que plantea el gobierno en el comunicado 060 del 2015 se acoge a las normas internacionales.
AS TÉCNICAS DE NEUROMARKETING NOS CONTRATOS ELETRÔNICOS E O VÍCIO DO CONSENTIMENTO NA ERA DIGITAL
Authors: Parchen Charles Emmanuel , Freitas Cinthia Obladen de Almendra , De Meireles Jussara Maria Leal 
Published: September 2018

A sociedade contemporânea vive alterações sociais e comportamentais à medida que novas tecnologias são desenvolvidas e incorporadas ao dia a dia. Vive-se a quebra de paradigmas. Conceitos como velocidade, mobilidade e distância estão em modificação e o consumidor necessita usar produtos e serviços que em suas cláusulas contratuais preveem a Mineração de Dados como mecanismo de coleta, filtragem e catalogação dos gostos e das preferências. Os dados pessoais fomentam um mercado lucrativo, que lança mão de técnicas de neuromarketing para existir e se retroalimentar. Propõe-se a mudança de paradigma do atual mercado de compartilhamento de dados, por meio da atuação do Poder Judiciário, que, por exemplo, pode ser instado a revisar ou a modificar as cláusulas contratuais consideradas desproporcionais ao consumidor. Por meio do método dedutivo, o artigo analisa os vícios do consentimento em contratos eletrônicos sob a ótica do neuromarketing como técnica que fomenta o consumo irrefletido e compulsivo.
Spatial Distribution of Human Development Index in the Regions of Russia
Authors: SHAMSUTDINOVA Nailya K. , ISIANGULOVA Elmira I. , LAKMAN Irina A. , PRUDNIKOV Vadim B. , SADIKOVA Liana F. 
Published: September 2018

Spatial effects in human development levels among different regions of a territory are important to study in the context of the core-periphery model. We use different methods to study human development index (HDI) for 85 Russian regions. The authors studied the human development index (HDI) for 85 Russian regions. Methods of spatial statistics (econometrics) are used to estimate the ‘spatial gradient’ in economic geography (Moran’s global and local I, Geary’s C, Getis-Ord global G indices). As a weighting matrix we used a contiguity matrix, taking into account the HDI levels only in neighboring regions. Analysis of the global indices of Moran’s I, Geary’s C and Getis-Ord G and Morans scatter plots showed the presence of time-inconsistent spatial autoregressive dependence of the level of HDI in regions of Russia. The ‘spatial gradient’ of the level of human development in Russia is influenced by historically existing imbalances (due to strong oil and gas export-oriented nature of the economy) and insufficient use of human capital. To our view the regional differentiation in human development among the regions is caused primarily by the ‘catching up’ style of Russian economy: human capital is concentrated in regions with already high level of development, although in terms of growth rates Moscow and St. Petersburg are not the leaders. The territorial and geopolitical policies of Russian Federation also influence HDI distribution. For example, huge public investments in the regions of Russian Far East are often ineffective.
Machine Translation in Indian Languages: Challenges and Resolution
Authors: Patel Raj Nath , Pimpale Prakash B. , Sasikumar M. 
Published: September 2018

Abstract
English to Indian language machine translation poses the challenge of structural and morphological divergence. This paper describes English to Indian language statistical machine translation using preordering and suffix separation. The preordering uses rules to transfer the structure of the source sentences prior to training and translation. This syntactic restructuring helps statistical machine translation to tackle the structural divergence and hence provides better translation quality. The suffix separation is used to tackle the morphological divergence between English and highly agglutinative Indian languages. We demonstrate that the use of preordering and suffix separation helps in improving the quality of English to Indian language machine translation.