Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study

Immunoterapia; Pembrolizumab; neoplàsies mamàries triple-negativesInmunoterapia; Pembrolizumab; neoplasias mamarias triple-negativasImmunotherapy; Pembrolizumab; triple-negative breast neoplasmsBackground: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods: Eligible patients had centrally confirmed mTNBC, ?1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ?24 weeks), progression-free survival, and overall survival. Results: All enrolled patients (N¼170) were women, 61.8% had PD-L1–positive tumors, and 43.5% had received ?3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1–positive populations. Disease control rate (95% CI) was 7.6% (4.4–12.7) and 9.5% (5.1–16.8), respectively. Median duration of response was not reached in the total (range, 1.2þ–21.5þ) and in the PD-L1–positive (range, 6.3–21.5þ) populations. Median PFS was 2.0 months (95% CI, 1.9–2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6–11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study

Abemaciclib; Adjuvant; Early breast cancerAbemaciclib; Adjuvant; Càncer de mama precoçAbemaciclib; Adyuvante; Cáncer de mama precozBackground Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. Patients and methods This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. Results At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. Conclusion Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.This work was supported by the sponsor (Eli Lilly and Company) and designed together with the study Executive Committee (no grant number)

Reducing Non-Radiative Voltage Losses by Methylation of Push–Pull Molecular Donors in Organic Solar Cells

Organic solar cells are approaching power conversion efficiencies of other thin-film technologies. However, in order to become truly market competitive, the still substantial voltage losses need to be reduced. Here, the synthesis and characterization of four novel arylamine-based push-pull molecular donors was described, two of them exhibiting a methyl group at the para-position of the external phenyl ring of the arylamine block. Assessing the charge-transfer state properties and the effects of methylation on the open-circuit voltage of the device showed that devices based on methylated versions of the molecular donors exhibited reduced voltage losses due to decreased non-radiative recombination. Modelling suggested that methylation resulted in a tighter interaction between donor and acceptor molecules, turning into a larger oscillator strength to the charge-transfer states, thereby ensuing reduced non-radiative decay rates

Human alpha 2A-adrenergic receptor gene expressed in transgenic mouse adipose tissue under the control of its regulatory elements.

Catecholamines regulate white adipose tissue function and development by acting through beta- and alpha2-adrenergic receptors (ARs). Human adipocytes express mainly alpha 2A- but few or no beta 3-ARs while the reverse is true for rodent adipocytes. Our aim was to generate a mouse model with a human-like alpha2/beta-adrenergic balance in adipose tissue by creating transgenic mice harbouring the human alpha 2A-AR gene under the control of its own regulatory elements in a combined mouse beta 3-AR-/- and human beta 3-AR+/+ background. Transgenic mice exhibit functional human alpha 2A-ARs only in white fat cells. Interestingly, as in humans, subcutaneous adipocytes expressed higher levels of alpha2-AR than perigonadal fat cells, which are associated with a better antilipolytic response to epinephrine. High-fat-diet-induced obesity was observed in transgenic mice in the absence of fat cell size modifications. In addition, analysis of gene expression related to lipid metabolism in isolated adipocytes suggested reduced lipid mobilization and no changes in lipid storage capacity of transgenic mice fed a high-fat diet. Finally, the development of adipose tissue in these mice was not associated with significant modifications of glucose and insulin blood levels. Thus, these transgenic mice constitute an original model of diet-induced obesity for in vivo physiological and pharmacological studies with respect to the alpha2/beta-AR balance in adipose tissue

ANALISIS YURIDIS SOSIOLOGIS PROSEDUR PENYELAMATAN KREDIT BERMASALAH BANK DANAMON BERDASARKAN PERATURAN BANK INDONESIA NOMOR 14/15/PBI/2012 TENTANG PENILAIAN KUALITAS ASET BANK UMUM (Studi Pada Kasus Konflik Bank Danamon Tanjung Balai Karimun Provinsi Kepualauan Riau Dengan Nasabah Bank Danamon)

Kasus mengenai penanganan kredit bermasalah di Bank Danamon sering mengalami permasalahan terutama dalam hal pelelangan. Kejadian tersebut dikarenakan bahwa Bank Danamon sering melakukan tindakan pelelangan tanpa pemberitahuan oleh nasabah serta tidak melakukan proses penyelamatan kredit bermasalah terlebih dahulu terhadap nasabah yang mengalami kredit bermasalah. Penelitian ini mengambil rumusan masalah Bagaimana prosedur penyelamatan kredit bermasalah yang dilakukan oleh PT.Bank Danamon dikaitkan dengan Peraturan Bank Indonesia Nomor 14/15/PBI/2012 Tentang Penilaian Kualitas Aset Bank Umum dan Apa faktor yang mendasari PT.Bank Danamon melakukan pelelangan terhadap jaminan nasabah. Penelitian ini menggunakan pendekatan Yuridis Sosiologis. Berdasarkan hasil penelitian tersebut ada beberapa peraturan dari Bank Danamon yang tidak mengikuti prosedur dari BI serta terjadi ketidaksesuain dengan peraturan yang dikeluarkan oleh Bank Danamon pusat dengan tindakan yang dilakukan oleh Bank Danamon Tanjung Balai Karimun. Proses penyelamatan kredit bermasalah yang dilakukan oleh bank adalah dengan mengeluarkan surat penggilan yang berisi mengenai pelunasan pembayaran, Bank Danamon tidak melakukan restrukturisasi sebelum nasabah sendiri yang membuat permohonan untuk dapat restrukturisasi. Mengenai pelelangan Bank Danmon kurang melengkapi salah satu persyaratan untuk melakukan lelng yaitu tidak adanya surat pemberitahuan lelang kepada debitur sehingga pelelangan yang dilakukan oleh bank danamon kurang sempurna. Kesimpulannya bahwa Bank Danamon Tanjung Balai Karimun kurang menerapkan peraturan yang telah dikeluarkan oleh Bank Danamon Pusat. Saran, Bank Danamon Tanjung Balai Karimun dapat memperbaiki kinerja bank dan melakukan perbuatan sesuai dengan perturan yang telah dikeluarkan

Mapping synergies and trade-offs between energy and the Sustainable Development Goals

The 2030 Agenda for Sustainable Development—including 17 interconnected Sustainable Development Goals (SDGs) and 169 targets—is a global plan of action for people, planet and prosperity. SDG7 calls for action to ensure access to affordable, reliable, sustainable and modern energy for all. Here we characterize synergies and trade-offs between efforts to achieve SDG7 and delivery of the 2030 Agenda as a whole. We identify 113 targets requiring actions to change energy systems, and published evidence of relationships between 143 targets (143 synergies, 65 trade-offs) and efforts to achieve SDG7. Synergies and trade-offs exist in three key domains, where decisions about SDG7 affect humanity’s ability to: realize aspirations of greater welfare and well-being; build physical and social infrastructures for sustainable development; and achieve sustainable management of the natural environment. There is an urgent need to better organize, connect and extend this evidence, to help all actors work together to achieve sustainable development. On 5 September 2015, the 193 members states of the United Nations (UN) adopted a new 2030 Agenda for Sustainable Development. The 2030 Agenda succeeds the UN’s Millennium Development Goals (MDGs), and features 17 Sustainable Development Goals (SDGs) with 169 targets, which UN member states have committed to implement by 2030. Energy was not explicitly referred to in the MDGs, and came to be referred to as the ‘missing’ MDG. During the operational period of the MDGs and negotiation of the 2030 Agenda, it was increasingly recognized that energy underpins economic and social development, without which it would not be possible to eliminate poverty. This change in status made sustainable energy provision and access one of the central themes of the 2030 Agenda, whose preamble calls for “universal access to affordable, reliable and sustainable energy” and recognizes that “social and economic development depends of the sustainable management of our planet’s natural resources”. SDG7 is accompanied by five targets to be achieved by 2030: ensure universal access to affordable, reliable and modern energy services (7.1); increase the share of renewable energy in the global energy mix (7.2); double the global rate of improvement in energy efficiency (7.3); enhance international cooperation to facilitate access to clean energy research and technology (7.a), and promote investment in energy infrastructure and clean energy technology (7.b). By understanding the complex links between the SDGs and their constituent targets, researchers can better support policymakers to think systematically about interactions between the different SDGs, including how actions to achieve each goal affect each other within and between sectors. Studies to date have lacked a target-level approach or have focussed on only a few of the SDGs. Here we present a formative attempt by an interdisciplinary group of researchers to identify the full range of goals and targets in the 2030 Agenda that call for changes in energy systems, and characterize evidence of synergies or trade-offs between delivery of each of the 169 targets and efforts focussed on pursuit of SDG7 and each of its constituent targets. The purpose of this Perspective is not to provide definitive answers. Instead we aim to lay a foundation for systematic (and context-specific) exploration of the interlinkages between each of the SDG targets, in the context of decision-making about development and the transformation of energy systems

Factors associated with return of spontaneous circulation after out-of-hospital cardiac arrest in Poland : a one-year retrospective study

Background: Out-of-hospital cardiac arrest (OHCA) is a common reason for calls for intervention by emergency medical teams (EMTs) in Poland. Regardless of the mechanism, OHCA is a state in which the chance of survival is dependent on rapid action from bystanders and responding health professionals in emergency medical services (EMS). We aimed to identify factors associated with return of spontaneous circulation (ROSC). Methods: The medical records of 2137 EMS responses to OHCA in the city of Wroclaw, Poland between July 2017 and June 2018 were analyzed. Results: The OHCA incidence rate for the year studied was 102 cases per 100,000 inhabitants. EMS were called to 2317 OHCA events of which 1167 (50.4%) did not have resuscitation attempted on EMS arrival. The difference between the number of successful and failed cardiopulmonary resuscitations (CPRs) was statistically significant (p < 0.001). Of 1150 patients in whom resuscitation was attempted, ROSC was achieved in 250 (27.8%). Rate of ROSC was significantly higher when CPR was initiated by bystanders (p < 0.001). Patients presenting with asystole or pulseless electrical activity (PEA) had a higher risk of CPR failure (86%) than those with ventricular fibrillation/ventricular tachycardia (VF/VT). Patients with VF/VT had a higher chance of ROSC (OR 2.68, 1.86–3.85) than those with asystole (p < 0.001). The chance of ROSC was 1.78 times higher when the event occurred in a public place (p < 0.001). Conclusions: The factors associated with ROSC were occurrence in a public place, CPR initiation by witnesses, and presence of a shockable rhythm. Gender, age, and the type of EMT did not influence ROSC. Low bystander CPR rates reinforce the need for further efforts to train the public in CPR

Evolution of microstructure and crystallographic texture during dissimilar friction stir welding of duplex stainless steel to low carbon-manganese structural steel

Electron backscattered diffraction (EBSD) was used to analyze the evolution of microstructure and crystallographic texture during friction stir welding of dissimilar type 2205 duplex stainless steel (DSS) to type S275 low carbon-manganese structural steel. The results of microstructural analyses show that the temperature in the center of stirred zone reached temperatures between Ac 1 and Ac 3 during welding, resulting in a minor ferrite-to-austenite phase transformation in the S275 steel, and no changes in the fractions of ferrite and austenite in the DSS. Temperatures in the thermomechanically affected and shoulder-affected zones of both materials, in particular toward the root of the weld, did not exceed the Ac 1 of S275 steel. The shear generated by the friction between the material and the rotating probe occurred in austenitic/ferritic phase field of the S275 and DSS. In the former, the transformed austenite regions of the microstructure were transformed to acicular ferrite, on cooling, while the dual-phase austenitic/ferritic structure of the latter was retained. Studying the development of crystallographic textures with regard to shear flow lines generated by the probe tool showed the dominance of simple shear components across the whole weld in both materials. The ferrite texture in S275 steel was dominated by D 1, D 2, E, E¯ , and F, where the fraction of acicular ferrite formed on cooling showed a negligible deviation from the texture for the ideal shear texture components of bcc metals. The ferrite texture in DSS was dominated by D 1, D 2, I, I¯ , and F, and that of austenite was dominated by the A, A¯ , B, and B¯ of the ideal shear texture components for bcc and fcc metals, respectively. While D 1, D 2, and F components of the ideal shear texture are common between the ferrite in S275 steel and that of dual-phase DSS, the preferential partitioning of strain into the ferrite phase of DSS led to the development of I and I¯ components in DSS, as opposed to E and E¯ in the S275 steel. The formations of fine and ultrafine equiaxed grains were observed in different regions of both materials that are believed to be due to strain-induced continuous dynamic recrystallization (CDRX) in ferrite of both DSS and S275 steel, and discontinuous dynamic recrystallization (DDRX) in austenite phase of DSS