bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter, randomized phase III study of asciminib (ABL001) versus bosutinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs).
Authors: Mauro Michael J. , Hochhaus Andreas , Boquimpani Carla , Minami Yosuke , Allepuz Alex , Polydoros Fotis , Bédoucha Véronique , Aimone Paola , Réa Delphine 
Published: March 2020

TPS7070 Background: There is a need for new treatment options for pts with CML who are intolerant/resistant to currently available BCR-ABL1 ATP-binding site targeted TKIs. Asciminib is a potent and specific BCR-ABL1 inhibitor with a novel allosteric mechanism of action targeting the ABL1 myristoyl pocket. This results in a mutation-driven resistance profile different from that of ATP binding-site TKIs, providing potential for both monotherapy and combination therapy with ATP-binding-site TKIs. In a phase 1 study (NCT02081378), asciminib showed clinical activity and good safety/tolerability in CML pts with resistance/intolerance to ≥2 TKIs and in pts with the T315I mutation. The recommended dose for asciminib monotherapy in CML pts without the T315I mutation was established as 40 mg BID. An ongoing phase 3 study (NCT03106779) is evaluating asciminib monotherapy vs bosutinib in pts with CML who have been treated with ≥2 prior ATP-binding-site TKIs. Methods: Eligible pts are adults with CML-CP who previously received ≥2 TKIs, with intolerance or failure to the most recent TKI. Treatment failure is defined per 2013 European LeukemiaNet (ELN) recommendations. Pts harboring T315I or V299L mutations are excluded. Pts are randomized 2:1 – stratified by baseline cytogenetic response status – to receive asciminib 40 mg BID or bosutinib 500 mg QD (planned enrollment: N = 222). Primary and key secondary objectives are to compare the rate of major molecular response ( BCR-ABL1IS≤0.1%) with asciminib vs bosutinib at 24 and 96 weeks, respectively. In a recent protocol amendment, the baseline BCR-ABL1IS threshold for enrollment was lowered from ≥1% to > 0.1% for pts with intolerance to the most recent TKI. This change was implemented to align with clinical practice and satisfy the treatment need to avoid waiting for an increase in BCR-ABL1IS levels to ≥1%. In addition, pts with documented bosutinib treatment failure as per ELN recommendations may switch to receive asciminib therapy at any time, as such pts may have limited treatment options outside of this study. This study is ongoing with 149 participating study sites in 30 countries. Clinical trial information: NCT03106779.
A phase I study of AMV564 in patients with intermediate or high-risk myelodysplastic syndromes.
Authors: Garcia-Manero Guillermo , Jacoby Meagan , Sallman David Andrew , Han Tae , Guenot Jeanmarie , Feldman Eric 
Published: March 2020

TPS7071 Background: The CD33 antigen is expressed on myeloblasts in approximately 75% of patients with myelodysplastic syndromes (MDS) and is also expressed on immunosuppressive myeloid-derived suppressor cells (MDSCs) that are prevalent in MDS. AMV564 is a novel bivalent, bispecific (2:2) T-cell engager that binds both CD33 and the invariant CD3ε on T-cells with strong avidity. AMV564 has significant cytotoxic activity against CD33-postive cells, including MDSCs, in animal models, in vitro studies, and in patients (Reusch et al. Clin Can Res 2016 and List et al. ASH 2017). Preliminary results from the phase 1 acute myeloid leukemia (AML) trial have demonstrated safety and activity in patients with AML arising from prior MDS (Westervelt et al. ASH 2018). Methods: AMV564-201 is an open label, phase 1, multicenter, dose-escalation with expansion trial of AMV564 in patients with intermediate-2 or high-risk MDS who are refractory to or relapsed from hypomethylating agents (HMAs) or intensive chemotherapy. The key objectives of the dose-escalation stage of the study are to characterize the safety and tolerability of AMV564, identify a maximum tolerated dose and/or a dose-schedule to evaluate in the dose expansion portion of the study. In the dose expansion stage of the study, the safety and tolerability of AMV564 will be further characterized in addition to a preliminary assessment of efficacy. Other objectives include characterization of AMV564 pharmacokinetics, pharmacodynamics, and immunogenic potential. Approximately 80 patients with intermediate-2 or high-risk MDS will be enrolled. The Dose Escalation Stage will include up to approximately 30 patients, depending on the dose at which the MTD is determined for each schedule, and approximately 50 additional patients will be enrolled in the Expansion Stage. AMV564 will be administered daily as a continuous intravenous (CIV) infusion over a period of 24 hours for 14 days in each cycle. Each cycle will be approximately 4 weeks. A lead-in dose regimen will be utilized for all patients treated at dose levels at or above 50 mcg/day. Patients will receive up to 4 cycles of AMV564 treatment at the assigned dose level. Clinical trial information: NCT03516591.
ALPINE: Phase III zanubrutinib (BGB-3111) versus ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
Authors: Hillmen Peter , Brown Jennifer R. , Byrd John C. , Eichhorst Barbara , Lamanna Nicole , O'Brien Susan Mary , Qiu Lugui , Paik Jason C. , Hilger James D. , Huang Jane , Tam Constantine S. 
Published: March 2020

TPS7572 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib, an investigational inhibitor of BTK, was specifically engineered to optimize selectivity, half-life and solubility in an effort to decrease toxicities and better penetrate tumor tissue. Early clinical data suggested that zanubrutinib treatment in patients with treatment-naïve (TN; n = 16) or R/R (n = 50) CLL/SLL induced deep responses: 94% overall response rate (ORR), including 6% and 2% complete response rates in TN and R/R CLL/SLL, respectively (ICML 2017). This study is designed to evaluate whether zanubrutinib monotherapy exhibits non-inferior and potentially superior efficacy based on the ORR vs ibrutinib monotherapy in patients with R/R CLL/SLL. Methods: This ongoing phase 3, randomized, open-label, global study (NCT03734016, BGB-3111-305) is comparing the efficacy and safety of zanubrutinib vs ibrutinib in adult patients with R/R CLL/SLL. Approximately 400 patients will be randomized, 1:1 to each arm and stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region, and del(17p)/ TP53 mutation status (present vs absent). Key inclusion criteria include R/R CLL/SLL requiring treatment per iwCLL criteria, ECOG PS 0-2, and adequate hematologic function. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL and per 2014 Lugano Classification for patients with SLL. The study is powered to test the non-inferiority and superiority of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, safety, duration of response, and overall survival. Recruitment is ongoing. Clinical trial information: NCT03734016.
Phase 1 study of AMG 119, a chimeric antigen receptor (CAR) T cell therapy targeting DLL3, in patients with relapsed/refractory small cell lung cancer (SCLC).
Authors: Byers Lauren Averett , Chiappori Alberto , Smit Marie-Anne Damiette 
Published: March 2020

TPS8576 Background: SCLC is an aggressive neuroendocrine tumor, with initial sensitivity to chemotherapy and radiotherapy often followed by chemoresistant disease progression. Notch signaling is a key regulator of neuroendocrine differentiation in SCLC, and delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors. DLL3 is expressed in most SCLC tumors but minimally expressed in normal tissues, suggesting that it may be a promising target for cancer immunotherapy. AMG 119 is an adoptive cellular therapy that consists of a patient’s autologous T cells that have been genetically modified ex vivo to express a transmembrane CAR that targets DLL3 and redirects cytotoxic T cell specificity to DLL3-positive cells. AMG 119 CAR T cells show potent killing of SCLC cells expressing DLL3 in vitro and inhibit tumor growth in an SCLC xenograft model in vivo. Methods: This phase 1 study will evaluate the safety and tolerability of AMG 119 administered as a single infusion in adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. The primary objectives are to evaluate safety and tolerability and determine the maximum tolerated cell dose (MTCD) or recommended phase 2 cell dose (RP2CD). Secondary objectives are to evaluate preliminary evidence of antitumor activity, expansion and persistence of AMG 119, and trafficking of AMG 119 to the tumor in post-treatment biopsy. Key inclusion criteria include histologically confirmed SCLC with radiographically documented disease progression or recurrence after at least 1 platinum-based regimen, ECOG performance status 0–1, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. In the cell dose exploration phase, 3–4 patients will receive a single IV infusion of AMG 119 at each cell dose. Cell dose escalation/de-escalation decisions will be guided by a modified toxicity probability interval design. The dose expansion phase will seek to confirm the MTCD or RP2CD and obtain further safety and efficacy data. Clinical trial information: NCT03392064.
Phase 1 study of AMG 757, a half-life extended bispecific T cell engager (BiTE) antibody construct targeting DLL3, in patients with small cell lung cancer (SCLC).
Authors: Smit Marie-Anne Damiette , Borghaei Hossein , Owonikoko Taofeek Kunle , Hummel Horst-Dieter , Johnson Melissa Lynne , Champiat Stéphane , Salgia Ravi , Udagawa Hibiki , Boyer Michael J. , Govindan Ramaswamy 
Published: March 2020

TPS8577 Background: SCLC is an aggressive neuroendocrine tumor; response to initial chemotherapy and radiotherapy is often followed by recurrence, rapid progression, and resistance to current therapies. Delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors that is expressed in most SCLC tumors but minimally expressed in normal tissues. DLL3 may therefore be a promising target for T cell–redirecting immunotherapy. AMG 757 is a half-life extended BiTE antibody construct that is designed to transiently connect DLL3-positive cells to CD3-positive T cells and induce T cell–mediated cell lysis and concomitant T cell proliferation. AMG 757 induces potent killing of SCLC cell lines in vitro and inhibits tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose toxicology study in cynomolgus monkeys, with no evidence of tissue damage at weekly doses up to 4.5 mg/kg. Methods: NCT03319940 is an open-label, ascending, multiple dose, phase 1 study evaluating AMG 757. The study will initially enroll adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. Additional inclusion criteria include ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary antitumor activity. In the dose exploration phase, patients will be monitored for dose-limiting toxicities during the first 28 days. A Bayesian logistic regression model will be used to inform dose escalation/de-escalation decisions. The dose expansion phase will confirm the MTD or RP2D and collect further safety and efficacy data. AMG 757 will be administered as a short-term intravenous infusion once every 2 weeks. Alternative dosing schedules may be explored based on emerging PK and safety data. Clinical trial information: NCT03319940.
Gene regulatory network controlling carpel number variation in cucumber
Authors: Che Gen , Gu Ran , Zhao Jianyu , Liu Xiaofeng , Song Xiaofei , Zi Hailing , Cheng Zhihua , Shen Junjun , Wang Zhongyi , Liu Renyi , Yan Liying , Weng Yiqun , Zhang Xiaolan 
Published: March 2020

ABSTRACT
The WUSCHEL-CLAVATA3 pathway genes play an essential role in shoot apical meristem maintenance and floral organ development, and under intense selection during crop domestication. The carpel number is an important fruit trait that affects fruit shape, size and internal quality in cucumber, but the molecular mechanism remains elusive. Here, we found that CsCLV3 expression was negatively correlated with carpel number in cucumber cultivars. CsCLV3-RNAi led to increased number of petals and carpels, whereas overexpression of CsWUS resulted in more sepals, petals and carpels, suggesting that CsCLV3 and CsWUS function as a negative and a positive regulator for carpel number variation, respectively. Biochemical analyses indicated that CsWUS directly bound to the promoter of CsCLV3 and activated its expression. Overexpression of CsFUL1A, a FRUITFULL-like MADS-box gene, resulted in more petals and carpels. CsFUL1A can directly bind to the CsWUS promoter to stimulate its expression. Furthermore, we found that auxin participated in carpel number variation in cucumber through interaction of CsARF14 with CsWUS. Therefore, we have identified a gene regulatory pathway involving CsCLV3, CsWUS, CsFUL1A and CsARF14 in determining carpel number variation in an important vegetable crop – cucumber.
Role of nutrient-driven O-GlcNAc-post-translational modification in pancreatic exocrine and endocrine islet development
Authors: Baumann Daniel , Wong Alicia , Akhaphong Brian , Jo Seokwon , Pritchard Samantha , Mohan Ramkumar , Chung Grace , Zhang Ying , Alejandro Emilyn U. 
Published: March 2020

ABSTRACT
Although the developing pancreas is exquisitely sensitive to nutrient supply in utero, it is not entirely clear how nutrient-driven post-translational modification of proteins impacts the pancreas during development. We hypothesized that the nutrient-sensing enzyme O-GlcNAc transferase (Ogt), which catalyzes an O-GlcNAc-modification onto key target proteins, integrates nutrient-signaling networks to regulate cell survival and development. In this study, we investigated the heretofore unknown role of Ogt in exocrine and endocrine islet development. By genetic manipulation in vivo and by using morphometric and molecular analyses, such as immunofluorescence imaging and single cell RNA sequencing, we show the first evidence that Ogt regulates pancreas development. Genetic deletion of Ogt in the pancreatic epithelium (OgtKOPanc) causes pancreatic hypoplasia, in part by increased apoptosis and reduced levels of of Pdx1 protein. Transcriptomic analysis of single cell and bulk RNA sequencing uncovered cell-type heterogeneity and predicted upstream regulator proteins that mediate cell survival, including Pdx1, Ptf1a and p53, which are putative Ogt targets. In conclusion, these findings underscore the requirement of O-GlcNAcylation during pancreas development and show that Ogt is essential for pancreatic progenitor survival, providing a novel mechanistic link between nutrients and pancreas development.
Characterization of Calcium Ion Release from a Polymer-Coated Electrode with a Plasticized PVC Membrane Containing Calcium Salts, and Its Contraction Examination of Vorticella Convallaria
Authors: Nakamura Fumiya , Nakayama Taisei , Kageyama Itsuki , Kato Ryo , Nagai Moeto , Shibata Takayuki , Sawada Kazuaki , Hattori Toshiaki 
Published: March 2020

Abstract
Up to now several bio-imaging methods have taken very good pictures and/or recordings. With bio-imaging growing, a micro-stimulation method to limit in a fine region is required. Conventional chemical stimulation methods face difficulty in fulfilling this requirement, however, an electrochemical device is a potential response to this issue. This paper reports on the fabrication and the use of an electrochemical Ca2+-releasing device. The device consists of a three-layer electrode, including two transducers, a PVC membrane, PEDOT layer, and gold or carbon. The dynamic behavior of Ca2+ released from the device is evaluated by a two-dimensional 16 K pixel array Ca2+ image sensor, and is simulated using a diffusion model of Ca2+. Both experimental and calculated time and distance dependent profiles are almost in agreement when the PVC membrane is thin. As its biological application, a permeabilized Vorticella convallaria was set at a distance of ca. 0.1 mm from the Ca2+-releasing device. There was no response for some time just after switching-on, and then it gradually contracted. The gradual contraction after the interval proved that the Ca2+-releasing device can be used as a soft insertion based on the concentration diffusion.
The Effect of Exercise on Gene Expression and Signaling in Mouse Melanoma Tumors
Authors: XIA ZHI , SHANG HUAYU , CHOLEWA JASON , WANG QIANJIN , DING XIAOMIN , SU QUANSHENG , ZHAO YAN , ZANCHI NELO EIDY 
Published: March 2020

ABSTRACT

Purpose
To screen for candidate hub genes associated with the effects of exercise on melanoma tumor tissues and to review the potential signaling pathways involved in this process using bioinformatics analysis.

Methods
The GSE62628 expression profile was downloaded from Gene Expression Omnibus database. This data set contains 10 melanoma tumor tissues from two groups of exercise and nonexercise mice. The R software was utilized to identify differentially expressed genes between samples, and functional annotation and pathway analysis were performed. Results were visualized using Cytoscape software.

Results
In total, 315 differentially expressed genes were obtained, including 294 upregulated and 21 downregulated genes. The functional analysis showed that these genes were mainly enriched in immune response, inflammatory response, and positive regulation of the ERK1/2 cascade in biological process functional groups. The top 10 candidate hub genes were C3, Kng1, C3ar1, Ptafr, Fgg, Alb, Pf4, Orm1, Aldh3b1, and Apob. The pathway analysis of the most significant module identified from the protein–protein interaction network revealed that the complement and coagulation cascades, Staphylococcus aureus infection, cytokine–cytokine receptor interaction, chemokine signaling pathway and phagosome were mainly involved. C3, C3ar1, Kng1, Ptafr, and Fgg may be the critical genes in the complement and coagulation cascades pathway, and S. aureus in the infection pathway.

Conclusions
Exercise may ameliorate the immune response and inflammatory response in melanoma tissue, and further studies exploring their relationships are warranted.
Diagnosis of Exercise-induced Bronchoconstriction in Swimmers: Context Matters
Authors: LEAHY MICHAEL GEORGE , PETERS CARLI M. , GEARY CAITLIN M. , KOEHLE MICHAEL S. , MCKENZIE DONALD C. , BROTHERHOOD JAMES , SHEEL A. WILLIAM 
Published: March 2020

ABSTRACT
Swimmers have a high prevalence of exercise-induced bronchoconstriction (EIB), which may be associated with repeated exposure to chlorinated pool water. The eucapnic voluntary hyperpnea (EVH) test is used to diagnose EIB; however, it fails to replicate the environmental conditions experienced by swimmers. The relationship between the composition of the EVH inspired gas and the development of EIB from swim exercise remains unclear.

Purpose
This study aimed to compare the bronchoconstrictive effect of a chlorinated inspirate EVH test and swim test to a laboratory-based EVH test in swimmers.

Methods
Fifteen collegiate swimmers (n = 5 male, n = 10 female; 21 ± 2 yr) completed 3 d of testing in pseudorandom order; a standard EVH test (EVHL), a pool air EVH test (EVHCl), and a swimming test (Swim). Spirometry was measured at baseline, and 3, 5, 10, 15, and 20 min after each test.

Results
EVHL elicited a forced expired volume in 1 s (FEV1) fall index of −9.7% ± 6.4% compared with −6.6% ± 9.2% and −3.0% ± 7.5% after EVHCl and Swim, respectively (P < 0.05). Using Bland–Altman analysis, we found good agreement between EVHL and EVHCl (bias = −2.8, r = 0.79; P < 0.05) with poor agreement between EVHL and Swim (bias = −6.7, r = 0.20) and between EVHCl and Swim (bias = −3.9, r = 0.50; both P < 0.05). Forced expired flow between 25% and 75% lung volume and peak expired flow were significantly reduced by the EVHL compared with the EVHCl and Swim tests (P < 0.05).

Conclusions
EVHL elicits a greater forced expired volume in 1-s fall index compared with EVHCl and Swim. The unique aquatic environment of swimmers potentially protects against bronchoconstriction and should be considered in the determination of EIB.
Evaluation of antioxidant, antibacterial and wound healing activities of Vitex pinnata
Authors: Shafie Nurul Ashifah , Suhaili Nur Atiqah , Taha Hussein , Ahmad Norhayati 
Published: March 2020

Background: Vitex pinnata is one of the many plants known for its ethnomedicinal properties. However, the pharmacological properties of this plant have not been well studied. This study aims to determine the antioxidant, antimicrobial and wound healing properties of the methanolic extract of the leaves and the hexane, chloroform and ethyl acetate fractions. Methods: The leaves of Vitex pinnata underwent methanol extraction and the methanol extract was fractionated with hexane, chloroform and ethyl acetate solvents. The antioxidant activity was determined using the DPPH radical scavenging assay. The antimicrobial activity was assessed by disc diffusion assay against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa. For the wound healing studies, the methanolic extracts of V. pinnata were used to prepare ointments with compositions of 10% (w/w) and 50% (w/w), which were evaluated for wound healing activity in an excision wound model in Wistar rats. Results: All the extracts showed antioxidant activities, with the ethyl acetate extract having the highest DPPH radical scavenging activity, followed by the methanol, chloroform and hexane extracts. Similarly, their quercetin equivalent concentrations were 33.1, 31, 20.3 and 4.5 mg/mL, respectively. Except for the methanol extract, the disc diffusion assay showed that the extracts demonstrated species-specific antibacterial activities, with the ethyl acetate extract showing antibacterial activities against all four tested strains. The wound healing activity of the high dose treated group (50% [w/w]) shows significant increase of wound contraction when compared to the control group. Conclusion: In the current study, the ethyl acetate extract showed activity for all tested bacteria and also had the highest DPPH activity. The methanolic extracts of V. pinnata leaves show modest wound healing activity in an excision wound model.