bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular determinants associated with long-term response to apalutamide (APA) in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Feng Felix Y , Aguilar-Bonavides Clemente , Lucas Justin , Thomas Shibu , Gormley Michael , McCarthy Sharon Anne , Brookman-May Sabine Doris , Triantos Spyros , Mundle Suneel , Smith Matthew Raymond , Small Eric Jay 
Published: March 2021

8 Background: SPARTAN, a phase 3 placebo (PBO)-controlled study in patients (pts) with nmCRPC, showed that APA plus androgen deprivation therapy (ADT) significantly improves metastasis-free survival compared with PBO + ADT. This exploratory analysis investigated potential biological signatures of pts with long-term responses to APA and PBO. Methods: The biomarker cohort of SPARTAN was characterized as long-term responders (LTR) or early progressors (EP) based on time to metastasis, and separated into quartiles for APA and PBO groups. Pts progressing in the first quartile (APA, 21; PBO, 17), with shortest time to metastatic event, were classified as EP, those progressing in the last quartile (APA, 39; PBO, 20) as LTR. Gene expression profiles were generated from 233 archival primary prostate tumors. Predefined gene signatures indicative of cancer biology were compared between LTR and EP groups within the APA and PBO arms using 2 sample t tests. Signatures associated with LTR and EP were identified using p values of less than 0.05. Results: Median time to metastatic progression was 40.5 months in APA pts and 22 months in PBO pts in the LTR group and 7.3 and 3.6 months in APA and PBO pts, respectively, in the EP group. Signatures categorized into 3 general mechanistic classes (immune regulation, proliferation, and hormone dependence) associated with LTR on APA included increased T cell activity reflected by T cell activation ( p = 0.0045), stimulation ( p = 0.0642), cytokine response ( p = 0.0489), and interferon production (gamma response p = 0.0227 ), and decreased T cell exclusion ( p = 0.0652), low proliferative capacity ( p = 0.0435), and increased hormonal dependence ( p = 0.0485). High risk (DECIPHER p = 0.0406, metastatic potential p = 0.0077), hormone nonresponsive (basal p = 0.0115; androgen receptor activity-low, p = 0.0437), and neuroendocrine-like tumors ( p = 0.0125) were associated with early progression on treatment with PBO. Conclusions: Although the data require confirmation in larger studies, these molecular determinants may have utility in selecting pts with nmCRPC who may derive the most benefit from APA and other androgen signaling inhibitors. Clinical trial information: NCT01946204.
Fractionated docetaxel and radium-223 (Ra223) in metastatic castration-resistant prostate cancer (CRPC): A phase I trial.
Authors: Connell Brendan James , Folefac Edmund , Hwang Clara , Lawlor Christian , Mathew Paul 
Published: March 2021

TPS175 Background: Disease progression following highly-active androgen-axis therapy (HAAT) in CRPC remains bone-dominant and docetaxel-responsive. Combination bone-homing Ra223 isotope therapy with docetaxel would be a logical combination therapy to follow but myelosuppression is dose-limiting. With 3-weekly bolus schedules of docetaxel (D), dose-reduction to 60mg/m2 Q3wkly and Ra223 to every 6 weeks has been required representing a reduction in the dose-intensity of both agents. Fractionated schedules of docetaxel Q2wkly (DQ2) have comparable activity to D 75mg/m2 Q3wkly (DQ3) with mitigated myelosuppression. We hypothesize that a fractionated dose-schedule of DQ2 in combination with standard Ra223 dosing will be feasible without reduction in dose-intensity of Ra-223 or D. Methods: Outcomes: The primary objective is to determine the feasibility and maximal tolerated dose (MTD) of the combination. Secondary objectives include PSA kinetics, objective response, bone marker outcomes, progression free and overall survival, and description of toxicity and quality of life. Eligibility: Progressive bone-metastatic CRPC, ECOG PS 0-2 with no prior Ra223, no prior docetaxel for CRPC, and no bulky visceral disease. Design: Phase I (6+6) design; 4 week lead-in with DQ2. Dose-level 1a: 40mg/m2; 2a: 50mg/m2, both with PEGylated G-CSF on Day 16. If tolerated (≤ Grade 2 toxicity, ANC ≥ 1500, Platelets ≥ 100,000), lead-in is followed by C1D1 of DQ2 plus Ra223 Q4wkly x 6 doses. Dose level 1a has accrued 6 subjects without DLT. Enrollment to Dose Level 2a began in August, 2020. An expansion cohort of 25 subjects is planned after the MTD is determined. Clinical trial information: NCT03737370.
Pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): The phase III KEYNOTE-991 study.
Authors: Gratzke Christian , Niu Cuizhen , Poehlein Christian Heinrich , Burgents Joseph E. 
Published: March 2021

TPS184 Background: The combination of pembro, an anti–PD-1 antibody, added to enza, a nonsteroidal antiandrogen agent, has shown antitumor activity in abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC) in the KEYNOTE-365 trial (NCT02861573) and in pts with mCRPC for whom enza was ineffective in the KEYNOTE-199 trial (NCT02787005). The efficacy of enza may be proimmunogenic, suggesting that it may be additive or synergistic in antitumor activity when combined with pembro. These data indicate that pembro + enza with ADT warrants phase 3 evaluation. Methods: KEYNOTE-991 (NCT04191096) is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial evaluating the efficacy and safety of enza + ADT (luteinizing hormone-releasing hormone agonist/antagonist during study treatment or bilateral orchiectomy) + pembro or placebo in pts with mHSPC. Eligibility criteria include age ≥18 years, mHSPC, ≥2 bone lesions or visceral disease, no prior treatment with next-generation hormone agents, adequate organ function, and ECOG PS 0 or 1. Pts must provide tissue for biomarker analysis. Approximately 1232 pts will be randomized in a 1:1 ratio to receive enza 160 mg orally once daily + ADT + pembro 200 mg intravenously (IV) every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. Treatment will continue with pembro up to 35 cycles and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Computed tomography or magnetic resonance imaging and radionuclide bone imaging will be used to assess response according to Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) every 12 weeks (Q12W) from the date of randomization. Imaging will continue until the end of treatment and will resume Q12W during the posttreatment period. The dual-primary endpoints are BICR-assessed radiographic progression-free survival (rPFS; according to PCWG3-modified RECIST v1.1) and overall survival (OS). Key secondary endpoints are time to first subsequent anticancer therapy (TFST) and time to symptomatic skeletal-related event (TTSSRE). Safety and tolerability will be evaluated using a tiered approach. The dual-primary (rPFS and OS) and key secondary (TFST and TTSSRE) endpoints will be evaluated using a stratified log-rank test. Event rates will be summarized using the Kaplan-Meier method, and hazard ratios will be estimated using a stratified Cox regression model. KEYNOTE-991 is enrolling at 40 sites in Australia, Chile, Colombia, Germany, Israel, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, and the United States. Clinical trial information: NCT04191096.
P3BEP (ANZUP 1302): An international randomized phase III trial of accelerated versus standard BEP chemotherapy for male and female adults and children with intermediate and poor-risk metastatic germ cell tumors (GCTs).
Authors: Subramaniam Shalini , Toner Guy C. , Stockler Martin R. , Martin Andrew James , Pashankar Farzana D. , Tran Ben , Jeffery Mark , Mazhar Danish , Huddart Robert A , Walpole Euan Thomas , Stevanovic Amanda Gwendolyn , Wyld David , Hanning Fritha J. , Wheater Matthew James , Balagtas Jay R. , Troon Simon , Birtle Alison Jane , White Jeff D. , Grimison Peter S. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: March 2021

TPS390 Background: Bleomycin, etoposide, and cisplatin (BEP) given 3-weekly x 4 is standard first-line chemotherapy for metastatic GCT categorised as intermediate risk or poor risk. Acceleration of standard regimens by shortening the cycle length improved cure rates in other cancers. We aim to determine the superiority of accelerated BEP versus standard BEP in this setting. Methods: This open label, randomised, phase III trial is conducted seamlessly in 2-stages. The primary endpoint for stage I (n=150) is complete response (CR); and for stage II (n=500) is progression free survival at 2 years (PFS2y). These sample sizes provide >80% power with a two-sided type error rate of 5% to detect an absolute improvement of 25% in the CR rate (stage II) and of 7% in the PFS2y (stage II). The target population is males and females aged 11 to 45 with intermediate-risk or poor-risk metastatic GCT of the testis, ovary, retroperitoneum, or mediastinum. Participants are randomised (1:1) to 4 cycles of standard BEP (q3w) or accelerated-BEP (q2w) with cisplatin 20mg/m2 D1-5, etoposide 100mg/m2 D1-5, bleomycin 30 KIU weekly x 12, and pegylated G-CSF D6 or filgrastim daily. Study assessments are 30 days after completing chemotherapy, 6 months from randomisation, and after completion of all post-chemotherapy treatments (e.g. surgery). Tumour tissue and baseline blood samples are collected for translational substudies including assessment of favourable versus unfavourable rates of decline in the novel biomarker miR-371. As of 13 October 2020, 140 participants have been recruited from 25 ANZ sites, 14 UK sites (led by Cambridge Clinical Trials Unit), and 140 USA sites (led by Children’s Oncology Group). The first planned interim analysis for safety (n=76) identified no safety concerns. The stage I analysis is anticipated mid-2021. This international randomised trial of chemotherapy for intermediate and poor-risk metastatic GCT is the first to include adults and children of both sexes. ClinicalTrials.gov: NCT02582697 Clinical trial information: NCT02582697.
A kinetic generator for classical field theories with conservation laws
Authors: Otomo Hiroshi , Boghosian Bruce M. , Succi Sauro 
Published: March 2021

Abstract
In this study, we demonstrate that, by suitably modifying the equilibrium distribution, the Bhatnagar-Gross-Krook form of the Boltzmann equation can serve as a generator of a broad class of nonlinear partial differential equations via a suitable generalization of the Chapman-Enskog method. We achieve this by properly choosing the relaxation time and moments of the equilibrium state in such a way as to suppress the dynamics of the zeroth moment, density, at increasingly faster time scales. As concrete examples, explicit analytical formulations of the Burgers', Korteweg-de Vries and Kuramoto-Sivashinsky equations are presented, along with a discussion of the associated conservation laws of the corresponding moments. The concept is numerically demonstrated by solving the BGK Boltzmann equation with the finite-element method. Because the Boltzmann-BGK equation can be equipped with a H-theorem, the framework developed in this work indicates a path towards the development of new algorithms for the numerical solution of the aforementioned equations with enhanced stability.
Enhancement of Unruh effect near hyperbolic metamaterials
Authors: Smolyaninov Igor 
Published: March 2021

Abstract
Laser fields acting on free electrons were proposed to create sufficiently large accelerations to enable detection of Unruh radiation. However, the currently achievable electron accelerations are not large enough. Here we demonstrate that the Unruh effect in laser fields is strongly enhanced near hyperbolic metamaterials, so that many orders of magnitude smaller accelerations may be used to detect Unruh radiation.
Extending Postpartum Medicaid: State and Federal Policy Options during and after COVID-19
Authors: Daw Jamie R. , Eckert Emily , Allen Heidi L. , Underhill Kristen 
Published: March 2021

Abstract
The United States is facing a maternal health crisis with rising rates of maternal mortality and morbidity and stark disparities in maternal outcomes by race and socioeconomic status. Among the efforts to address this issue, one policy proposal is gaining particular traction: extending the period of Medicaid eligibility for pregnant women beyond 60 days after childbirth. The authors examine the legislative and regulatory pathways most readily available for extending postpartum Medicaid, including their relative political, economic, and public health trade-offs. They also review the state and federal policy activity to date and discuss the impact of the COVID-19 pandemic on the prospects for policy change.
Extensive crosstalk of G protein-coupled receptors with the Hedgehog signalling pathway
Authors: Saad Farah , Hipfner David R. 
Published: March 2021

ABSTRACT
Hedgehog (Hh) ligands orchestrate tissue patterning and growth by acting as morphogens, dictating different cellular responses depending on ligand concentration. Cellular sensitivity to Hh ligands is influenced by heterotrimeric G protein activity, which controls production of the second messenger 3′,5′-cyclic adenosine monophosphate (cAMP). cAMP in turn activates Protein kinase A (PKA), which functions as an inhibitor and (uniquely in Drosophila) as an activator of Hh signalling. A few mammalian Gαi- and Gαs-coupled G protein-coupled receptors (GPCRs) have been shown to influence Sonic hedgehog (Shh) responses in this way. To determine whether this is a more-general phenomenon, we carried out an RNAi screen targeting GPCRs in Drosophila. RNAi-mediated depletion of more than 40% of GPCRs tested either decreased or increased Hh responsiveness in the developing Drosophila wing, closely matching the effects of Gαs and Gαi depletion, respectively. Genetic analysis indicated that the orphan GPCR Mthl5 lowers cAMP levels to attenuate Hh responsiveness. Our results identify Mthl5 as a new Hh signalling pathway modulator in Drosophila and suggest that many GPCRs may crosstalk with the Hh pathway in mammals.
Social immunity in honey bees: royal jelly as a vehicle in transferring bacterial pathogen fragments between nestmates
Authors: Harwood Gyan , Salmela Heli , Freitak Dalial , Amdam Gro 
Published: March 2021

ABSTRACTSocial immunity is a suite of behavioral and physiological traits that allow colony members to protect one another from pathogens, and includes the oral transfer of immunological compounds between nestmates. In honey bees, royal jelly is a glandular secretion produced by a subset of workers that is fed to the queen and young larvae, and which contains many antimicrobial compounds. A related form of social immunity, transgenerational immune priming (TGIP), allows queens to transfer pathogen fragments into their developing eggs, where they are recognized by the embryo's immune system and induce higher pathogen resistance in the new offspring. These pathogen fragments are transported by vitellogenin (Vg), an egg-yolk precursor protein that is also used by nurses to synthesize royal jelly. Therefore, royal jelly may serve as a vehicle to transport pathogen fragments from workers to other nestmates. To investigate this, we recently showed that ingested bacteria are transported to nurses' jelly-producing glands, and here, we show that pathogen fragments are incorporated into the royal jelly. Moreover, we show that consuming pathogen cells induces higher levels of an antimicrobial peptide found in royal jelly, defensin-1.
Postoperative Inflammatory Marker Surveillance in Colorectal Peritoneal Carcinomatosis
Authors: Thiagarajan Sasinthiran , Tan Joey Wee-Shan , Zhou Siqin , Tan Qiu Xuan , Hendrikson Josephine , Ng Wai Har , Ng Gillian , Liu Ying , Tan Grace Hwei Ching , Soo Khee Chee , Teo Melissa Ching Ching , Chia Claramae Shulyn , Ong Chin-Ann Johnny 
Published: March 2021

Abstract
Background
The prognostic significance of inflammatory markers in solid cancers is well-established, albeit with considerable heterogeneity. This study sought to investigate the postoperative inflammatory marker trend in peritoneal carcinomatosis (PC), with a focus on colorectal PC (CPC), and to propose optimal surveillance periods and cutoffs.

Methods
Data were collected from a prospectively maintained database of PC patients treated at the authors’ institution from April 2001 to March 2019. The platelet–lymphocyte ratio (PLR), the neutrophil–lymphocyte ratio (NLR), and the lymphocyte–monocyte ratio (LMR) were collected preoperatively and on postoperative days 0, 1 to 3, 4 to 7, 8 to 21, 22 to 56, and 57 to 90 as averages. Optimal surveillance periods and cutoffs for each marker were determined by maximally selected rank statistics. The Kaplan–Meier method and Cox proportional hazard regression models were used to investigate the association of inflammatory markers with 1-year overall survival (OS) and recurrence-free survival (RFS) using clinicopathologic parameters.

Results
The postoperative inflammatory marker trend and levels did not differ between the patients with and those without hyperthermic intraperitoneal chemotherapy (HIPEC). Low postoperative LMR (days 4–7), high postoperative NLR (days 8–21), and high postoperative PLR (days 22–56) were optimal for prognosticating poor 1-year OS, whereas high postoperative PLR and NLR (days 57–90) and low postoperative LMR (days 8–21) were associated with poor 1-year RFS. A composite score of these three markers was prognostic for OS in CPC.

Conclusions
The reported cutoffs should be validated in a larger population of CPC patients. Future studies should account for the inflammatory response profile when selecting appropriate surveillance periods.
Wide dynamic laser ranging based on diode laser and photon-counting techniques
Authors: Tang Yumei , Yang Runze , Qiu Jian , Liu Kefu 
Published: March 2021

Ultrafast diode laser and photon-counting techniques were united to solve the trade-off between the dynamic range and high precision in the time of flight (TOF) laser ranging. Based on the direct time of flight (D-TOF) laser ranging method, we developed a wide dynamic laser ranging system. The peak power of the emission laser can reach 70 W, the width of pulsed laser is less than 2 ns, and the repetition rate can reach 500 kHz. The experimental results show that the precision is 7.5 mm when the echo signal is saturated. The maximum range can reach kilometer level, the accuracy is within 30 cm, and the repetition rate of measurement can reach 100 kHz. The system has the advantages of small size, low cost, fast detection speed, and high accuracy, which can be used in the fields of dynamic target measurement and high-speed environment perception.
Proving Chinese Law in the Courts of the United States
Authors: Wagner Richard K 
Published: March 2021

The volume of disputes heard by United States (US) courts containing a China element continues to be robust even against a backdrop of political rhetoric concerning an economic ‘de-coupling’ of the US and China. These cross-border disputes often involve Chinese parties and special issues, some of which concern Chinese business culture, but many of which involve interpreting questions of Chinese law. How is proving Chinese law accomplished in these cases and how have US courts performed in interpreting Chinese law? This article first discusses the approach to proving Chinese law in US courts. While expert testimony is often submitted and can be valuable to a US court, the applicable US rule offers no standards by which these opinions are to be judged. And, in the China context, without specific guidance, it can be challenging for a judge, unaccustomed with China or the Chinese legal system to determine which version of the law to believe. Moreover, under the applicable rule, the US court can simply ignore competing Chinese law opinions and conduct its own Chinese law legal research, presumably using English language sources. This can lead to interesting interpretations of Chinese law to say the least. The article anchors its discussion in an examination of those recent cases which have interpreted Article 277 of the Civil Procedure Law of the People’s Republic of China. This is the legal provision of Chinese law that can be implicated in certain situations involving cross-border discovery, and there are now numerous Article 277 cases among the reported US decisions. The article analyses Article 277 by placing it within the larger context of Chinese civil procedure and argues that the language used in the provision has a special meaning within Chinese evidence law that has been obscured in those US case decisions interpreting it, leading to erroneous results. The article concludes by offering judges and practitioners some suggestions for interpreting Chinese law in future US cases.
Keywords: Chinese law; US courts; Article 277; deposition; cross-border discovery; Hague Evidence Convention; Chinese civil procedure.
Medical Negligence Dispute Resolution in China
Authors: Tang Cedric 
Published: March 2021

Medical negligence is an important issue in China today, threatening to undermine the party-state policy objectives of social stability and the right to health, thus requiring effective solutions. China’s response includes a dispute resolution regime for issues of medical negligence, structured as a bifurcated administrative and court regime and supplemented by mediation. This Note examines this dispute resolution regime, its difficulties and possible ways of reform. More specifically, it explores whether the current assignment of liability is appropriate when considered in the context of the system’s relationship to the policy objective of social stability and suggests that social stability may be more efficiently achieved by greater utilization of preventative measures.
Keywords: medical negligence; medical disputes; China; mediation; social stability; right to health.