bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) for metastatic urothelial carcinoma (mUC) treatment-experienced (DAD) and with pembrolizumab (P) in treatment naïve UC (DAD-IO).
Authors: McGregor Bradley Alexander , Kwak Lucia , Sonpavde Guru P. , Berg Stephanie A. , CHOUEIRI Toni K. , Bellmunt Joaquim , Mantia Charlene 
Published: June 2024

TPS4618 Background: In the DAD study (NCT04724018) the combination of SG+EV demonstrated favorable safety determining a maximum tolerated dose of 10 mg/kg and 1.25 mg/kg IV D1,8 every 21 days along with encouraging efficacy in treatment resistant mUC as evidenced by an objective response rate (ORR) of 70% in 23 evaluable patients. Given cumulative toxicities and efficacy across dose levels, the recommended phase 2 dose was SG 7.5 mg/kg and EV 1.25 mg/kg D1,8 of 21-day cycle. As EV+P is now a standard of care for front line urothelial carcinoma, NCT04724018 was amended to include 2 cohorts of distinct patient populations; one expanding SG+EV (DAD) and a second exploring the SG+EV+P (DAD-IO) combination. Methods: In DAD cohort, patients with mUC progressing on platinum and immunotherapy or on one line of therapy receive SG 7.5 mg/kg + EV 1.25 mg/kg intravenously (IV) on day(D)s 1 and 8 every 3 weeks (1 cycle) until progression or intolerable toxicities. In DAD-IO cohort, patients with treatment naïve mUC are given SG 7.5 mg/kg+EV 1.25 mg/kg IV D1, 8 of a 21-day cycle with P 200 mg every 3 weeks or 400 mg every 6 weeks per investigator discretion. In both cohorts, prophylactic granulocyte colony stimulating factor (GCSF) support is given per supportive care guidelines with cycle 1. Following first dose on trial, SG and EV can be reduced and held independently for toxicity with reductions of SG to 5 mg/kg, and EV to 1, 0.75 and 0.5 mg/kg. P dose reductions are not allowed but can be held as needed for immune related adverse events. Laboratory evaluation is performed on days 1 and 8 every cycle. Imaging is performed at baseline and every 6 weeks for the first 4 cycles followed by every 9 weeks thereafter. In both cohorts, the primary endpoint is RECIST 1.1 ORR with secondary endpoints being progression free survival, overall survival, and safety. DAD aims to enroll 41 eligible patients, assuming an ORR of 65% for EV+SG, to detect a 25% improvement with over 90% power at a one-sided type I error rate of 0.05 using a single-stage exact one-sample binomial design; ³ 23 responses would rule out a null of 40% ORR. DAD-IO plans to enroll 41 eligible patients, assuming an ORR of 75% for SG+EV+P to detect a 20% improvement with 90% power at a one-sided type I error rate 0.09 based on a Simon optimal two-stage design. If ³ 11 responses are observed in the first 18 patients, an additional 23 patients will be enrolled. At least 27 responses among a total of 41 will be needed to confirm its efficacy. The study includes a 12-patient safety lead in using a Bayesian toxicity monitoring. If ≤2 dose limiting toxicities (DLTs) occur in the first 6 patients, the next 6 are enrolled. The study halts if ≥5 DLTs occur among 12 evaluable patients. Clinical trial information: NCT04724018 . [Table: see text]
CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA: Phase 3 MK-5684-004 study.
Authors: Fizazi Karim , Vile Donald Charles , Chen Zheng Hong , Poehlein Christian Heinrich , Todoric Jelena , Gratzke Christian 
Published: June 2024

TPS5114 Background: Activating androgen receptor (AR) somatic mutation is a known mechanism of resistance to AR-directed therapies in mCRPC, and it may permit continued hormone dependence. Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR-directed therapies in patients with mCRPC. MK-5684 (ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. Thus, MK-5684 has the potential to suppress the production of all steroid hormones and precursors that may activate the AR signaling pathway. MK-5684 demonstrated antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations, in the phase 1/2 CYPIDES study. The efficacy and safety of MK-5684 in patients with molecularly unselected mCRPC after 1 prior NHA will be evaluated in the randomized, open-label, phase 3 MK-5684-004 study (NCT06136650). Methods: Eligible patients have mCRPC unselected for AR-LBD mutations that progressed during androgen deprivation therapy ≤6 months before screening and during or after 1 NHA for hormone-sensitive prostate cancer (HSPC) or nonmetastatic CRPC for ≥8 weeks (≥14 weeks with bone progression). Prior NHA + docetaxel for HSPC is permitted if patients received ≤6 cycles of docetaxel without radiographic disease progression. Approximately 1500 patients (AR-LBD mutation–positive, 375 patients; AR-LBD mutation–negative, 1125 patients) will be randomly assigned 1:1 to receive MK-5684 5 mg PO BID + dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD or abiraterone acetate 1000 mg PO QD + prednisone 5 mg PO BID (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone). Randomization will be stratified by metastasis (bone only/liver/other), AR-LBD mutation status (positive/negative), and prior docetaxel for HSPC (yes/no). Treatment will continue until unacceptable toxicity, radiographic disease progression (verified per Prostate Cancer Working Group 3 [PCWG3]–modified RECIST v1.1 by BICR), or other discontinuation criteria are met. Tumor assessments will be performed every 8 weeks through week 24, then every 12 weeks thereafter. Dual primary end points are radiographic PFS per PCWG3-modified RECIST v1.1 by BICR and OS in patients with AR-LBD mutation–positive and –negative disease, separately. Secondary end points include time to initiation of first subsequent anticancer therapy or death; ORR and DOR per PCWG3-modified RECIST v1.1 by BICR; time to pain progression; time to prostate-specific antigen (PSA) progression; PSA response rate; time to first symptomatic skeletal-related event; and safety and tolerability. Recruitment is ongoing. Clinical trial information: NCT06136650 .
Simulating Healthy Participant Pharmacokinetics for Renal and Hepatic Impairment Studies: Retrospective Assessment of the Approach
Authors: Prybylski John P. , Wang Yuchen , Sahasrabudhe Vaishali , Purohit Vivek 
Published: June 2024

AbstractThe recruitment of a parallel, healthy participants (HPs) arm in renal and hepatic impairment (RI and HI) studies is a common strategy to assess differences in pharmacokinetics. Limitations in this approach include the underpowered estimate of exposure differences and the use of the drug in a population for which there is no benefit. Recently, a method was published by Purohit et. al. (2023) that leveraged prior population pharmacokinetic (PopPK) modeling-based simulation to infer the distribution of exposure ratios between the RI/HI arms and HPs. The approach was successful, but it was a single example with a robust model having several iterations of development and fitting to extensive HP data. To test in more studies and models at different stages of development, our catalogue of RI/HI studies was searched, and those with suitable properties and from programs with available models were analyzed with the simulation approach. There were 9 studies included in the analysis. Most studies were associated with models that would have been available at the time (ATT) of the study, and all had a current, final model. For 3 studies, the HP PK was not predicted well by the ATT (2) or final (1) models. In comparison to conventional analysis of variance (ANOVA), the simulation approach provided similar point estimates and confidence intervals of exposure ratios. This PopPK based approach can be considered as a method of choice in situations where the simulation of HP data would not be an extrapolation, and when no other complicating factors are present.
Graphical Abstract
Self-consistent equilibrium of a force-free magnetic flux rope
Authors: Cheremnykh Oleg K. , Lashkin Volodymyr M. 
Published: June 2024

Abstract
We present an exact solution to the problem of a self-consistent equilibrium force-free magnetic flux rope. Unlike other approaches, we use magnetostatic equations and assume only a relatively rapid decrease in the axial magnetic field at infinity. For the first time we obtain a new nonlinear equation for the axial current density, the derivation of which does not require any phenomenological assumptions. From the resulting nonlinear equation, we analytically find the radial profiles of the components of the magnetic field strength and current density.
Classicism in Digital Times
Authors: Yang Zhiyi , Wang David Der-Wei 
Published: June 2024

Abstract
This article, the introduction to the special issue, proposes “Sinophone classicism” as a new paradigm to investigate Chineseness as an identity shaped by cultural and digital memories in the global cyberspace. Digital technology has drastically transformed the world we inhabit, particularly the way in which we symbiotically remember and imagine our cultural legacies and visions. To rethink the relations between the humanities and digital technicity, we seek to invoke “classicism” as a keyword through which to engage questions from temporality to virtuality and “Sinophone” as a topos through which to discover the pluriverse of China. Being “Chinese” in cyberspace, therefore, entails a constant and dynamic process of remembering, performing, (re)imagining, and (re)negotiating one's cultural identities.
China in the Skin
Authors: Sh-Chen Yedong 
Published: June 2024

Abstract
How do video games tell “the good China story”? In reviewing Chinese official media's months-long criticism of the mobile MOBA game, Honor of Kings (Wangzhe rongyao 王者榮耀), and the game's rounds of responses in 2017 and 2018, this article investigates a unique digital object that affords storytelling in video games: skin (pifu 皮膚). Neither a playable character per se nor a player's avatar, skin constitutes a special digital milieu where China stories are told, debated, and their “goodness” performed. It traverses various composing strata of video games and distributes narrative into a game's mechanics, procedure, representation, playing experience, and more. Skin, the author argues, is a yet-theorized differentiator that anchors “Chineseness” in the world of video gaming. It is a new site in a digital age in which the theoretical problem of Chineseness manifests different kinds of difficulty. The article ends with a discussion of the significance of researching skin to our understanding of what a Chinese video game is. The author calls for a new conceptualization of a Chinese video game that accounts for video game's medium specificity. Speaking to scholars of both Chinese studies and digital game studies, this article anticipates more scholarly interest in the intersection of the two fields.
Digital Preoperative Huddle Platform Use Leads to Decreased Surgical Cost
Authors: Eremiev Alexander , London Dennis , Ber Roee , Kurland David B. , Sheerin Kathleen , Dennett Haleigh , Pacione Donato , Laufer Ilya 
Published: June 2024

BACKGROUND AND OBJECTIVES:
Communication has a well-established effect on improving outcomes. The current study evaluated the effect of multidisciplinary preoperative team communication using a digital huddle software platform on operating room costs.

METHODS:
A digital huddle software platform was implemented in March 2022 for neurosurgical procedures performed at a single tertiary care center. Surgeons were encouraged, but not required, to participate. General linear models were used to test the association between participation and the difference in supply-related cost and case length, using intergroup comparison and historical controls.

RESULTS:
A total of 29626 cases (performed by 97 surgeons), conducted between March 2021 and June 2023, were included in our analysis. Cases from participating neurosurgeons (12 surgeons, 4064 cases) were compared with cases from nonparticipating neurosurgeons (6 surgeons, 2452 cases), non-neurosurgery cases carried out by the same operating room staff (20 orthopedic spine surgeons, 6073 cases), and non-neurosurgery cases performed in a different operating room unit (59 surgeons, 21 996 cases). In aggregate, operating room (OR) costs increased by 7.3% (95% CI: 0.9-14.1, P = .025) in the postintervention period. In the same period, participation in the digital huddle platform was associated with an OR utilization and supply-related cost decrease of 16.3% (95% CI: 8.3%-23.6%, P < .001). Among neurosurgeons specifically, participation was associated with a supply-related cost decrease of 17.5% (95% CI: 6.0%-27.5%, P = .0037). There was no change in case length (median case length 171 minutes, change: +2.7% increase, 95% CI:-2.2%-7.9%, P = .28).

CONCLUSION:
The implementation of a digital huddle software platform resulted in an OR utilization and supply cost decrease among participants during a period when the overall nonparticipating control cohort experienced an increase in cost.
Histone acylation at a glance
Authors: Bhattacharya Saikat , Tu Benjamin P. 
Published: June 2024

ABSTRACT
An important mechanism of gene expression regulation is the epigenetic modification of histones. The cofactors and substrates for these modifications are often intermediary metabolites, and it is becoming increasingly clear that the metabolic and nutritional state of cells can influence these marks. These connections between the balance of metabolites, histone modifications and downstream transcriptional changes comprise a metabolic signaling program that can enable cells to adapt to changes in nutrient availability. Beyond acetylation, there is evidence now that histones can be modified by other acyl groups. In this Cell Science at a Glance article and the accompanying poster, we focus on these histone acylation modifications and provide an overview of the players that govern these acylations and their connections with metabolism.
CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses
Authors: Prajapati Bina , Sokolova Maria , Sidorenko Ekaterina , Kyriacou Mikael , Kyheröinen Salla , Vihervaara Anniina , Vartiainen Maria K. 
Published: June 2024

ABSTRACT
Myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF), and thereby regulate cytoskeletal gene expression in response to actin dynamics. MRTFs have also been implicated in transcription of heat shock protein (HSP)-encoding genes in fly ovaries, but the mechanisms remain unclear. Here, we demonstrate that, in mammalian cells, MRTFs are dispensable for gene induction of HSP-encoding genes. However, the widely used small-molecule inhibitors of the MRTF-SRF transcription pathway, derived from CCG-1423, also efficiently inhibit gene transcription of HSP-encoding genes in both fly and mammalian cells in the absence of MRTFs. Quantifying RNA synthesis and RNA polymerase distribution demonstrates that CCG-1423-derived compounds have a genome-wide effect on transcription. Indeed, tracking nascent transcription at nucleotide resolution reveals that CCG-1423-derived compounds reduce RNA polymerase II elongation, and severely dampen the transcriptional response to heat shock. The effects of CCG-1423-derived compounds therefore extend beyond the MRTF-SRF pathway into nascent transcription, opening novel opportunities for their use in transcription research.
Strong acclimation effect of temperature and humidity on heat tolerance of the Arctic collembolan Megaphorura arctica
Authors: Christoffersen Sara Nørris , Pertoldi Cino , Sørensen Jesper Givskov , Kristensen Torsten Nygård , Bruhn Dan , Bahrndorff Simon 
Published: June 2024

ABSTRACT
The Arctic is a highly variable environment in which extreme daily and seasonal temperature fluctuations can occur. With climate change, an increase in the occurrence of extreme high temperatures and drought events is expected. While the effects of cold and dehydration stress on polar arthropods are well studied in combination, little is known about how these species respond to the combined effects of heat and dehydration stress. In this paper, we investigated how the heat tolerance of the Arctic collembola Megaphorura arctica is affected by combinations of different temperature and humidity acclimation regimes under controlled laboratory conditions. The effect of acclimation temperature was complex and highly dependent on both acclimation time and temperature, and was found to have a positive, negative or no effect depending on experimental conditions. Further, we found marked effects of the interaction between temperature and humidity on heat tolerance, with lower humidity severely decreasing heat tolerance when the acclimation temperature was increased. This effect was more pronounced with increasing acclimation time. Lastly, the effect of acclimation on heat tolerance under a fluctuating temperature regime was dependent on acclimation temperature and time, as well as humidity levels. Together, these results show that thermal acclimation alone has moderate or no effect on heat tolerance, but that drought events, likely to be more frequent in the future, in combination with high temperature stress can have large negative impacts on heat tolerance of some Arctic arthropods.
Coronary circulation enhances the aerobic performance of wild Pacific salmon
Authors: Van Wert Jacey C. , Ekström Andreas T. , Gilbert Matthew J. H. , Hendriks Brian J. , Cooke Steven J. , Patterson David A. , Hinch Scott G. , Eliason Erika J. 
Published: June 2024

ABSTRACT
Female Pacific salmon often experience higher mortality than males during their once-in-a-lifetime up-river spawning migration, particularly when exposed to secondary stressors (e.g. high temperatures). However, the underlying mechanisms remain unknown. One hypothesis is that female Pacific salmon hearts are more oxygen-limited than those of males and are less able to supply oxygen to the body's tissues during this demanding migration. Notably, female hearts have higher coronary blood flow, which could indicate a greater reliance on this oxygen source. Oxygen limitations can develop from naturally occurring coronary blockages (i.e. coronary arteriosclerosis) found in mature salmon hearts. If female hearts rely more heavily on coronary blood flow but experience similar arteriosclerosis levels as males, they will have disproportionately impaired aerobic performance. To test this hypothesis, we measured resting (RMR) and maximum metabolic rate (MMR), aerobic scope (AS) and acute upper thermal tolerance in coho salmon (Oncorhynchus kisutch) with an intact or artificially blocked coronary oxygen supply. We also assessed venous blood oxygen and chemistry (cortisol, ions and metabolite concentrations) at different time intervals during recovery from exhaustive exercise. We found that coronary blockage impaired MMR, AS and the partial pressure of oxygen in venous blood (PvO2) during exercise recovery but did not differ between sexes. Coronary ligation lowered acute upper thermal tolerance by 1.1°C. Although we did not find evidence of enhanced female reliance on coronary supply, our findings highlight the importance of coronary blood supply for mature wild salmon, where migration success may be linked to cardiac performance, particularly during warm water conditions.
Individual differences in the boldness of female zebrafish are associated with alterations in serotonin function
Authors: Beigloo Fatemeh , Davidson Cameron J. , Gjonaj Joseph , Perrine Shane A. , Kenney Justin W. 
Published: June 2024

ABSTRACT
One of the most prevalent axes of behavioral variation in both humans and animals is risk taking, where individuals that are more willing to take risk are characterized as bold while those that are more reserved are regarded as shy. Brain monoamines (i.e. serotonin, dopamine and noradrenaline) have been found to play a role in a variety of behaviors related to risk taking. Using zebrafish, we investigated whether there was a relationship between monoamine function and boldness behavior during exploration of a novel tank. We found a correlation between serotonin metabolism (5-HIAA:5-HT ratio) and boldness during the initial exposure to the tank in female animals. The DOPAC:DA ratio correlated with boldness behavior on the third day in male fish. There was no relationship between boldness and noradrenaline. To probe differences in serotonergic function in bold and shy fish, we administered a selective serotonin reuptake inhibitor, escitalopram, and assessed exploratory behavior. We found that escitalopram had opposing effects on thigmotaxis in bold and shy female animals: the drug caused bold fish to spend more time near the center of the tank and shy fish spent more time near the periphery. Taken together, our findings indicate that variation in serotonergic function has sex-specific contributions to individual differences in risk-taking behavior.
Flies on the rise: acclimation effect on mitochondrial oxidation capacity at normal and high temperatures in Drosophila melanogaster
Authors: Blanchard Arianne , Aminot Mélanie , Gould Nathalie , Léger Adèle , Pichaud Nicolas 
Published: June 2024

ABSTRACT
Increased average temperatures and extreme thermal events (such as heatwaves) brought forth by climate change impose important constraints on aerobic metabolism. Notably, mitochondrial metabolism, which is affected by both long- and short-term temperature changes, has been put forward as an important determinant for thermal tolerance of organisms. This study examined the influence of phenotypic plasticity on metabolic and physiological parameters in Drosophila melanogaster and the link between mitochondrial function and their upper thermal limits. We showed that D. melanogaster acclimated to 15°C have a 0.65°C lower critical thermal maximum (CTmax) compared with those acclimated to 24°C. Drosophila melanogaster acclimated to 15°C exhibited a higher proportion of shorter saturated and monounsaturated fatty acids, concomitant with lower proportions of polyunsaturated fatty acids. No mitochondrial quantitative changes (fractional area and number) were detected between acclimation groups, but changes of mitochondrial oxidation capacities were observed. Specifically, in both 15°C- and 24°C-acclimated flies, complex I-induced respiration was increased when measured between 15 and 24°C, but drastically declined when measured at 40°C. When succinate and glycerol-3-phosphate were added, this decrease was however compensated for in flies acclimated to 24°C, suggesting an important impact of acclimation on mitochondrial function related to thermal tolerance. Our study reveals that the use of oxidative substrates at high temperatures is influenced by acclimation temperature and strongly related to upper thermal tolerance as a difference of 0.65°C in CTmax translates into significant mitochondrial changes.