bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased CD8+ T-cell Infiltration and Efficacy for Multikinase Inhibitors After PD-1 Blockade in Hepatocellular Carcinoma
Authors: Kikuchi Hiroto , Matsui Aya , Morita Satoru , Amoozgar Zohreh , Inoue Koetsu , Ruan Zhiping , Staiculescu Daniel , Wong Jeffrey Sum-Lung , Huang Peigen , Yau Thomas , Jain Rakesh K , Duda Dan G 
Published: March 2022

Abstract
Immune checkpoint blockade combined with antiangiogenic therapy induces vascular normalization and antitumor immunity and is efficacious in hepatocellular carcinoma (HCC); but whether and how initial immunotherapy affects the efficacy of subsequent antiangiogenic therapy are unknown. We evaluated a cohort of HCC patients (n = 25) who received the pan–vascular endothelial growth factor receptor multikinase inhibitor sorafenib after initial therapy with an antiprogrammed cell death protein (PD)–1 antibody and found superior outcomes in these patients (12% overall response rate to sorafenib and a median overall survival of 12.1 months). To prove this potential benefit, we examined the impact of an anti–PD-1 antibody on response to subsequent sorafenib treatment in orthotopic models of murine HCC. Prior anti–PD-1 antibody treatment amplified HCC response to sorafenib therapy and increased survival (n = 8-9 mice per group, hazard ratio = 0.28, 95% confidence interval = 0.09 to 0.91; 2-sided P = .04). Anti–PD-1 therapy showed angioprotective effects on HCC vessels to subsequent sorafenib treatment, which enhanced the benefit of this therapy sequence in a CD8+ T-cell–dependent manner. This priming approach using immunotherapy provides an immediately translatable strategy for effective HCC treatment while reducing drug exposure.
Variation and adaptation in leaf sulfur content across China
Authors: Zhao Wenzong , Xiao Chunwang , Li Mingxu , Xu Li , He Nianpeng 
Published: March 2022

Abstract
Sulfur is an essential functional element in leaves, and it plays important roles in regulating plant growth, development and abiotic stress resistance in natural communities. However, there has been limited information on the spatial variation in leaf sulfur content (LSC) and adaptive characters on a large community scale. Sulfur in leaves of 2207 plant species from 80 widespread ecosystems (31 forests, 38 grasslands and 11 deserts) in China was measured. One-way analysis of variance with Duncan’s multiple-range tests were used to evaluate the differences in LSC among different plant growth forms and ecosystems. We fitted the relationships of LSC to spatial and climate factors using regression. Structural equation modeling analysis and phylogenetic analysis helped us further explore the main factors of LSC variation. LSC ranged from 0.15 to 48.64 g kg–1, with an average of 2.13 ± 0.04 g kg–1 at the community scale in China. We observed significant spatial variation in LSC among different ecosystems and taxa. Overall, LSC was higher in arid areas and herbs. Furthermore, higher LSC was observed under environments of drought, low temperatures and intense ultraviolet radiation. Temperature, precipitation, radiation, soil sulfur content and aridity jointly regulated LSC, explaining 79% of the spatial variation. However, LSC was not significantly related to phylogeny. Our results demonstrate that LSC plays an important role in plant adaptations to extreme environments and further extend our understanding of the biological function of sulfur from the organ to the community level. These findings highlight the importance of sulfur metabolism for our understanding of the impact of global climate change on plants.
The role of bars on the dynamical-friction-driven inspiral of massive objects
Authors: Bortolas Elisa , Bonetti Matteo , Dotti Massimo , Lupi Alessandro , Capelo Pedro R , Mayer Lucio , Sesana Alberto 
Published: March 2022

ABSTRACT
In this paper, we systematically explore the impact of a galactic bar on the inspiral time-scale of a massive object (MO) within a Milky Way-like galaxy. We integrate the orbit of MOs in a multicomponent galaxy model via a semi-analytical approach that accounts for dynamical friction generalized to rotationally supported backgrounds. We compare the MO evolution in a galaxy featuring a Milky Way-like rotating bar to the evolution within an analogous axisymmetric galaxy without the bar. In agreement with previous studies, we find that the bar presence may significantly affect the inspiral, sometimes making it shorter by a factor of a few, and sometimes hindering it for a Hubble time. The erratic behaviour is mainly impacted by the relative phase at which the MO encounters the stronger bar-induced resonances. In particular, the effect of the bar is more prominent for initially in-plane, prograde MOs, especially those crossing the bar co-rotation radius or outer Lindblad resonance. In the barred galaxy, we find the sinking of the most massive MOs ($\gtrsim 10^{7.5}\, \mathrm{M}_{\odot {}}$) approaching the galaxy from large separations (≳8 kpc) to be most efficiently hampered. Neglecting the effect of global torques associated with the non-symmetric mass distribution is thus not advisable even within an idealized, smooth galaxy model; we further note that spiral patterns are unlikely to affect the inspiral due to their transient and fluctuating nature. We speculate that the sinking efficiency of massive black holes involved in minor galaxy mergers may be hampered in barred galaxies, making them less likely to host a gravitational wave signal accessible to low-frequency detectors.
A comprehensive analysis of WASP-17b’s transmission spectrum from space-based observations
Authors: Alderson L , Wakeford H R , MacDonald R J , Lewis N K , May E M , Grant D , Sing D K , Stevenson K B , Fowler J , Goyal J , Batalha N E , Kataria T 
Published: March 2022

ABSTRACT
Due to its 1770 K equilibrium temperature, WASP-17b, a 1.99 RJup, 0.486 MJup exoplanet, sits at the critical juncture between hot and ultra-hot Jupiters. We present its 0.3–5 $\rm{\mu m}$ transmission spectrum, newly obtained with Hubble Space Telescope (HST) Wide Field Camera 3 (WFC3) measurements, and, taking advantage of improved analysis techniques, reanalysed HST Space Telescope Imaging Spectrograph and Spitzer Space Telescope Infrared Array Camera observations. We achieve a median precision of 132 ppm, with a mean of 272 ppm across the whole spectrum. We additionally make use of Transiting Exoplanet Survey Satellite (TESS) and ground-based transit observations to refine the orbital period of WASP-17b. To interpret the observed atmosphere, we make use of free and equilibrium chemistry retrievals using the POSEIDON and ATMO retrieval codes, respectively. We detect absorption due to H2O at &gt;7σ and find evidence of absorption due to CO2 at &gt;3σ. We see no evidence of previously detected Na i and K i absorption. Across an extensive suite of retrieval configurations, we find that the data favour a bimodal solution with high- or low-metallicity modes as a result of poor constraints in the optical and demonstrate the importance of using multiple statistics for model selection. Future JWST GTO observations, combined with the presented transmission spectrum, will enable precise constraints on WASP-17b’s atmosphere.
Looking through the Lens of the Ribosome Biogenesis Evolutionary History: Possible Implications for Archaeal Phylogeny and Eukaryogenesis
Authors: Jüttner Michael , Ferreira-Cerca Sébastien 
Published: March 2022

Abstract
Our understanding of microbial diversity and its evolutionary relationships has increased substantially over the last decade. Such an understanding has been greatly fueled by culture-independent metagenomics analyses. However, the outcome of some of these studies and their biological and evolutionary implications, such as the origin of the eukaryotic lineage from the recently discovered archaeal Asgard superphylum, is debated. The sequences of the ribosomal constituents are amongst the most used phylogenetic markers. However, the functional consequences underlying the analysed sequence diversity and their putative evolutionary implications are essentially not taken into consideration. Here, we propose to exploit additional functional hallmarks of ribosome biogenesis to help disentangle competing evolutionary hypotheses. Using selected examples, such as the multiple origins of halophily in archaea or the evolutionary relationship between the Asgard archaea and Eukaryotes, we illustrate and discuss how function-aware phylogenetic framework can contribute to refining our understanding of archaeal phylogeny and the origin of eukaryotic cells.
A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients
Authors: Degener Max J F , van Cruchten Remco T P , Otero Brittney A , Wang Eric T , Wansink Derick G , ‘t Hoen Peter A C 
Published: March 2022

AbstractIn patients with myotonic dystrophy type 1 (DM1), dysregulation of RNA-binding proteins like MBNL and CELF1 leads to alternative splicing of exons and is thought to induce a return to fetal splicing patterns in adult tissues, including the central nervous system (CNS). To comprehensively evaluate this, we created an atlas of developmentally regulated splicing patterns in the frontal cortex of healthy individuals and DM1 patients, by combining RNA-seq data from BrainSpan, GTEx and DM1 patients. Thirty-four splice events displayed an inclusion pattern in DM1 patients that is typical for the fetal situation in healthy individuals. The regulation of DM1-relevant splicing patterns could partly be explained by changes in mRNA expression of the splice regulators MBNL1, MBNL2 and CELF1. On the contrary, interindividual differences in splicing patterns between healthy adults could not be explained by differential expression of these splice regulators. Our findings lend transcriptome-wide evidence to the previously noted shift to fetal splicing patterns in the adult DM1 brain as a consequence of an imbalance in antagonistic MBNL and CELF1 activities. Our atlas serves as a solid foundation for further study and understanding of the cognitive phenotype in patients.
Laboratories of Bureaucracy: How Bureaucrats Learn across States in Setting Early Childhood Education Standards
Authors: Smith Kelly B 
Published: March 2022

Abstract
How and under what conditions might bureaucrats look to other states? Using a novel dataset of state early learning standards, I conduct dyad analysis to explain across-state citations in bureaucratic documents. Federal government programs can affect which states are looked to for ideas by defining which states are successful through competitive grant programs. Furthermore, the success of programs within the state affect whether bureaucrats look to other states. This article makes two important contributions to our understanding of policy. First, it explores how bureaucrats can participate in policy knowledge diffusion by looking to other states for information. Second, it sheds light on how we measure states as laboratories by marshaling an innovative dataset of citations within state documents. The article suggests states may not be limited to acting as laboratories through electoral institutions, but rather, they may also innovate as laboratories of bureaucracy.
Treatment of childhood-onset Takayasu arteritis: switching between anti-TNF and anti-IL-6 agents
Authors: Sener Seher , Basaran Ozge , Kaya Akca Ummusen , Atalay Erdal , Kasap Cuceoglu Muserref , Balik Zeynep , Aliyev Emil , Bayindir Yagmur , Batu Ezgi Deniz , Hazirolan Tuncay , Bilginer Yelda , Ozen Seza 
Published: March 2022

Abstract

Objectives
Biologics are new treatment alternatives in Takayasu arteritis (TA), although data in childhood are limited. The aim of this study was to share our experience in seven childhood-onset TA patients who received a TNF-α inhibitor (adalimumab) or an IL-6 receptor inhibitor (tocilizumab) and the effect of switching therapy.

Methods
We retrospectively evaluated the medical treatment records of seven patients with TA, followed between August 2005 and January 2021 at the Pediatric Rheumatology Department of Hacettepe University Faculty of Medicine.

Results
The median age of patients was 14 (IQR 4) years, and six were female. All of the patients had severe disease and high acute-phase reactants. The patients initially received only steroids or steroids+CYC. Prednisone was decreased, and biologic agents were started once the acute phase reactants decreased, and the Indian Takayasu Activity Score (ITAS) returned to normal. Initially, four patients received tocilizumab (TCZ) [median 25.5 (IQR 41) months] and three patients received adalimumab (ADA) [median 13 (IQR 31) months]. However, due to the progression of MR angiography findings or persistent elevation in acute-phase reactants, the biologic agents were switched from TCZ to ADA in four patients and from ADA to TCZ in three patients. The patients' median follow-up time after changing was 50 (IQR 77) months, and median ITAS was evaluated as ‘0’ after 2 (IQR 4) months.

Conclusions
In conclusion, both TNF-α and IL-6 inhibitors are effective alternatives in treating patients with childhood-onset TA. However, prospective randomized controlled trials are needed for the comparison of their effectiveness.
Anti-Bartlett clauses after IQEQ in the Hong Kong Court of Final Appeal
Authors: Hayton David 
Published: March 2022

Abstract
As a donor of assets over a continuing period via a trustee, the settlor and the trustee are free to negotiate how far an exoneration clause can extend to oust a trustee's duties and so limit the extent of the bounty conferred on beneficiaries by the settlor. In particular, where an aggressive speculative investment policy is required to be pursued via a controlled underlying company, so that beneficiaries may benefit from massive gains or suffer the burden of massive losses, the vulnerable trustee is entitled to protect itself from all liability for losses unless guilty of dishonesty or of failing to intervene in circumstances where it had actual knowledge of dishonesty in the management of the company.
Pain Characteristics, Fear-avoidance Variables, and Pelvic Floor Function as Predictors of Treatment Response to Physical Therapy in Women With Provoked Vestibulodynia
Authors: Bélanger Clémence , Dumoulin Chantale , Bergeron Sophie , Mayrand Marie-Hélène , Khalifée Samir , Waddell Guy , Dubois Marie-France ,   PVD Group, Morin Mélanie 
Published: March 2022

Objective:
The aim was to investigate whether pretreatment pain characteristics, psychological variables, and pelvic floor muscle (PFM) function predict the response to physical therapy (PT) in women with provoked vestibulodynia (PVD).

Materials and Methods:
One hundred-five women diagnosed with PVD underwent 10 weekly sessions of individual PT comprising education, PFM exercises with biofeedback, manual therapy, and dilators. Treatment outcomes were evaluated at pretreatment, post-treatment, and 6-month follow-up and included pain intensity (numerical rating scale 0 to 10) and sexual function (Female Sexual Function Scale). Multilevel analyses were used to examine the potential predictors of response over time including pain characteristics (PVD subtype, pain duration), psychological variables (fear of pain, pain catastrophizing), and PFM function assessed with a dynamometric speculum (tone, flexibility, and strength).

Results:
PVD subtype and PFM tone were significant predictors of greater treatment response for pain intensity reduction. Secondary PVD (ie, pain developed after a period of pain-free intercourse) and lower PFM tone at baseline were both associated with greater reduction in pain intensity after PT and at follow-up. Among the psychological variables, fear of pain was the only significant predictor of better treatment response when assessed through improvement in sexual function, where higher fear of pain at baseline was associated with greater improvement after PT.

Discussion:
This study identified PVD secondary subtype, lower PFM tone, and higher fear of pain as significant predictors of better treatment response to PT in women with PVD.
Preoperative immunotherapy for head and neck cancers: state of art
Authors: Egloff Ann Marie , Uppaluri Ravindra 
Published: March 2022

Purpose of review
Programmed cell death 1 (PD-l)-targeting agents have been FDA-approved for treatment of recurrent/ metastatic head and neck squamous cell carcinoma (HNSCC). Clinical studies employing these agents preoperatively for HNSCC in the definitive setting are emerging and have important implications.

Recent findings
Preclinical studies demonstrate enhanced effectiveness of preoperative PD-1 targeting compared with postoperative treatment. Nine HNSCC clinical studies evaluating preoperative treatment with PD-1-targeted pembrolizumab/nivolumab alone or in combination therapy were recently reported. These studies differed by preoperative treatment type and duration and reported no surgical delays, no unexpected surgical complications and grade 3–4 immune-related adverse events consistent with the employed immunotherapeutic agent(s). Rates of major pathologic response (MPR), reduced residual viable tumour to 10% or less, ranged from 2.9–31% across eight trials without neoadjuvant radiation therapy. Higher PD-1 ligand (PD-L1) expression, increased inflammatory gene expression and enhanced immune cell tumour infiltration in baseline biopsies were associated with pathologic tumour response (pTR) in some studies. Any degree of pTR was associated with improved survival/relapse outcomes in two studies.

Summary
Emerging preoperative anti-PD-1 HNSCC clinical studies indicate that preoperative treatment does not impact surgical management. Defining predictive biomarkersand tumour pathologic response implications for patient survival are areas for further investigation.
Hepatopancreatoduodenectomy for advanced biliary malignancies
Authors: Wu Xiangsong , Li Maolan , Wu Wenguang , Wang Xu’an , Li Huaifeng , Bao Runfa , Shu Yijun , Shen Jun , Gu Jun , Wang Xuefeng , Gong Wei , Peng Shuyou , Liu Yingbin 
Published: March 2022

Abstract

Background:
Hepatopancreatoduodenectomy (HPD) has been considered the only curative treatment for metastatic cholangiocarcinoma and some locally advanced gallbladder cancers (GBCs). However, HPD has not yet been included in treatment guidelines as a standard surgical procedure in consideration of its morbidity and mortality rates. The aim of this study was to evaluate the safety and effectiveness of HPD in treating biliary malignancies.

Methods:
The medical records of 57 patients with advanced biliary cancer undergoing HPD from January 2009 to December 2019 were retrospectively retrieved. A case–control analysis was conducted at our department. Patients with advanced GBC who underwent HPD (HPD-GBC group) were compared with a control group (None-HPD-GBC group) Baseline characteristics, preoperative treatments, tumor pathologic features, operative results, and prognosis were assessed.

Results:
Thirteen patients with cholangiocarcinoma and 44 patients with GBC underwent HPD at our department. Significant postoperative complications (grade III or greater) and postoperative pancreatic fistula were observed in 24 (42.1%) and 15 (26.3%) patients, respectively. One postoperative death occurred in the present study. Overall survival (OS) was longer in patients with advanced cholangiocarcinoma than in those with GBC (median survival time [MST], 31 months vs. 11 months; P
< 0.001). In the subgroup analysis of patients with advanced GBC, multivariate analysis demonstrated that T4 stage tumors (P = 0.012), N2 tumors (P = 0.001), and positive margin status (P = 0.004) were independently associated with poorer OS. Patients with either one or more prognostic factors exhibited a shorter MST than patients without those prognostic factors (P < 0.001).

Conclusion:
HPD could be performed with a relatively low mortality rate and an acceptable morbidity rate in an experienced high- volume center. For patients with advanced GBC without an N2 or T4 tumor, HPD can be a preferable treatment option.
Childhood maltreatment and the menopause transition in a cohort of midlife New Zealand women
Authors: Cleland Lana , McLeod Geraldine F.H. , Dhakal Bhubaneswor , Fenton Anna , Welch Jacqui-Lyn , Horwood L. John , Boden Joseph M. 
Published: March 2022

Abstract

Objective
Knowledge surrounding the link between childhood adversity and reproductive outcomes at midlife is limited. The present study examined the relationship between childhood maltreatment (childhood sexual abuse [CSA], childhood physical punishment [CPP]), and menopause status at age 40.

Methods
Data were gathered from female members of the Christchurch Health and Development Study, a longitudinal birth cohort of 1,265 individuals (630 females) born in Christchurch, New Zealand in 1977. Menopause status was defined by categorizing the female cohort at age 40 as either: 1) premenopausal, or 2) peri/ postmenopausal. Retrospective reports of CSA (<16 y) and CPP (<16 y) were obtained at ages 18 and 21 years.

Results
The analysis sample comprised n = 468 women with data recorded on both their menopause status at age 40 and history of maltreatment (<16 y), of whom 22% (n = 104) were classified as peri/postmenopausal. A statistically significant association was found between and severity of CSA and menopause status, but not between CPP and menopause status. The association with CSA was robust to control for both childhood confounding factors (<16 y) and intervening adult factors (18-40 y) associated with the menopause transition. In the fully adjusted model, women who had experienced severe CSA involving attempted/completed sexual penetration had twice the rate of entering peri/postmenopause compared with those who reported no CSA (39.0% vs 18.8%).

Conclusions
Severity of CSA exposure was associated with earlier menopausal transition in this female cohort. These findings are consistent with the emerging literature on the long-term health and developmental impacts of CSA.
Effect of socioeconomic status on survival in patients on the Diabetes Shared Care Program: Finding from a Taiwan nationwide cohort
Authors: Chuang Wan-Chi , Chu Chih-Hsun , Hsu Ying Hsin , Yao Cai-Sin 
Published: March 2022

Background:
The Diabetes Shared Care Program (DSCP) is an integrated care model in Taiwan to improve the care quality of patients with diabetes. Socioeconomic status (SES) is one of the important factors affecting health, and it is confirmed as a predictor of various diseases and deaths.This study aimed to determine the relationship between survival rate and SES among patients who participated in the DSCP.

Methods:
A cohort population-based study was conducted using the National Health Insurance Research Database of Taiwan from 2008 to 2013. The study subjects were type 2 diabetes. We defined individual SES and neighborhood SES by each patient’s job category and household income, which were characterized as advantaged or disadvantaged. Then we compared the survival rates of SES groups by Cox proportional hazards model to adjust risk factors.

Results:
This study included 16 614 patients with type 2 diabetes who participated in the DSCP program. The DSCP cohort showed a high hospitalization rate in low individual SES. In terms of 10-year overall survival, DSCP participants with high individual SES living in advantaged and disadvantaged neighborhoods had lower risk of mortality than those with low SES living in advantaged and disadvantaged neighborhoods, after adjustment for age and comorbidity. DSCP participants with low individual SES living in disadvantaged neighborhoods had no significant difference of mortality as those with low individual SES living in advantaged neighborhoods.

Conclusion:
In this study, we found that low individual SES, but not neighborhood SES, was associated with an increased mortality rate among DSCP participants.