bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Soluble Fas Levels and Incidence of Liver Cancer in Nested Case–Control Study
Authors: Adachi Yasushi , Nojima Masanori , Mori Mitsuru , Kubo Toshiyuki , Akutsu Noriyuki , Sasaki Yasushi , Nakase Hiroshi , Lin Yingsong , Kurozawa Youichi , Wakai Kenji , Tamakoshi Akiko ,   for the Japan Collaborative Cohort Study
Published: December 2022

Abstract

Background:
Soluble Fas (sFas) plays various roles in carcinogenesis and tumor dissemination by preventing apoptosis via binding to Fas ligand. We analyzed associations of serum sFas levels with the incidence of liver cancer in a prospective case–control study nested in the Japan Collaborative Cohort Study.

Methods:
A baseline survey was conducted from 1988, with blood samples obtained from 39,242 subjects. Patients diagnosed with liver cancer were regarded as cases. Two or three controls were selected and matched for sex, age, and geographic area. Conditional logistic regression was used to estimate ORs for cancer incidence associated with sFas.

Results:
This study contained 86 cases and 249 controls. After controlling for alcohol intake, body mass index, smoking, and hepatitis viral infection, participants with high sFas showed elevated risk of cancer (Ptrend = 0.003) and the third tertile of sFas showed a higher risk compared with the first tertile [OR, 3.53; 95% confidence interval (CI), 1.28–9.69]. In hepatocellular carcinoma, high sFas was associated with elevated risk (Ptrend &lt; 0.001). In men and the elderly, subjects in the highest tertiles showed higher cancer risk. Limiting subjects to those followed for 3 years, high sFas was related to liver cancer risk (Ptrend = 0.033) and the third tertile showed a higher risk compared with the first (OR, 2.94; 95% CI, 0.94–9.14).

Conclusions:
High serum sFas may be related to future risk of liver cancer.

Impact:
Our findings highlight this biomarker for further analysis in pooled investigations with different/larger prospective cohorts.
Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma
Authors: Song Xuyang , Kelley Robin Kate , Khan Anis A. , Standifer Nathan , Zhou Diansong , Lim KyoungSoo , Krishna Rajesh , Liu Lu , Wang Kun , McCoon Patricia , Negro Alejandra , He Philip , Gibbs Megan , Kurland John F. , Abou-Alfa Ghassan K. 
Published: December 2022

AbstractPurpose:A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab [Single Tremelimumab Regular Interval Durvalumab (STRIDE)] has demonstrated a favorable benefit-risk profile in the phase I/II Study 22 (NCT02519348) and phase III HIMALAYA study (NCT03298451). This study evaluated the pharmacokinetics, exposure–response, and exposure–pharmacodynamics relationships of tremelimumab in patients with unresectable hepatocellular carcinoma (uHCC).Patients and Methods:A previous tremelimumab population pharmacokinetic model was validated using data from parts 2 and 3 of Study 22. Exposure–response analyses explored relationships of tremelimumab exposure with efficacy and safety. Pharmacokinetics and pharmacodynamics relationships were evaluated using linear and nonlinear regression models.Results:The observed pharmacokinetics of tremelimumab in uHCC were consistent with predictions; no significant covariates were identified. Tremelimumab exposure was not significantly associated with adverse events, objective response rate, or progression-free survival. Overall survival (OS) was longer for patients with tremelimumab exposure, minimum serum drug concentration (Cmin1) ≥ median versus Cmin1 &lt; median (18.99 months vs. 10.97 months), but this exposure-survival analysis might be confounded with baseline characteristics of albumin level and neutrophil to lymphocyte ratio, which had a significant impact on OS (P = 0.0004 and 0.0001, respectively). The predicted Cmin1 of tremelimumab in STRIDE regimen (12.9 μg/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC50 = 5.24 μg/mL) in CD8+Ki67+ T-cell counts.Conclusions:Our findings support novel insights into tremelimumab pharmacokinetics and exposure–response relationships in HCC and support the clinical utility of the STRIDE regimen in patients with uHCC.
Comparison of Pyrrolobenzodiazepine Dimer Bis-imine versus Mono-imine: DNA Interstrand Cross-linking, Cytotoxicity, Antibody–Drug Conjugate Efficacy and Toxicity
Authors: Tiberghien Arnaud C. , Vijayakrishnan Balakumar , Esfandiari Arman , Ahmed Mahammad , Pardo Raul , Bingham John , Adams Lauren , Santos Kathleen , Kang Gyoung-Dong , Pugh Kathryn M. , Afif-Rider Shameen , Vashisht Kapil , Haque Kemal , Tammali Ravinder , Rosfjord Edward , Savoca Adriana , Hartley John A. , Howard Philip W. 
Published: December 2022

Abstract
Antibody–drug conjugates (ADC) delivering pyrrolobenzodiazepine (PBD) DNA cross-linkers are currently being evaluated in clinical trials, with encouraging results in Hodgkin and non–Hodgkin lymphomas. The first example of an ADC delivering a PBD DNA cross-linker (loncastuximab tesirine) has been recently approved by the FDA for the treatment of relapsed and refractory diffuse large B-cell lymphoma. There has also been considerable interest in mono-alkylating PBD analogs. We conducted a head-to-head comparison of a conventional PBD bis-imine and a novel PBD mono-imine. Key Mitsunobu chemistry allowed clean and convenient access to the mono-imine class. Extensive DNA-binding studies revealed that the mono-imine mediated a type of DNA interaction that is described as “pseudo cross-linking,” as well as alkylation. The PBD mono-imine ADC demonstrated robust antitumor activity in mice bearing human tumor xenografts at doses 3-fold higher than those that were efficacious for the PBD bis-imine ADC. A single-dose toxicology study in rats demonstrated that the MTD of the PBD mono-alkylator ADC was approximately 3-fold higher than that of the ADC bearing a bis-imine payload, suggesting a comparable therapeutic index for this molecule. However, although both ADCs caused myelosuppression, renal toxicity was observed only for the bis-imine, indicating possible differences in toxicologic profiles that could influence tolerability and therapeutic index. These data show that mono-amine PBDs have physicochemical and pharmacotoxicologic properties distinct from their cross-linking analogs and support their potential utility as a novel class of ADC payload.
Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
Authors: Lidström Tommy , Cumming Joshua , Gaur Rahul , Frängsmyr Lars , Pateras Ioannis S. , Mickert Matthias J. , Franklin Oskar , Forsell Mattias N.E. , Arnberg Niklas , Dongre Mitesh , Patthey Cedric , Öhlund Daniel 
Published: December 2022

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell–produced protein that was deposited into the ECM of PDAC tumors and detected high-circulating levels of gal 4 in patients with PDAC. In orthotopic transplantation experiments, we observed increased infiltration of T cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1−/− mice, demonstrating that the effect was mediated by the adaptive immune system. By performing single-cell RNA-sequencing, we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression associated with a higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T cells, and antigen-presenting dendritic cells in tumors with reduced gal 4 expression. Using a coculture system, we observed that extracellular gal 4 induced apoptosis in T cells by binding N-glycosylation residues on CD3ε/δ. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC.
Saúde do solo: múltiplas perspectivas e percepções
Authors:   Universidade de São Paulo. Escola Superior de Agricultura ", Cherubin Maurício Roberto ,   Luiz de Queiroz", Schiebelbein Bruna Emanuele ,   Universidade de São Paulo. Escola Superior de Agricultura "Luiz de Queiroz"
Published: December 2022

O livro está subdividido em quatro seções. A primeira seção apresenta os conceitos e a importância da saúde do solo, em que o objetivo central é difundir a multifuncionalidade do solo e sua interrelação com a saúde das plantas, animais, pessoas, meio ambiente e, por fim, com a saúde do planeta como um todo. A segunda seção conta com as melhores fotografias e as três premiadas que representam a saúde do solo. A terceira seção conta com as melhores ilustrações/infográficos e os três premiados que ilustraram, de forma criativa, como se identificam os solos saudáveis. Por fim, a última seção informa o leitor sobre as condições que compõem a fertilidade de um solo. Espera-se que esse material seja uma fonte de informação e que atinja desde profissionais inseridos na área de Ciências Agrárias até o público em geral, contribuindo para popularizar e ressaltar a importância de manter nossos solos saudáveis, tornando a agricultura brasileira mais produtiva e em consonância com o meio ambiente.
BioMatrix Versus Orsiro Stents for Coronary Artery Disease: A Multicenter, Randomized, Open-Label Study
Authors: Yoon Chang-Hwan , Kwun Ju-Seung , Choi Young Jin , Park Jin Joo , Kang Si-Hyuck , Kim Sun-Hwa , Suh Jung-Won , Youn Tae-Jin , Kim Myeong-Kon , Cha Kwang Soo , Lee Seung-Hwan , Hong Bum-Kee , Rha Seung-Woon , Kang Woong Chol , Lee Jae-Hwan , Kim Sang-Hyun , Chae In-Ho 
Published: December 2022

Background:
Comparative studies of ultrathin-strut biodegradable polymer sirolimus-eluting stent (BP-SES) have reported promising results and validated its excellent outcomes in terms of safety and efficacy. However, there are limited studies comparing BP drug-eluting stents with struts of different thicknesses. We compared the long-term clinical outcomes of patients treated with an ultrathin-strut BP-SES or a thick-strut biodegradable polymer biolimus-eluting stent (BP-BES).

Methods:
The BIODEGRADE trial (Biomatrix and Orsiro Drug-Eluting Stents in Angiographic Result in Patients With Coronary Artery Disease) is a multicenter prospective randomized study comparing coronary revascularization in patients with ultrathin-strut BP-SES and thick-strut BP-BES with the primary end point of target lesion failure at 18 months posttreatment. We performed the prespecified analysis of 3-year clinical outcomes.

Results:

In total, 2341 patients were randomized to receive treatment with ultrathin-strut BP-SES (N=1175) or thick-strut BP-BES (N=1166). The 3-year incidence rate of target lesion failure was 3.2% for BP-SES and 5.1% for BP-BES (
P
=0.023). The difference was primarily due to differences in ischemia-driven target lesion revascularization (BP-SES, 1.5%; BP-BES, 2.8%;
P
=0.035) between groups. A landmark analysis of the late follow-up period showed significant differences in target lesion failure, with outcomes being better in BP-SES. Cardiac death and target lesion revascularization were significantly lower in the BP-SES group.

Conclusions:
In a large, randomized trial, the long-term clinical outcome of target lesion failure at 3 years was significantly better among patients treated with the ultrathin-strut BP-SES. The results indicate the superiority of the ultrathin-strut BP-SES compared with the thick-strut BP-BES.

Registration:

URL:
https://clinicaltrials.gov
; Unique identifier: NCT02299011.
From Government to Governance, From Judiciary to…?
Authors: Ng Gar Yein 
Published: December 2022

Abstract
It can be seen from the research that there is very little actually written about the role of the judge in relation to regulatory power. It is clear from the research on the political and legal constitutions around regulatory power that it is a complex picture. Therefore, this paper maps out how the judiciary in England and France has responded to changes in government. The first part of this paper will start to chart out the expansion and contraction of judicial power in relation to executive powers. The second part will provide a comparison between England and France’s regulatory systems and their relationships to their respective judiciaries. The conclusion sets out to answer the main question of where the judiciary sits in an a complex political, economic and legal tapestry to control a hybrid institution that sits outside of a legal constitution.
The prevalence of mental frailty in ICU survivors and informal caregiver strain: A 1-year retrospective study of the Frisian aftercare cohort
Authors: Beumeler Lise F E , Bethlehem Carina , Hoogstins-Vlagsma Thialda T , van Zutphen Tim , Buter Hanneke , Navis Gerjan J , Boerma E Christiaan 
Published: December 2022

Background: Intensive care unit (ICU) survivors often suffer from long-term mental problems and a reduced health-related quality of life (HRQoL). Symptoms of depression, anxiety, and post-traumatic stress disorder may render patients mentally frail post-ICU, resulting in impaired recovery and an increased informal caregiver burden. The aim of this study was to investigate the prevalence of mental frailty up to 12 months after ICU admission and pinpoint markers for early risk-assessment in clinical practice. Methods: A retrospective cohort study (2012–2018) in which clinical and post-ICU data of long-stay (⩾48 h) ICU-patients was used. Mental frailty was identified as clinically relevant symptoms of depression, anxiety, or post-traumatic distress disorder at 12 months after discharge. Results: The prevalence of mental frailty at 12 months post-ICU among the total group of 239 patients was 38%. Mental frailty was defined as clinically relevant symptoms of depression, anxiety, and/or trauma. To achieve this, previously validated cut off values were used for the HADS (HADS-Anxiety ⩾ 8; HADS-Depression ⩾ 8) and TSQ (⩾6), and CSI (⩾7). Conclusion: A significant proportion of ICU-survivors can be identified as mentally frail, which is associated with impaired HRQoL at baseline and post-ICU, and high caregiver strain. These findings emphasize the need for integrative aftercare programs for both the patient and their informal caregivers.
Should China Expand Its Medical Education Scale? Evidence From Comparative Research
Authors: Hou (侯建林) Jianlin , Liao (廖凯举) Kaiju , Liao (廖鹏) Peng , Wang (王维民) Weimin , Xie (谢阿娜) Ana , Ke (柯杨) Yang 
Published: December 2022

Purpose This study compares doctor staffing level and the scale of medical education in China with those of other countries and proposes policy recommendations for future adjustments to the scale of China's medical education. Design/Approach/Methods This study employs a literature review and descriptive analysis. Findings China had 1.98 medical doctors per 1,000 people in 2018, ranking 85th out of the 193 member-states of the World Health Organization (WHO). In 2017, China had 1.99 practicing doctors per 1,000 people, only ranking above Turkey (1.88) in Organisation for Economic Co-operation and Development (OECD) countries. China had only 10.28 medical graduates per 100,000 people—placing in the bottom third of OECD countries. China's provision of 1.4 medical schools per 10 million people was also significantly lower than the global average (3.9). However, the average number of students enrolled in medical schools (509) in China was significantly higher than the global average (160). Originality/Value Although the scale of admission in undergraduate medical education must be expanded in China, this needs to be achieved while controlling the average number of medical students per school and reducing enrollment in low-quality medical schools. Furthermore, it is necessary to establish new medical schools while improving the operating level of existing ones.
Development of risk inventory for hospitals in India
Authors: Fidelis Joseph S , Joseph Lallu , Souza Keerthi D , Sankaranarayanan Krishnan , Agarwal Vijay 
Published: December 2022

Introduction With the ever-increasing hazards and associated risks in healthcare, the healthcare facilities should have a comprehensive enterprise risk management program. Risk management in Indian Healthcare is nascent and not structured. With the increasing potentially compensable events, workplace violence, cybersecurity threats, complex accreditation standards, old infrastructure and ever-changing legal and political scenarios, the risk inventory is expanding, leading to litigations due to lack of mitigation strategies. This study focuses on developing a comprehensive organization wide enterprise risk inventory for the healthcare facilities in India. Method Secondary data from published studies were collated and 25 risk factors were identified. Interviews with 12 domain experts further identified 38 context and country-specific risks. The identified 63 risks were sent to 20 senior healthcare risk managers. Forty-three risks were unique and were validated by the senior healthcare risk managers. Twenty risks out of 63 identified had similar meaning. These 20 risks were reworded, rephrased and merged into eight risks by the senior healthcare risk managers. The 51 risks were endorsed by the 12 domain experts. The identified risk factors were surveyed among the risk managers from various hospitals to understand the importance and ranking of the risk in the Indian context. Results Sentinel events/Never events appeared in different rank orders and seems to be among the top five risks as perceived by professionals in India. Second highest ranked risk was ‘Staff attrition’. The data analysis showed the different attributes of survey participants, such as the size of the organization with respect to bed capacity and length of time working in the field of risk management. Conclusion The results provide valuable insights into the perception of risk based on hospital size and the educational background of risk managers. This inventory may help hospitals develop strategies for mitigating, controlling and monitoring risks for better hospital management.
S100A9 upregulated by IFNGR signaling blockade functions as a novel GVHD suppressor without compromising GVL in mice
Authors: Kim Sena , Lim Sora , Kim Boram , Ritchey Julie , Vij Kiran , Prior Julie , Marsala Lynne , Stoner Alyssa , Gao Feng , Achilefu Samuel , Cooper Matthew L. , DiPersio John F. , Choi Jaebok 
Published: December 2022

Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for both malignant and nonmalignant hematologic disorders. However, graft-versus-host disease (GVHD) and malignant relapse limit its therapeutic success. We previously demonstrated that the blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells resulted in a reduction in GVHD while preserving graft-versus-leukemia (GVL) effects. However, the underlying molecular mechanisms remain inconclusive. In this study, we found that S100A9 is a novel GVHD suppressor upregulated when IFNGR is blocked in T cells. Both Ifngr1−/− and S100a9-overexpressing T cells significantly reduced GVHD without compromising GVL, altering donor T-cell trafficking to GVHD target organs in our mouse model of allo-HSCT. In addition, in vivo administration of recombinant murine S100A9 proteins prolongs the overall survival of recipient mice. Furthermore, in vivo administration of anti-human IFNGRα neutralizing antibody (αhGR-Nab) significantly upregulates the expression of S100A9 in human T cells and improved GVHD in our mouse model of xenogeneic human peripheral blood mononuclear cell transplantation. Consistent with S100a9-overexpressing T cells in our allo-HSCT model, αhGR-Nab reduced human T-cell trafficking to the GVHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GVHD suppressor without compromising GVL.
Salvage therapy with brentuximab-vedotin and bendamustine for patients with R/R PTCL: a retrospective study from the LYSA group
Authors: Aubrais Raphaelle , Bouabdallah Krimo , Chartier Loic , Herbaux Charles , Banos Anne , Brice Pauline , Sibon David , Schiano Jean Marc , Cluzeau Thomas , Laribi Kamel , Le Calloch Ronan , Bellal Mathieu , Delapierre Baptiste , Daguindau Nicolas , Amorim Sandy , Agbetiafa Kossi , Chauchet Adrien , Besson Caroline , Durot Eric , Bonnet Christophe , Fouillet Ludovic , Bijou Fontanet , Tournilhac Olivier , Gaulard Philippe , Parrens Marie-Cécile , Damaj Gandhi 
Published: December 2022

Abstract
Patients with relapsed or refractory (R/R) peripheral T-cell lymphomas (PTCL) have a poor prognosis. Bendamustine (B) and brentuximab-vedotin (Bv) have shown interesting results in this setting. However, little information is available about their efficacy in combination. This multicenter and retrospective study aimed to evaluate the efficacy and safety of the combination of BBv in patients with noncutaneous R/R PTCL among 21 LYSA centers in France and Belgium. The primary objective was the overall response rate. A total of 82 patients with R/R PTCL were included. The best overall response rate (ORR) was 68%, with 49% of patients in complete response (CR). In multivariable analysis, only the disease status after the last regimen (relapse vs refractory) was associated with the response with an ORR of 83% vs 57%. Median duration of response was 15.4 months for patients in CR. With a median follow-up of 22 months, the median progression free survival (PFS) and overall survival (OS) were 8.3 and 26.3 months respectively. Moreover, patients in CR, who underwent an allogeneic transplant, had a better outcome than patients who did not with a median PFS and OS of 19.3 vs 4.8 months and not reached vs 12.4 months, respectively. Fifty-nine percent of patients experienced grade 3/4 adverse events that were mainly hematologic. BBv is highly active in patients with R/R PTCL and should be considered as a one of the best options of immunochemotherapy salvage combination in this setting and particularly as a bridge to allogeneic transplant for eligible patients.