bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mass spectrometry quantifies target engagement for a KRASG12C inhibitor in FFPE tumor tissue
Authors: Chambers Andrew G. , Chain David C. , Sweet Steve M. , Song Zifeng , Martin Philip L. , Ellis Matthew J. , Rooney Claire , Kim Yeoun Jin 
Published: October 2023

Abstract
Background
Quantification of drug-target binding is critical for confirming that drugs reach their intended protein targets, understanding the mechanism of action, and interpreting dose-response relationships. For covalent inhibitors, target engagement can be inferred by free target levels before and after treatment. Targeted mass spectrometry assays offer precise protein quantification in complex biological samples and have been routinely applied in pre-clinical studies to quantify target engagement in frozen tumor tissues for oncology drug development. However, frozen tissues are often not available from clinical trials so it is critical that assays are applicable to formalin-fixed, paraffin-embedded (FFPE) tissues in order to extend mass spectrometry-based target engagement studies into clinical settings.

Methods
Wild-type RAS and RASG12C was quantified in FFPE tissues by a highly optimized targeted mass spectrometry assay that couples high-field asymmetric waveform ion mobility spectrometry (FAIMS) and parallel reaction monitoring (PRM) with internal standards. In a subset of samples, technical reproducibility was evaluated by analyzing consecutive tissue sections from the same tumor block and biological variation was accessed among adjacent tumor regions in the same tissue section.

Results
Wild-type RAS protein was measured in 32 clinical non-small cell lung cancer tumors (622–2525 amol/µg) as measured by FAIMS-PRM mass spectrometry. Tumors with a known KRASG12C mutation (n = 17) expressed a wide range of RASG12C mutant protein (127–2012 amol/µg). The variation in wild-type RAS and RASG12C measurements ranged 0–18% CV across consecutive tissue sections and 5–20% CV among adjacent tissue regions. Quantitative target engagement was then demonstrated in FFPE tissues from 2 xenograft models (MIA PaCa-2 and NCI-H2122) treated with a RASG12C inhibitor (AZD4625).

Conclusions
This work illustrates the potential to expand mass spectrometry-based proteomics in preclinical and clinical oncology drug development through analysis of FFPE tumor biopsies.
Impact of Seed Origin and Genetic Drift of Improved Rice Variety IR841 in Benin
Authors: Sedah Paulin , Djedatin Lambert Gustave , Loko Laura Yêyinou Estelle , Ewedje Eben-Ezer Baba Kayodé , Orobiyi Azize , Gbemavo Chalemagne Dossou Seblodo Judes , Toffa Joelle , Tchakpa Cyrille , Cubry Philippe , Sabot Francois 
Published: October 2023

Abstract
Background
Rice production is important for food security in Benin, with a national production largely dominated by the cultivation of the aromatic ecotype IR841, by far the most appreciated by Beninese consumers. However, to maintain agronomical qualities of a given cultivar, the origin and quality of seeds are mandatory and at the heart of the maintenance of yield and of market requests. Following this idea, the objective of the current study was thus to investigate the genetic purity of IR841 varieties collected from rice producers across 22 villages in Benin in relation to their agronomical performances.

Results
For this, agromorphological evaluation of 72 accessions based on 13 quantitative descriptors followed by genotyping with the Illumina Infinium rice 7 K SNP array of 9 accessions was carried out in the presence of 2 controls. Agromorphologic as well as genetic and phylogenetic analyses revealed two groups, the first one Okouta97, Koum47, Nana30, Man118, Ang1 and control sample IR841-2) was characterized by seed accessions provided by the formal seed system, while the second (Koum53, Tchaka41 and Koud46) comprising seeds from local markets or from previous harvests and showing a depression in agronomic performances.

Conclusion
We showed that IR841 seed purity is mandatory for the completion of agronomical performance, and that the farmers’ choice of seeds must be guided and informed to ensure sustainability and food security.
Modelling public attitude towards drone delivery in Germany
Authors: Kellermann Robin , Biehle Tobias , Mostofi Hamid 
Published: October 2023

Abstract
Background
Last-mile delivery by drone is expected to be a promising innovation for future urban logistics. However, in addition to adoption of services by customers, leveraging this delivery method will depend essentially on a positive public perception of such services in urban airspace.

Objective
This article provides novel and comprehensive insights into factors driving or impeding citizens' attitudes towards drone delivery.

Methodology
The article develops a structural equation model that derives from a sequential exploratory mixed methods design. In the first step, factors affecting attitudes towards drone delivery were identified within the scope of five focus groups and converted into the development of a questionnaire. In the second step, a German population-representative survey was conducted through telephone interviews, which provided reliable data to test the model (n = 819).

Results
Expected risks (particularly stress due to traffic in lower airspace, noise, and visual disturbances), as well as expected benefits (particularly fast and time-flexible delivery), significantly affect attitudes towards drone-based delivery, while the individual level of technological openness (technophilia) does not have a significant association. Moreover, the model reveals that the expected risks of drone deliveries are stronger associated with public attitude than with expected benefits.

Conclusions
The provided framework suggests fashioning policies and drone delivery applications that focus on mitigating social, spatial, and visual risks while achieving maximum utility for customers.
Adaptive evolution and co-evolution of chloroplast genomes in Pteridaceae species occupying different habitats: overlapping residues are always highly mutated
Authors: Gu Xiaolin , Li Lingling , Li Sicong , Shi Wanxin , Zhong Xiaona , Su Yingjuan , Wang Ting 
Published: October 2023

Abstract
Background
The evolution of protein residues depends on the mutation rates of their encoding nucleotides, but it may also be affected by co-evolution with other residues. Chloroplasts function as environmental sensors, transforming fluctuating environmental signals into different physiological responses. We reasoned that habitat diversity may affect their rate and mode of evolution, which might be evidenced in the chloroplast genome. The Pteridaceae family of ferns occupy an unusually broad range of ecological niches, which provides an ideal system for analysis.

Results
We conducted adaptive evolution and intra-molecular co-evolution analyses of Pteridaceae chloroplast DNAs (cpDNAs). The results indicate that the residues undergoing adaptive evolution and co-evolution were mostly independent, with only a few residues being simultaneously involved in both processes, and these overlapping residues tend to exhibit high mutations. Additionally, our data showed that Pteridaceae chloroplast genes are under purifying selection. Regardless of whether we grouped species by lineage (which corresponded with ecological niches), we determined that positively selected residues mainly target photosynthetic genes.

Conclusions
Our work provides evidence for the adaptive evolution of Pteridaceae cpDNAs, especially photosynthetic genes, to different habitats and sheds light on the adaptive evolution and co-evolution of proteins.
Statin use and the risk of hepatocellular carcinoma among patients with chronic hepatitis B: an emulated target trial using longitudinal nationwide population cohort data
Authors: Sinn Dong Hyun , Kang Danbee , Park Yewan , Kim Hyunsoo , Hong Yun Soo , Cho Juhee , Gwak Geum-Youn 
Published: October 2023

Abstract
Background
No randomized controlled trials have been completed to see whether statin can decrease hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients. We used large-scale, population-based, observational data to emulate a target trial with two groups, statin user and statin non-user.

Methods
Among 1,379,708 nonunique individuals from the Korean National Health Insurance Service data, 2,915 CHB patients with serum cholesterol level of 200 mg/dL or higher who started statin therapy and 8,525 propensity-score matched CHB patients with serum cholesterol level of 200 mg/dL or higher who did not start statin therapy were analyzed for the development of HCC. In addition, liver cancer or liver-related mortality and all-cause mortality were assessed.

Results
During follow-up, 207 participants developed HCC. Incidence rate of HCC was 0.2 per 1,000 person-years in the statin user group and 0.3 per 1,000 person-years in the statin non-user group. Fully adjusted hazard ratio (HR) for incident HCC comparing statin user group to statin nonuser group was 0.56 (95% confidence interval [CI]: 0.39 to 0.80). The association between statin use and decreased HCC risk was consistent in all subgroups analyzed. Fully adjusted HR comparing statin user to statin nonuser was 0.59 (95% CI: 0.35 to 0.99) for liver cancer or liver-related mortality and 0.93 (95% CI: 0.78 to 1.11) for all-cause mortality.

Conclusions
Statin might have a benefit for preventing HCC in CHB patients with elevated cholesterol levels. Statin should be actively considered for CHB patients with dyslipidemia.
Comparative effectiveness of seven interventions for chronic hepatitis D: a systematic review and network meta-analysis of randomized controlled trials
Authors: Rong Yangdan , Ju Xuegui , Sun Peng , Wang Yali 
Published: October 2023

Abstract
Objective
To compare the effectiveness of seven major interventions [Bulevirtide (BLV), Interferon (IFN), Nucleoside analogs (NAs), BLV + IFN, BLV + NAs, IFN + NAs, and Placebo] to treat chronic hepatitis D.

Methods
We followed PRISMA-NMA guidelines, searched databases (Cochrane Library, PubMed, EMBASE, and Web Of Science) for eligible randomized controlled trials (RCTs), and applied STATA17.0 software to execute the meta-analysis.

Results
We included 14 randomized controlled trials (814 patients) comparing seven different interventions. The results of the network meta-analysis showed that: ① Sustained virological response (after 24 weeks of follow-up): Four intervention groups (BLV + IFN, IFN alone, IFN + NAs, and NAs alone) were effective (relative risk (RR) = 13.30, 95% confidence interval (Cl) [1.68,105.32], RR = 12.13, 95% Cl [1.46,101.04], RR = 5.05, 95% Cl [1.68,15.19], RR = 5.03, 95% Cl [1.66,15.20]), with no statistically significant differences between the four groups. The top three in probability rankings were: BLV + NAs, BLV + IFN, and BLV alone (surface under the cumulative ranking curve (SUCRA) = 86.8%, 80.3%, and 48.4%; ② Sustained biochemical response (after 24 weeks of follow-up): BLV + IFN and IFN were superior to BLV (RR = 14.71, 95% Cl [1.14,189.07], RR = 16.67, 95% Cl [1.39,199.52]). The top three were BLV alone, BLV + NAs, and BLV + IFN (SUCRA = 86.9%,81.2%, and 64.3%). ③ Histological response: NAs were superior to BLV (RR = 2.08, 95% Cl [1.10,3.93]), whereas the difference between other treatment regimens was not statistically significant, and the top three in the probability ranking were BLV alone, BLV + NAs, and BLV + IFN (SUCRA = 75.6%, 75.6%, and 61.8%).

Conclusions
IFN, IFN + BLV, and IFN + NAs were effective in clearing HDV RNA and normalizing alanine aminotransferase levels; however, IFN and IFN + NAs had a high rate of viral relapse at 24 weeks post-treatment follow-up. There was no additional benefit of adding NAs to IFN therapy for chronic hepatitis D; however, the combination of IFN + BLV significantly improved short-term HDV RNA clearance, which showed strong synergistic effects. The seven regimens included in the study did not contribute significantly to liver histological improvement. Therefore, the IFN + BLV combination has the most potential as a treatment option to improve the long-term prognosis or even cure chronic hepatitis D.

Trial registration
This systematic evaluation and meta-analysis was registered with PROSPERO under the registration number: CRD42022314544.)
UK Kidney Association Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease 2023 UPDATE
Authors: Roddick Alistair J. , Wonnacott Alexa , Webb David , Watt Angela , Watson Michael A. , Staplin Natalie , Riding Alex , Lioudaki Eirini , Kuverji Apexa , Kossi Mohsen El , Holmes Patrick , Holloway Matt , Fraser Donald , Carvalho Chris , Burton James O. , Bhandari Sunil , Herrington William G. , Frankel Andrew H. 
Published: October 2023

AbstractLarge placebo-controlled trials have demonstrated kidney and cardiovascular clinical benefits of SGLT-2 inhibitors. Data from the EMPA-KIDNEY and DELIVER trials and associated meta-analyses triggered an update to the UK Kidney Association Clinical Practice Guideline on Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease. We provide a summary of the full guideline and highlight the rationale for recent updates. The use of SGLT-2 inhibitors in people with specific medical conditions, including type 1 diabetes, kidney transplants, and people admitted to hospital with heart failure is also considered, along with Recommendations for future research and Recommendations for implementation. A full “lay” summary of the guidelines is provided as an appendix to ensure that these guidelines are accessible and understandable to people who are not medical professionals.
Developing and designing an internet-based support and education program for patients awaiting kidney transplantation with deceased donors through: a Delphi study
Authors: Nilsson Kristina , Andersson Gerhard , Johansson Peter , Lundgren Johan 
Published: October 2023

Abstract
Aims
The aim of this study was to develop and refine the content and design of an internet-based support and education program for patients awaiting kidney transplantation from deceased donors.

Design
A Delphi process was used.

Methods
A prototype internet-based intervention was drafted, based on previous research. The intervention included educational and psychological support to manage the uncertain waiting time and specific education enabling preparation for transplantation and adjustment to life after transplantation. In a two-round Delphi process, patients who had received a kidney transplant from a deceased donor within the last 2 years (n = 27), significant others (n = 6), health-care personnel with renal (n = 20) or transplant (n = 14) expertise, rated importance of content and design aspects of the prototype intervention on a 5-point scale using web questionnaires. A median of ≥ 3 was considered as consensus. Quantitative data was analyzed using descriptive statistics. Free text answers were encouraged and analyzed using deductive content analysis. The STROBE-checklist was used.

Results
Consensus was reached for all suggested content and design items in round 1, with median ratings of 4 or 5. Qualitative analysis from round 1 suggested four new content and design items which were rated in round 2, on all which consensus was reached; information about life with young children as relatives, expansion of kidney transplantation specific information, program extension by one week and individualization by making information available based on individual needs.

Conclusion
There was consensus among heterogenous experts regarding suggested educational and psychological support content and design aspects, and additional content and design aspects were identified for an internet-based support and education program for patients awaiting kidney transplantation from deceased donors.
Efficacy and safety analysis of TACE + Donafenib + Toripalimab versus TACE + Sorafenib in the treatment of unresectable hepatocellular carcinoma: a retrospective study
Authors: Lu Haohao , Liang Bin , Xia Xiangwen , Zheng Chuansheng 
Published: October 2023

Abstract
Objective
To compare the efficacy and safety of TACE combined with Donafenib and Toripalimab versus TACE combined with Sorafenib in the treatment of unresectable hepatocellular carcinoma (HCC), aiming to guide personalized treatment strategies for HCC and improve patient prognosis.

Materials and methods
A retrospective analysis was conducted on the clinical data of 169 patients with unresectable advanced-stage HCC who underwent treatment at the Interventional Department of Wuhan Union Hospital from January 2020 to December 2022. Based on the patients’ treatment strategies, they were divided into two groups: TACE + Donafenib + Toripalimab group (N = 81) and TACE + Sorafenib group (N = 88). The primary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) of the two groups’ tumors. The secondary endpoint was the occurrence of treatment-related adverse events in the two groups of patients.

Results
The TACE + Donafenib + Toripalimab group showed higher ORR and DCR compared to the TACE + Sorafenib group (66.7% vs. 38.6%, 82.6% vs. 68.2%, P < 0.05). The TACE + Donafenib + Toripalimab group also demonstrated longer median progression-free survival (mPFS) (10.9 months vs. 7.0 months, P < 0.001) and median overall survival (mOS) (19.6 months vs. 10.9 months, P < 0.001) compared to the TACE + Sorafenib group. When comparing the two groups, the TACE + Sorafenib group had a higher incidence of grade 3–4 hypertension (14.8% vs. 4.9%, P = 0.041), higher incidence of diarrhea (all grades) (18.2% vs. 7.4%, P = 0.042), and higher incidence of hand-foot syndrome (all grades) (26.1% vs. 12.3%, P = 0.032).

Conclusion
TACE combined with Donafenib and Toripalimab demonstrates superior efficacy and safety in treating unresectable HCC patients. This combination therapy may serve as a feasible option to improve the prognosis of unresectable HCC patients.
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin in combination with FOLFOX chemotherapy as a first-line treatment for gastric cancer patients with peritoneal metastases: single-arm phase II study
Authors: Luksta Martynas , Bausys Augustinas , Bickaite Klaudija , Rackauskas Rokas , Paskonis Marius , Luksaite-Lukste Raminta , Ranceva Anastasija , Stulpinas Rokas , Brasiuniene Birute , Baltruskeviciene Edita , Lachej Nadezda , Sabaliauskaite Rasa , Bausys Rimantas , Tulyte Skaiste , Strupas Kestutis 
Published: October 2023

Abstract
Background
Gastric cancer (GC) remains among the most common and most lethal cancers worldwide. Peritoneum is the most common site for distant dissemination. Standard treatment for GC peritoneal metastases (PM) is a systemic therapy, but treatment outcomes remain very poor, with median overall survival ranging between 3-9 months. Thus, novel treatment methods are necessary. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is the most novel technique for intraperitoneal chemotherapy. Some preliminary data suggest PIPAC can achieve improved long-term outcomes in patients with GC PM, especially when used in combination with systemic chemotherapy. However, there is a lack of data from well-design prospective studies that would confirm the efficacy of PIPAC and systemic therapy combination for first-line treatment.

Methods
This study is an investigator-initiated single-arm, phase II trial to investigate the efficacy of PIPAC combined with systemic FOLFOX (5-fluorouracil, oxaliplatin, leucovorin) as a first-line treatment for GC PM. The study is conducted in 2 specialized GC treatment centers in Lithuania. It enrolls GC patients with histologically confirmed PM without prior treatment. The treatment protocol consists of PIPAC with cisplatin (10.5 mg/m2 body surface in 150 mL NaCl 0.9%) and doxorubicin (2.1 mg/m2 in 50 mL NaCl 0.9%) followed by 2 cycles of FOLFOX every 6–7 weeks. In total 3 PIPACs and 6 cycles of FOLFOX will be utilized. The primary outcome of the study is the objective response rate (ORR) according to RECIST v. 1.1 criteria (Eisenhauer et al., Eur J Cancer 45:228–47) in a CT scan performed 7 days after the 4th cycle of FOLFOX. Secondary outcomes include ORR after all experimental treatment, PIPAC characteristics, postoperative morbidity, histological and biochemical response, ascites volume, quality of life, overall survival, and toxicity.

Discussion
This study aims to assess PIPAC and FOLFOX combination efficacy for previously untreated GC patients with PM.

Trial registration
NCT05644249. Registered on December 9, 2022.
Central retinal artery occlusion without cherry-red spots
Authors: Fan Wei , Huang Yanming , Zhao Yuancheng , Yuan Rongdi 
Published: October 2023

Abstract
Background
Cherry-red spots are a very important sign for the clinical diagnosis of central retinal artery occlusion (CRAO). We retrospectively summarized the clinical manifestations of CRAO and analysed the causes and characteristics of CRAO without cherry-red spots. In this study, we explored a diagnostic method for CRAO without cherry red spots.

Methods
Seventy patients (70 eyes) with CRAO were examined retrospectively. Corrected distance visual acuity, fundus photos, FA and OCT images were collected at the first outpatient visit. The causes of CRAO without cherry-red spots were analysed through fundus photos. The incidence of increased hyperreflectivity of the inner retina, central macular thickness (CMT) and arteriovenous transit time in patients with and without cherry-red spots were compared.

Results
Fundus examination showed posterior retinal whitening in 57 cases (81.43%) and cherry-red spots in 39 cases (55.71%). Thirty-one patients presented at the first outpatient visit without cherry-red spots. The reasons for the absence of cherry-red spots included leopard fundus (32.26%), retinal vein occlusion (25.81%), no obvious inner retinal coagulative necrosis (19.35%), ciliary retinal artery sparing (12.90%), high macular oedema (9.68%) and cherry-red spot enlargement (3.23%). OCT revealed increased hyperreflectivity of the inner retina in 67 CRAO patients (95.71%). All 3 patients without increased hyperreflectivity of the inner retina did not present with cherry-red spots at the first visit. The median CMT in patients without cherry-red spots was 166.00 μm, while the median MCT in patients with cherry-red spots was 180.00 μm; there was no significant difference between these two groups (P = 0.467). FA showed delayed arteriovenous transit time > 23 s in 20 patients (28.57%), > 15 s in 43 patients (61.43%) and no delay in 27 patients (30.77%). The median arteriovenous transit time in patients without cherry-red spots was 19.00 s, while it was 18.00 s in patients with cherry-red spots; there was no significant difference between these two groups (P = 0.727).

Conclusions
There are multiple factors that could cause the absence of cherry-red spots in CRAO. The use of OCT to observe increased hyperreflectivity of the inner retina is the most effective imaging method for the early diagnosis of CRAO without cherry-red spots.