bluuebunny/crossref_metadata_2025_split huggingface dataset:
National improvements in resident physician-reported patient safety after limiting first-year resident physicians’ extended duration work shifts: a pooled analysis of prospective cohort studies
Authors: Weaver Matthew D , Landrigan Christopher P , Sullivan Jason P , O'Brien Conor S , Qadri Salim , Viyaran Natalie , Czeisler Charles A , Barger Laura K 
Published: May 2022

BackgroundThe Accreditation Council for Graduate Medical Education (ACGME) enacted a policy in 2011 that restricted first-year resident physicians in the USA to work no more than 16 consecutive hours. This was rescinded in 2017.MethodsWe conducted a nationwide prospective cohort study of resident physicians for 5 academic years (2002–2007) before and for 3 academic years (2014–2017) after implementation of the 16 hours 2011 ACGME work-hour limit. Our analyses compare trends in resident physician-reported medical errors between the two cohorts to evaluate the impact of this policy change.Results14 796 residents provided data describing 78 101 months of direct patient care. After adjustment for potential confounders, the work-hour policy was associated with a 32% reduced risk of resident physician-reported significant medical errors (rate ratio (RR) 0.68; 95% CI 0.64 to 0.72), a 34% reduced risk of reported preventable adverse events (RR 0.66; 95% CI 0.59 to 0.74) and a 63% reduced risk of reported medical errors resulting in patient death (RR 0.37; 95% CI 0.28 to 0.49).ConclusionsThese findings have broad relevance for those who work in and receive care from academic hospitals in the USA. The decision to lift this work hour policy in 2017 may expose patients to preventable harm.
Associated genetic variants and potential pathogenic mechanisms of brain arteriovenous malformation
Authors: Liu Junyu , Li Yifeng , Zhang Hao , Luo Chun , Yuan Dun , Jiang Weixi , Yan Junxia 
Published: May 2022

BackgroundThe pathogenic mechanism of brain arteriovenous malformation (bAVM) is poorly understood. A growing body of evidence indicates that genetic factors play crucial roles in bAVM. This study examined genetic variants associated with bAVM through quantitative synthesis and qualitative description of literature.MethodsFive databases were searched to gather potentially relevant articles published up to January 2022. STATA 14.0 software was used for statistical analyses. Pooled odds ratios and 95% confidence intervals were calculated with random effect models, and heterogeneity was assessed using the Cochran Q test and quantified with the I2test. Sensitivity and publication bias were analyzed to test the robustness of the associations. Variants identified in only one study or with great heterogeneity were not suitable for pooling association analysis, and therefore a qualitative systematic review was performed.ResultsIn total, 30 papers were included in a systematic review involving 4709 cases and 7832 controls, where 17 papers were in a meta-analysis. A suggested association of bAVM was observed withACVRL1rs2071219 in the additive model andCDKN2B-AS1rs1333040 in the recessive and additive models. Other variants of genes that could not be analyzed were summarized by qualitative description. These genes were mostly involved in bone morphogenic protein/transforming growth factor beta (BMP/TGF-β), vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR), and RAS-mitogen activated protein kinase (MAPK) signaling and inflammation.ConclusionsAccording to our meta-analysis,ACVRL1rs2071219 andCDKN2B-AS1rs1333040 were potentially associated with bAVM. Multiple pathological signaling pathways could affect disease development. Future studies should aim to determine the interaction of candidate genes with environmental risk factors and to elucidate detailed mechanisms of action of variants and genes.1
Finite basis problem for Catalan monoids with involution
Authors: Gao Meng , Zhang Wen Ting , Luo Yan Feng 
Published: May 2022

It is known, since the early 2000s, that the Catalan monoid [Formula: see text] generated by [Formula: see text] elements is finitely based if and only if [Formula: see text]. The main goal of this paper is to prove that the involution monoid [Formula: see text] is non-finitely based. Therefore, in contrast, combining with previous results yields that the involution Catalan monoid [Formula: see text] is finitely based if and only if [Formula: see text]. The Kiselman monoid [Formula: see text] generated by [Formula: see text] elements is also considered. Although the semigroups [Formula: see text] and [Formula: see text] have recently been shown to satisfy the same identities, it is unknown if the same result holds when they are considered as involution semigroups. Nevertheless, it is deduced from the main result that the involution Kiselman monoid [Formula: see text] is finitely based if and only if [Formula: see text].
Optimized Systematic Review Tool: Application to Candidate Biomarkers for the Diagnosis of Hepatocellular Carcinoma
Authors: U Mei Ran Abellona , Shen Eric Yi-Liang , Cartlidge Caroline , Alkhatib Alzhraa , Thursz Mark R. , Waked Imam , Gomaa Asmaa I. , Holmes Elaine , Sharma Rohini , Taylor-Robinson Simon D. 
Published: May 2022

AbstractThis review aims to develop an appropriate review tool for systematically collating metabolites that are dysregulated in disease and applies the method to identify novel diagnostic biomarkers for hepatocellular carcinoma (HCC). Studies that analyzed metabolites in blood or urine samples where HCC was compared with comparison groups (healthy, precirrhotic liver disease, cirrhosis) were eligible. Tumor tissue was included to help differentiate primary and secondary biomarkers. Searches were conducted on Medline and EMBASE. A bespoke “risk of bias” tool for metabolomic studies was developed adjusting for analytic quality. Discriminant metabolites for each sample type were ranked using a weighted score accounting for the direction and extent of change and the risk of bias of the reporting publication. A total of 84 eligible studies were included in the review (54 blood, 9 urine, and 15 tissue), with six studying multiple sample types. High-ranking metabolites, based on their weighted score, comprised energy metabolites, bile acids, acylcarnitines, and lysophosphocholines. This new review tool addresses an unmet need for incorporating quality of study design and analysis to overcome the gaps in standardization of reporting of metabolomic data. Validation studies, standardized study designs, and publications meeting minimal reporting standards are crucial for advancing the field beyond exploratory studies.
Safety and Efficacy of Irradiation Boost Based on 18F-FET-PET in Patients with Newly Diagnosed Glioblastoma
Authors: Harat Maciej , Blok Maciej , Miechowicz Izabela , Wiatrowska Izabela , Makarewicz Karolina , Małkowski Bogdan 
Published: May 2022

Abstract

Purpose:
Dual timepoint fluoro-ethyl-tyrosine (FET)-PET acquisition (10 and 60 minutes after FET injection) improves the definition of glioblastoma (GBM) location and shape. Here we evaluated the safety and efficacy of simultaneous integrated boost (SIB) planned using dual FET-PET for postoperative GBM treatment.

Patients and Methods:
In this prospective pilot study (March 2017–December 2020), 17 patients qualified for FET-PET–based SIB intensity-modulated radiotherapy after resection. The prescribed dose was 78 and 60 Gy (2.6 and 2.0 Gy per fraction, respectively) for the FET-PET– and magnetic resonance (MR)-based target volumes. Eleven patients had FET-PET within 9 months to precisely define biological responses. Progression-free survival (PFS), overall survival (OS), toxicities, and radiation necrosis were evaluated. Six patients (35%) had tumors with MGMT promoter methylation.

Results:
The 1- and 2-year OS and PFS rates were 73% and 43% and 53% and 13%, respectively. The median OS and PFS were 24 [95% confidence interval (CI), 9–26] and 12 (95% CI, 6–18) months, respectively. Two patients developed uncontrolled seizures during radiotherapy and could not receive treatment per protocol. In patients treated per protocol, 7 of 15 presented with new or increased neurologic deficits in the first month after irradiation. Radiation necrosis was diagnosed by MRI 3 months after SIB in 5 patients and later in another 2 patients. In 2 patients, the tumor was larger in FET-PET images after 6 months.

Conclusions:
Survival outcomes using our novel dose-escalation concept (total 78 Gy) were promising, even within the MGMT unmethylated subgroup. Excessive neurotoxicity was not observed, but radionecrosis was common and must be considered in future trials.
Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2− ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study
Authors: Cristofanilli Massimo , Rugo Hope S. , Im Seock-Ah , Slamon Dennis J. , Harbeck Nadia , Bondarenko Igor , Masuda Norikazu , Colleoni Marco , DeMichele Angela , Loi Sherene , Iwata Hiroji , O'Leary Ben , André Fabrice , Loibl Sibylle , Bananis Eustratios , Liu Yuan , Huang Xin , Kim Sindy , Lechuga Frean Maria Jose , Turner Nicholas C. 
Published: May 2022

Abstract

Purpose:
To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA).

Patients and Methods:
Patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent.

Results:
At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8–39.9) in the palbociclib group and 28.0 months (23.5–33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65–0.99). The 6-year OS rate (95% CI) was 19.1% (14.9–23.7) and 12.9% (8.0–19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified.

Conclusions:
The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with &gt;6 years of follow-up in patients with HR+/HER2− ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.
Pembrolizumab in Combination with Neoadjuvant Chemoradiotherapy for Patients with Resectable Adenocarcinoma of the Gastroesophageal Junction
Authors: Zhu Mojun , Chen Chunhua , Foster Nathan R. , Hartley Christopher , Mounajjed Taofic , Salomao Marcela A. , Fruth Briant F. , Beamer Staci E. , Kim Yohan , Harrington Susan M. , Pitot Henry C. , Sanhueza Cristobal T. , Feng Yening , Herrmann Joerg , McWilliams Robert R. , Lucien Fabrice , Huang Bing Q. , Ma Wen Wee , Bekaii-Saab Tanios S. , Dong Haidong , Wigle Dennis , Ahn Daniel H. , Hallemeier Chris L. , Blackmon Shanda , Yoon Harry H. 
Published: May 2022

Abstract

Purpose:
This phase Ib/2 trial investigated pembrolizumab-containing trimodality therapy in patients with gastroesophageal junction (GEJ) adenocarcinoma.

Patients and Methods:
Patients with GEJ adenocarcinoma (cT1–3NanyM0) received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab. The primary endpoints were tolerability in the first 16 patients and pathologic complete response [pCR (ypT0N0)]. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). An independent propensity-score-matched cohort (treated with CROSS without immunotherapy) was used for comparison. Exploratory analyses included immune biomarkers in the tumor microenvironment (TME) and plasma.

Results:
We enrolled 31 eligible patients, of whom 29 received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met. The primary efficacy endpoint was not met [7/31 (22.6%) achieved pCR]. Patients with high [i.e., combined positive score (CPS) ≥ 10] baseline expression of programmed death (PD)-L1 in the TME had a significantly higher pCR rate than those with low expression [50.0% (4/8) vs. 13.6% (3/22); P = 0.046]. Patients with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients. Among trial patients with PD-L1 CPS &lt; 10, unprespecified analysis explored whether extracellular vesicles (EV) could identify further responders: an elevated plasma level of PD-L1–expressing EVs was significantly associated with higher pCR.

Conclusions:
Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.
The Interaction of Specific Peptide Aptamers With the DNA Binding Domain and the Dimerization Domain of the Transcription Factor Stat3 Inhibits Transactivation and Induces Apoptosis in Tumor Cells
Authors: Nagel-Wolfrum Kerstin , Buerger Claudia , Wittig Ilka , Butz Karin , Hoppe-Seyler Felix , Groner Bernd 
Published: May 2022

Abstract
The transcription factor signal transducer and activator of transcription (Stat) 3 is activated through the interleukin-6 family of cytokines and by binding of growth factors to the epidermal growth factor (EGF) receptor. It plays an essential role in embryonic development and assumes specialized tasks in many differentiated tissues. Constitutively activated Stat3 has been found in tumor cell lines and primary tumors and plays a crucial role in tumor cell survival and proliferation. To inhibit the oncogenic action of Stat3 in tumor cells, we have selected short peptides, so-called peptide aptamers, which specifically interact with defined functional domains of this transcription factor. The peptide aptamers were selected from a peptide library of high complexity by an adaptation of the yeast two-hybrid procedure. Peptide aptamers specifically interacting with the Stat3 dimerization domain caused inhibition of DNA binding activity and suppression of transactivation by Stat3 in EGF-responsive cells. Similarly, a peptide aptamer selected for its ability to recognize the Stat3 DNA binding domain inhibited DNA binding and transactivation by Stat3 following EGF stimulation of cells. Peptide aptamers were expressed in bacteria as fusion proteins with a protein transduction domain and introduced into human myeloma cells. This resulted in dose-dependent growth inhibition, down-regulation of Bcl-xL expression, and induction of apoptosis. The inhibition of Stat3 functions through the interaction with peptide aptamers counteracts the transformed phenotype and could become useful in targeted tumor therapy.
Cystatin C Antagonizes Transforming Growth Factor β Signaling in Normal and Cancer Cells
Authors: Sokol Jonathan P. , Schiemann William P. 
Published: May 2022

Abstract
Cystatin C (CystC) is a secreted cysteine protease inhibitor that regulates bone resorption, neutrophil chemotaxis, and tissue inflammation, as well as resistance to bacterial and viral infections. CystC is ubiquitously expressed and present in most bodily fluids where it inhibits the activities of cathepsins, a family of cysteine proteases that can promote cancer cell invasion and metastasis. Transforming growth factor β (TGF-β) is a multifunctional cytokine endowed with both tumor-suppressing and tumor-promoting activities. We show herein that TGF-β treatment up-regulated CystC transcript and protein in murine 3T3-L1 fibroblasts. Moreover, CystC mRNA expression was down-regulated in ∼50% of human malignancies, particularly cancers of the stomach, uterus, colon, and kidney. Overexpression of CystC in human HT1080 fibrosarcoma cells antagonized their invasion through synthetic basement membranes in part via a cathepsin-dependent pathway. Independent of effects on cathepsin activity, CystC also reduced HT1080 cell gene expression stimulated by TGF-β. Invasion of 3T3-L1 cells occurred through both cathepsin- and TGF-β-dependent pathways. Both pathways were blocked by CystC, but only the TGF-β-dependent pathway was blocked by a CystC mutant (i.e., Δ14CystC) that is impaired in its ability to inhibit cathepsin activity. Moreover, CystC and Δ14CystC both inhibited 3T3-L1 cell gene expression stimulated by TGF-β. We further show that CystC antagonized TGF-β binding to its cell surface receptors, doing so by interacting physically with the TGF-β type II receptor and antagonizing its binding of TGF-β. Collectively, our findings have identified CystC as a novel TGF-β receptor antagonist, as well as a novel CystC-mediated feedback loop that inhibits TGF-β signaling.
Constitutive and DNA Damage Inducible Activation of pig3 and MDM2 Genes by Tumor-Derived p53 Mutant C277Y
Authors: Pospı́šilová Šárka , Siligan Christine , Ban Jozet , Jug Gunhild , Kovar Heinrich 
Published: May 2022

Abstract
The p53 gene is compromised in most human cancers by point mutation. Evidence is accumulating that these alterations frequently do not result in a complete loss of the sequence-specific transcriptional regulatory function of p53. Here, we describe the transcriptional activity of the p53 mutant C277Y isolated from a Ewing's sarcoma with high constitutive pig3 expression. Transient transfection of this mutant into a p53 null cell line resulted in activation not only of the pig3 but also of the MDM2 gene compatible with the presence of constitutively expressed MDM2 transcripts initiated from the P2 promoter in the p53-C277Y hemizygous Ewing's sarcoma cell line. Expression of endogenous pig3 and MDM2 genes was further enhanced on irradiation of this cell line. Here, suppression of p53-C277Y by RNAi reduced pig3 promoter activity, RNA, and protein expression. Reporter gene assays revealed that the potential of p53-C277Y to up-regulate MDM2 expression was similar to wild-type p53, whereas activation of the pig3 promoter was at least 5-fold increased over wild-type p53. The pentanucleotide microsatellite sequence present in exon 1 of the pig3 gene was found to be responsible for p53-C277Y-mediated activation. In concordance with a role of PIG3 protein for cell death, we showed residual apoptotic activity of p53-C277Y to which the described Ewing's sarcoma cell line was found to be resistant. p53-C277Y has previously been reported to bind to DNA with altered sequence specificity and to be unable to activate generic p53 target genes in yeast-based functional assays. Our results, therefore, show that a p53 mutant may behave differently when tested in its authentic cellular context.
Molecular Cloning and Characterization of the Catalytic Domain of Zebrafish Homologue of the Ataxia-Telangiectasia Mutated Gene
Authors: Garg Renu , Geng Chuan-Dong , Miller Jennifer L. , Callens Shannon , Tang Xi , Appel Bruce , Xu Bo 
Published: May 2022

Abstract
Inherited biallelic mutations of the ATM (ataxia-telangiectasia mutated) gene in humans cause ataxia-telangiectasia, a rare autosomal recessive disorder associated with progressive neuro-degeneration, cancer predisposition, immunodeficiency, and hypersensitivity to ionizing radiation. The ATM gene is highly conserved across a wide range of species. In an attempt to establish a zebrafish (Danio rerio) model of ataxia-telangiectasia, we cloned the coding sequence of the catalytic domain of the zebrafish homologue of ATM and found it to contain an open reading frame encoding 907 amino acids at the carboxyl terminus of the zebrafish ATM (zATM). The catalytic domain of zATM shares 67% and 66% homology with human ATM (hATM) and mouse ATM (mATM), respectively. The full-length mRNA encoding zATM is found to be approximately 11 kb by Northern hybridization, and the expression of zATM is observed in different adult and embryonic tissues. Overexpression of a kinase-inactive zATM domain in human cells has a dominant-negative effect against hATM function. Expression of the altered zATM in ZF4 cells leads to an A-T–like phenotype in response to ionizing radiation. These results taken together indicate that zATM is the homologue of hATM. Furthermore, using the kinase-inactive form of zATM should allow manipulation of zATM function in fish cells.
Nucleoside Diphosphate Kinase A/nm23-H1 Promotes Metastasis of NB69-Derived Human Neuroblastoma
Authors: Almgren Malin A.E. , Henriksson K. Cecilia E. , Fujimoto Jennifer , Chang Christina L. 
Published: May 2022

Abstract
Nucleoside diphosphate kinase A (NDPK-A), encoded by the nm23-H1 gene, acts as a metastasis suppressor in certain human tumors such as breast carcinoma. However, evidence also points to NDPK-A functioning as a metastasis promoter in other human tumors including neuroblastoma. In fact, amplification and overexpression of nm23-H1 as well as S120G mutation of NDPK-A (NDPK-AS120G) have been detected in 14% to 30% of patients with advanced stages of neuroblastoma. To test whether NDPK-A promotes neuroblastoma metastasis, we established stable transfectants and an orthotopic xenograft animal model from the human neuroblastoma NB69 cell line. We demonstrate that overexpressed NDPK-A or NDPK-AS120G increased both incidence and colonization of neuroblastoma metastasis in animal lungs without significantly affecting primary tumor development. In vitro, these metastasis-associated NDPK-A aberrations abrogated retinoic acid-induced neuronal differentiation while increasing cloning efficiency, cell survival, and colony formation of NB69 derivatives. Furthermore, NDPK-AS120G reduced cell adhesion and increased cell migration. Compared with its wild-type, NDPK-AS120G appears more effective in promoting neuroblastoma metastasis. Our results provide the first evidence that NDPK-A behaves as a metastasis promoter at least in human neuroblastoma derived from NB69 cells. The findings not only suggest a prognostic value of NDPK-A in neuroblastoma patients but also caution NDPK-A-targeted treatment for patients with different tumor types.