bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteogenomic characterization of cholangiocarcinoma
Authors: Deng Mengjie , Ran Peng , Chen Lingli , Wang Yunzhi , Yu Zixiang , Cai Ke , Feng Jinwen , Qin Zhaoyu , Yin Yanan , Tan Subei , Liu Yang , Xu Chen , Shi Guoming , Ji Yuan , Zhao Jian‐Yuan , Zhou Jian , Fan Jia , Hou Yingyong , Ding Chen 
Published: June 2022

Background and Aims:
Cholangiocarcinoma (CCA) is a highly heterogeneous cancer with limited understanding and few effective therapeutic approaches. We aimed at providing a proteogenomic CCA characterization to inform biological processes and treatment vulnerabilities.

Approach and Results:
Integrative genomic analysis with functional validation uncovered biological perturbations downstream of driver events including DPCR1, RBM47 mutations, SH3BGRL2 copy number alterations, and FGFR2 fusions in CCA. Proteomic clustering identified three subtypes with distinct clinical outcomes, molecular features, and potential therapeutics. Phosphoproteomics characterized targetable kinases in CCA, suggesting strategies for effective treatment with CDK and MAPK inhibitors. Patients with CCA with HBV infection showed increased antigen processing and presentation (APC) and T cell infiltration, conferring a favorable prognosis compared with those without HBV infection. The characterization of extrahepatic CCA recommended the feasible application of vascular endothelial‐derived growth factor inhibitors. Multiomics profiling presented distinctive molecular characteristics of the large bile duct and the small bile duct of intrahepatic CCA. The immune landscape further revealed diverse tumor immune microenvironments, suggesting immune subtypes C1 and C5 might benefit from immune checkpoint therapy. TCN1 was identified as a potential CCA prognostic biomarker, promoting cell growth by enhancing vitamin B12 metabolism.

Conclusions:
We characterized the proteogenomic landscape of 217 CCAs with 197 paired normal adjacent tissues and identified their subtypes and potential therapeutic targets. The multiomics analyses with other databases and some functional validations have indicated strategies regarding the clinical, biological, and therapeutic approaches to the management of CCA.
Neuroplastic changes inc‐Fos,ΔFosB,BDNF,trkB, and Arc expression in the hippocampus of male Roman rats: differential effects of sexual activity
Authors: Sanna Fabrizio , Serra Maria Pina , Boi Marianna , Bratzu Jessica , Poddighe Laura , Sanna Francesco , Carta Antonella , Corda Maria Giuseppa , Giorgi Osvaldo , Melis Maria Rosaria , Argiolas Antonio , Quartu Marina 
Published: June 2022

AbstractSexual activity causes differential changes in the expression of markers of neural activation (c‐Fos and ΔFosB) and neural plasticity (Arc and BDNF/trkB), as determined either by Western Blot (BDNF, trkB, Arc, and ΔFosB) or immunohistochemistry (BDNF, trkB, Arc, and c‐Fos), in the hippocampus of male Roman high (RHA) and low avoidance (RLA) rats, two psychogenetically selected rat lines that display marked differences in sexual behavior (RHA rats exhibit higher sexual motivation and better copulatory performance than RLA rats). Both methods showed (with some differences) that sexual activity modifies the expression levels of these markers in the hippocampus of Roman rats depending on: (i) the level of sexual experience, that is, changes were usually more evident in sexually naïve than in experienced rats; (ii) the hippocampal partition, that is, BDNF and Arc increased in the dorsal but tended to decrease in the ventral hippocampus; (iii) the marker considered, that is, in sexually experienced animals BDNF, c‐Fos, and Arc levels were similar to those of controls, while ΔFosB levels increased; and (iv) the rat line, that is, changes were usually larger in RHA than RLA rats. These findings resemble those of early studies in RHA and RLA rats showing that sexual activity influences the expression of these markers in the nucleus accumbens, medial prefrontal cortex, and ventral tegmental area, and show for the first time that also in the hippocampus sexual activity induces neural activation and plasticity, events that occur mainly during the first phase of the acquisition of sexual experience and depend on the genotypic/phenotypic characteristics of the animals.
Long‐term survival of nonlocalized epithelial ovarian cancer among women using menopausal hormone therapy prior to diagnosis: The extreme study
Authors: Baandrup Louise , Galanakis Michael , Hannibal Charlotte G. , Dehlendorff Christian , Hertzum‐Larsen Rasmus , Mørch Lina S. , Kjaer Susanne K. 
Published: June 2022

AbstractPrediagnostic use of menopausal hormone therapy (MHT) has been suggested to be associated with improved survival of epithelial ovarian cancer (EOC). We investigated the potential long‐term survival benefit of prediagnostic MHT use in women ≥50 years with nonlocalized EOC using the Extreme study including all women in Denmark registered with nonlocalized EOC during 2000 to 2014 (N = 3776). We obtained individual‐level information on prediagnostic use of systemic estrogen therapy (ET) and estrogen plus progestin therapy (EPT) from the National Prescription Registry and estimated absolute and relative 5‐ and 10‐year survival probabilities with 95% confidence intervals (CIs) using pseudo‐values, taking into account histology, comorbidity, income and residual disease. Among women not having used prediagnostic MHT, 5‐ and 10‐year absolute survival probabilities were 19% and 11%, respectively. Compared to MHT nonusers, prediagnostic systemic ET use for 3 to 4 years and ≥ 5 years was associated with 1.43 (95% CI: 1.01‐2.02) and 1.22 (95% CI: 0.96‐1.55) times higher 5‐year survival probabilities, respectively. Ten‐year survival probabilities were also increased but not statistically significantly. Among prediagnostic EPT users, increased 5‐year (1.14, 95% CI: 0.85‐1.53) and 10‐year (1.38, 95% CI: 0.91‐2.08) survival probabilities were observed after use for 3 to 4 years compared to MHT nonuse, whereas EPT use for ≥5 years was not associated with long‐term survival of nonlocalized EOC. Our findings may suggest a better long‐term survival of nonlocalized EOC in women having used long‐term prediagnostic ET. However, the statistical precision of our results did not allow firm conclusions and more studies are needed.
Adherence to a healthy lifestyle in relation to colorectal cancer incidence and all‐cause mortality after endoscopic polypectomy: A prospective study in three U.S. cohorts
Authors: Wang Liang , Knudsen Markus D. , Lo Chun‐Han , Wang Kai , He Mingming , Polychronidis Georgios , Hang Dong , He Xiaosheng , Zhong Rong , Wu Kana , Chan Andrew T. , Ogino Shuji , Giovannucci Edward L. , Song Mingyang 
Published: June 2022

AbstractIt remains unknown whether maintenance of a healthy lifestyle after endoscopic polypectomy could still confer benefit for colorectal cancer (CRC) incidence and mortality. In this study, we defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption and diet (range, 0‐5). We used Cox proportional hazards regression to estimate the hazard ratios (HRs) for the associations of healthy lifestyle score and individual lifestyle factors with CRC incidence and all‐cause mortality. During a median of 10 years of follow‐up of 24 668 participants who underwent endoscopic polypectomy, we documented 161 CRC cases and 4857 all‐cause deaths. A higher healthy lifestyle score after endoscopic polypectomy was associated with lower risk of CRC and all‐cause mortality. Compared with individuals with 0 to 1 healthy lifestyle factors, those with 2, 3 and 4 to 5 healthy lifestyle factors had a HR for CRC risk of 0.86 (95% confidence interval [CI], 0.60‐1.24), 0.73 (95% CI, 0.47‐1.14) and 0.52 (95% CI, 0.27‐1.01), respectively (Ptrend = .03). The corresponding HR (95% CI) for all‐cause mortality was 0.83 (95% CI, 0.76‐0.90), 0.63 (95% CI, 0.56‐0.70) and 0.56 (95% CI, 0.48‐0.65), respectively (Ptrend < .0001). In the joint analysis of pre‐ and postpolypectomy periods, patients with a healthy postpolypectomy lifestyle had a lower incidence of CRC regardless of their prepolypectomy exposure, whereas those with a healthy lifestyle in both periods had a lower mortality than those with an unhealthy lifestyle in either period. In conclusion, adherence to a healthy lifestyle after polypectomy may confer significant benefit for CRC prevention and reduction in all‐cause mortality.
Improving identification of symptomatic cancer at primary care clinics: A predictive modeling analysis in Botswana
Authors: Molebatsi Kesaobaka , Iyer Hari S. , Kohler Racquel E. , Gabegwe Kemiso , Nkele Isaac , Rabasha Bokang , Botebele Kerapetse , Barak Tomer , Balosang Siamisang , Tapela Neo M. , Dryden‐Peterson Scott L. 
Published: June 2022

AbstractIn resource‐limited settings, augmenting primary care provider (PCP)‐based referrals with data‐derived algorithms could direct scarce resources towards those patients most likely to have a cancer diagnosis and benefit from early treatment. Using data from Botswana, we compared accuracy of predictions of probable cancer using different approaches for identifying symptomatic cancer at primary clinics. We followed cancer suspects until they entered specialized care for cancer treatment (following pathologically confirmed diagnosis), exited from the study following noncancer diagnosis, or died. Routine symptom and demographic data included baseline cancer probability assessed by the primary care provider (low, intermediate, high), age, sex, performance status, baseline cancer probability by study physician, predominant symptom (lump, bleeding, pain or other) and HIV status. Logistic regression with 10‐fold cross‐validation was used to evaluate classification by different sets of predictors: (1) PCPs, (2) Algorithm‐only, (3) External specialist physician review and (4) Primary clinician augmented by algorithm. Classification accuracy was assessed using c‐statistics, sensitivity and specificity. Six hundred and twenty‐three adult cancer suspects with complete data were retained, of whom 166 (27%) were diagnosed with cancer. Models using PCP augmented by algorithm (c‐statistic: 77.2%, 95% CI: 73.4%, 81.0%) and external study physician assessment (77.6%, 95% CI: 73.6%, 81.7%) performed better than algorithm‐only (74.9%, 95% CI: 71.0%, 78.9%) and PCP initial assessment (62.8%, 95% CI: 57.9%, 67.7%) in correctly classifying suspected cancer patients. Sensitivity and specificity statistics from models combining PCP classifications and routine data were comparable to physicians, suggesting that incorporating data‐driven algorithms into referral systems could improve efficiency.
Eventual success rate and predictors of success for oncology drugs tested in phase I trials
Authors: Haslam Alyson , Olivier Timothée , Powell Kerrington , Tuia Jordan , Prasad Vinay 
Published: June 2022

AbstractPrevious estimates of the likelihood of a drug tested in phase I trials obtaining FDA clearance are out of date. In the intervening years, newer pharmaceuticals have been developed, resulting in new delivery systems and lines of therapies. We sought to explore and update these estimates by comprehensively searching drugs tested in phase I trials and to determine the factors associated with later receiving FDA approval. In a cross‐sectional analysis, we searched for anti‐tumor drugs tested in phase I trials and published in scientific journals or presented at hematology/oncology conferences. For each drug, we searched PubMed for phase II and phase III studies testing the drug for the same indication tested in phase I studies. We found 51 drug approvals; four were withdrawn. The probability of a drug tested in 2015 being approved by 2021 was 6.2%. Drugs tested as monotherapy were more likely to receive approval than drugs tested in combination, and monoclonal antibodies were more likely to receive approval than drugs of other mechanisms. In adjusted models, response rates higher than 40% in phase I studies, demonstrating an improvement in overall survival (OS) in phase III studies, and drugs tested as monotherapy were associated with receiving FDA approval. When looking at all drugs tested during a single year, most drugs were not approved, and among those that are approved, almost 8% are withdrawn. Response rates higher than 40%, testing a drug as monotherapy, and demonstrating an improvement in OS were associated with receiving FDA approval.
A modified contrast source inversion method for microwave tomographic imaging of Debye dispersive media
Authors: Liu Guangdong , Zhang Kaiyin 
Published: June 2022

AbstractThe Debye empirical formulas are often used for the description of the dispersion characteristics of common media, such as biological tissues, water, and soil. In order to reconstruct their frequency‐related electrical properties, a multi‐frequency contrast source inversion (CSI) method is modified from the direct estimation of the contrast between Debye scatterers and background medium, into the reconstruction of three kinds of Debye model parameters, namely, the optical relative permittivity, relative permittivity difference, and static conductivity. Through three two‐dimensional (2D) benchmark numerical experiments, detailed comparisons between the results by the improved CSI method, and those by the frequency hopping (FH) technique, single frequency subspace‐based optimization method (SOM) with deep learning (DL), multi frequency (MF) dispersive SOM, and time‐domain inverse scattering (TDIS) approach, show preliminarily that the modified CSI (M‐CSI) method is feasible and robust, and that it exhibits acceptable compromise performance by the comprehensive consideration of convergence characteristics, positioning accuracy, reconstruction errors, and computational efficiency. Also, the M‐CSI method has been successfully applied to quantitatively reconstruct the internal breast composition in a 2D cancerous phantom extracted from a realistic numerical breast, dielectrically and anatomically.
Engineering extracellular vesicles by three‐dimensional dynamic culture of human mesenchymal stem cells
Authors: Yuan Xuegang , Sun Li , Jeske Richard , Nkosi Dingani , York Sara B. , Liu Yuan , Grant Samuel C. , Meckes David G. , Li Yan 
Published: June 2022

AbstractHuman mesenchymal stem cell (hMSC) derived extracellular vesicles (EVs) have shown therapeutic potential in recent studies. However, the corresponding therapeutic components are largely unknown, and scale‐up production of hMSC EVs is a major challenge for translational applications. In the current study, hMSCs were grown as 3D aggregates under wave motion to promote EV secretion. Results demonstrate that 3D hMSC aggregates promote activation of the endosomal sorting complexes required for transport (ESCRT)‐dependent and ‐independent pathways. mRNA sequencing revealed global transcriptome alterations for 3D hMSC aggregates. Compared to 2D‐hMSC‐EVs, the quantity of 3D‐hMSC‐EVs was enhanced significantly (by 2‐fold), with smaller sizes, higher miR‐21 and miR‐22 expression, and an altered protein cargo (e.g., upregulation of cytokines and anti‐inflammatory factors) uncovered by proteomics analysis, possibly due to altered EV biogenesis. Functionally, 3D‐hMSC‐EVs rejuvenated senescent stem cells and exhibited enhanced immunomodulatory potentials. In summary, this study provides a promising strategy for scalable production of high‐quality EVs from hMSCs with enhanced therapeutic potential.
International multidisciplinary survey on the initial management of acute pancreatitis: Perspective of point‐of‐care specialists focused on daily practice
Authors: Lluís Nuria , Asbun Horacio , Besselink Marc G. , Capurso Gabriele , Garg Pramod Kumar , Gelrud Andres , Khannoussi Wafaa , Lee Hong Sik , Leppäniemi Ari , Löhr Johannes‐Matthias , Mahapatra Soumya Jagannath , Mancilla Carla , van Santvoort Hjalmar C , Zapater Pedro , Lluís Felix , de Madaria Enrique , Ramia José Manuel 
Published: June 2022

AbstractBackgroundThe initial management of patients with acute pancreatitis impacts both morbidity and mortality. Point‐of‐care decisions have been reported to differ from clinical guideline recommendations.MethodsAn online anonymous questionnaire was distributed through scientific associations and social media using REDCap. Multivariable logistic regression was used to identify the characteristics of participants associated with compliance with the recommendations.ResultsA total of 1054 participants from 94 countries completed the questionnaire; median age (IQR) was 39 (32–47) years; 30.7% were women. Among the participants, 37% opted for nonmoderate flow of i.v. fluid, 31% for fluid type other than Ringer’s lactate; 73.4% were in favor of nil per os to patients who could eat, 75.5% for other than enteral feeding to patients with oral intolerance; 15.5% used prophylactic antibiotic in patients with severe acute pancreatitis, 34.1% in necrotizing acute pancreatitis, and 27.4% in patients with systemic inflammatory response syndrome; 27.8% delayed cholecystectomy after biliary acute pancreatitis. Participants with publications in PubMed on acute pancreatitis showed better compliance (OR, 1.62; 95% CI: 1.15–2.32; P = .007) with recommendations of the clinical guidelines.ConclusionsFeeding and nutrition require the greatest improvement efforts, but also the use of prophylactic antibiotics and timing of cholecystectomy should be improved.
ALG8‐CDG: Molecular and phenotypic expansion suggests clinical management guidelines
Authors: Albokhari Daniah , Ng Bobby G. , Guberinic Alis , Daniel Earnest James Paul , Engelhardt Nicole M. , Barone Rita , Fiumara Agata , Garavelli Livia , Trimarchi Gabriele , Wolfe Lynne , Raymond Kimiyo M. , Morava Eva , He Miao , Freeze Hudson H. , Lam Christina , Edmondson Andrew C. 
Published: June 2022

AbstractCongenital disorders of glycosylation are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid glycan biosynthesis. These disorders mostly manifest with multisystem involvement. Individuals with ALG8‐CDG commonly present with hypotonia, protein‐losing enteropathy, and hepatic involvement. Here, we describe seven unreported individuals diagnosed with ALG8‐CDG based on biochemical and molecular testing and we identify nine novel variants in ALG8, bringing the total to 26 individuals with ALG8‐CDG in the medical literature. In addition to the typical multisystem involvement documented in ALG8‐CDG, our cohort includes the two oldest patients reported and further expands the phenotype of ALG8‐CDG to include stable intellectual disability, autism spectrum disorder and other neuropsychiatric symptoms. We further expand the clinical features in a variety of organ systems including ocular, musculoskeletal, dermatologic, endocrine, and cardiac abnormalities and suggest a comprehensive evaluation and monitoring strategy to improve clinical management.
Effect of Obesity on Left Ventricular Remodeling and Clinical Outcome in Chinese Patients With Hypertrophic Cardiomyopathy: Assessed by Cardiac MRI
Authors: Shi Ke , Huang Shan , Li Xiang , Xu Hua‐Yan , Yang Meng‐Xi , Li Yuan , Guo Ying‐Kun , Yang Zhi‐Gang 
Published: June 2022

BackgroundObesity is highly prevalent in patients with hypertrophic cardiomyopathy (HCM) and believed to influence its phenotype.PurposeTo explore the effects of obesity on left ventricular (LV) remodeling and long‐term clinical course in Chinese patients with HCM.Study TypeLongitudinal.PopulationA total of 247 patients with HCM classified according to body mass index (BMI) (normal weight: BMI = 18.0–22.9 kg/m2 [N = 90]; overweight: BMI = 23.0–24.9 kg/m2 [N = 58]; and obese: BMI ≥ 25 kg/m2 [N = 99]).Field Strength/Sequence3.0 T/Balanced steady‐state free precession sequence and phase‐sensitive inversion recovery late gadolinium enhancement (LGE) sequence.AssessmentLV function and geometry were measured. LV peak strain analysis was performed. The presence and percentage of LGE in the LV were recorded. The endpoints including heart failure, sudden cardiac death, and overall composite outcome were assessed during a median follow‐up of 4.1 years (interquartile range, 3.0–6.2 years).Statistical TestsOne‐way analysis of variance, Kruskal–Wallis test, or chi‐square test; Pearson correlation coefficient (r); multivariable linear regression analysis; Kaplan–Meier survival analysis; and Cox proportional hazards model analysis were conducted. A two‐tailed P‐value < 0.05 was considered statistically significant.ResultsObese patients exhibited a significant progressive increase in LV mass compared with normal‐weight patients. The magnitude of all LV strain indices gradually and significantly decreased as BMI increased, whereas LV ejection fraction was not significantly different among BMI groups (P = 0.364). Multivariable linear regression analysis showed that obesity had a significant association with impaired strain indices as well as with indexed LV mass. Multivariable Cox model analysis retained obesity as an independent marker for future endpoints, and conveyed a > 3‐fold increase in risk compared with patients with normal weight (hazard ratio, 3.04; 95% confidence interval, 1.07–6.57).Data ConclusionObesity is an important environmental modifier that is associated with adverse LV remodeling and is independently associated with future clinical outcomes in Chinese patients with HCM.Level of Evidence3Technical EfficacyStage 2
Correcting rotational error in rectal cancer radiation therapy: Can planning target volume margins be safely reduced?
Authors: Seah Vivian , Dundas Kylie , Hudson Felicity , Surjan Yolanda , Bartlett Rebecca , Ko Rebecca , Smith Sandie , Arumugam Sankar , Johnston Meredith , Wong Karen , Lee Mark 
Published: June 2022

AbstractIntroductionThe magnitude and impact of rotational error is unclear in rectal cancer radiation therapy. This study evaluates rotational errors in rectal cancer patients, and investigates the feasibility of planning target volume (PTV) margin reduction to decrease organs at risk (OAR) irradiation.MethodsIn this study, 10 patients with rectal cancer were retrospectively selected. Rotational errors were assessed through image registration of daily cone beam computed tomography (CBCT) and planning CT scans. Two reference treatment plans (TPR) with PTV margins of 5 mm and 10 mm were generated for each patient. Pre‐determined rotational errors (±1°, ±3°, ±5°) were simulated to produce six manipulated treatment plans (TPM) from each TPR. Differences in evaluated dose‐volume metrics between TPR and TPM of each rotation were compared using Wilcoxon Signed‐Rank Test. Clinical compliance was investigated for statistically significant dose‐volume metrics.ResultsMean rotational errors in pitch, roll and yaw were −0.72 ± 1.81°, −0.04 ± 1.36° and 0.38 ± 0.96° respectively. Pitch resulted in the largest potential circumferential displacement of clinical target volume (CTV) at 1.42 ± 1.06 mm. Pre‐determined rotational errors resulted in statistically significant differences in CTV, small bowel, femoral heads and iliac crests (P < 0.05). Only small bowel and iliac crests failed clinical compliance, with majority in the PTV 10 mm margin group.ConclusionRotational errors affected clinical compliance for OAR dose but exerted minimal impact on CTV coverage even with reduced PTV margins. Both PTV margin reduction and rotational correction decreased irradiated volume of OAR. PTV margin reduction to 5 mm is feasible, and rotational corrections are recommended in rectal patients to further minimise OAR irradiation.