bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic variability of T cell responses in hypersensitivity pneumonitis identified using the BXD genetic reference panel
Authors: Wang Jin , Yoon Tae Won , Read Robert , Yi Ae-Kyung , Williams Robert W. , Fitzpatrick Elizabeth A.
Published: January 2020

Hypersensitivity pneumonitis (HP) is an interstitial lung disease that may progress to fibrosis and significant risk of death. HP develops following repeated exposures to inhaled environmental antigens; however, only a fraction of the exposed population develops the disease, suggesting that host genetics contribute to disease susceptibility. We used the BXD family of mice with the Saccharopolyspora rectivirgula (SR) model of HP to investigate the role of genetics in susceptibility to HP. The BXD family is derived from a B6 mother and a D2 father and has been used to map susceptibility loci to numerous diseases. B6, D2, and BXD progeny strains were exposed to SR for 3 wk, and the development of HP was monitored. The B6 and D2 strains developed alveolitis; however, the cellular composition was neutrophilic in the D2 strain and more lymphocytic in the B6 strain. Hematoxylin-eosin staining of lung sections revealed lymphoid aggregates in B6 lungs, whereas D2 lungs exhibited a neutrophilic infiltration. Twenty-eight BXD strains of mice were tested, and the results reveal significant heritable variation for numbers of CD4+or CD8+T cells in the air spaces. There was significant genetic variability for lymphoid aggregates and alveolar wall thickening. We mapped a significant quantitative trait locus (QTL) on chromosome 18 for CD8+CD69+T cells that includes cadherin 2 ( Cdh2), an excellent candidate gene associated with epithelial-mesenchymal transition, which is upregulated in lungs of strains with HP. These results demonstrate that the BXD family is a valuable and translationally relevant model to identify genes contributing to HP and to devise early and effective interventions.
Responses of neurons in the rostral ventrolateral medulla of conscious cats to anticipated and passive movements
Authors: Miller Derek M. , Joshi Asmita , Kambouroglos Emmanuel T. , Engstrom Isaiah C. , Bielanin John P. , Wittman Samuel R. , McCall Andrew A. , Barman Susan M. , Yates Bill J.
Published: January 2020

The vestibular system contributes to regulating sympathetic nerve activity and blood pressure. Initial studies in decerebrate animals showed that neurons in the rostral ventrolateral medulla (RVLM) respond to small-amplitude (<10°) rotations of the body, as in other brain areas that process vestibular signals, although such movements do not affect blood distribution in the body. However, a subsequent experiment in conscious animals showed that few RVLM neurons respond to small-amplitude movements. This study tested the hypothesis that RVLM neurons in conscious animals respond to signals from the vestibular otolith organs elicited by large-amplitude static tilts. The activity of approximately one-third of RVLM neurons whose firing rate was related to the cardiac cycle, and thus likely received baroreceptor inputs, was modulated by vestibular inputs elicited by 40° head-up tilts in conscious cats, but not during 10° sinusoidal rotations in the pitch plane that affected the activity of neurons in brain regions providing inputs to the RVLM. These data suggest the existence of brain circuitry that suppresses vestibular influences on the activity of RVLM neurons and the sympathetic nervous system unless these inputs are physiologically warranted. We also determined that RVLM neurons failed to respond to a light cue signaling the movement, suggesting that feedforward cardiovascular responses do not occur before passive movements that require cardiovascular adjustments.
Fetal storage of osmotically inactive sodium
Authors: Segar Jeffrey L. , Grobe Connie C. , Grobe Justin L.
Published: January 2020

Work in adult humans and animals suggest sodium (Na) is stored in tissue reservoirs without commensurate water retention. These stores may protect from water loss, regulate immune function, and participate in blood pressure regulation. A role for such stores early in life, during which total body Na sufficiency is vital for optimal growth, has not been explored. Using data from previously published literature, we calculated total body stores of Na, potassium (K), and chloride (Cl) during fetal development (24–40 wk gestation) using two methods 1) based on the distribution of body water mass within extracellular and intracellular compartments, and 2) reported total mineral content. Based on differences between the models, we argue that Na, and to a lesser extent Cl, but not K, are stored in osmotically inactive pools within the fetus that increase with advancing gestational age. Because human breastmilk is relatively Na deficient, we speculate the fetal osmotically inactive Na pool is vital for providing a sufficient total body Na content that supports optimal postnatal growth.
Frequency-dependent integration of auditory and vestibular cues for self-motion perception
Authors: Shayman Corey S. , Peterka Robert J. , Gallun Frederick J. , Oh Yonghee , Chang Nai-Yuan N. , Hullar Timothy E.
Published: January 2020

Recent evidence has shown that auditory information may be used to improve postural stability, spatial orientation, navigation, and gait, suggesting an auditory component of self-motion perception. To determine how auditory and other sensory cues integrate for self-motion perception, we measured motion perception during yaw rotations of the body and the auditory environment. Psychophysical thresholds in humans were measured over a range of frequencies (0.1–1.0 Hz) during self-rotation without spatial auditory stimuli, rotation of a sound source around a stationary listener, and self-rotation in the presence of an earth-fixed sound source. Unisensory perceptual thresholds and the combined multisensory thresholds were found to be frequency dependent. Auditory thresholds were better at lower frequencies, and vestibular thresholds were better at higher frequencies. Expressed in terms of peak angular velocity, multisensory vestibular and auditory thresholds ranged from 0.39°/s at 0.1 Hz to 0.95°/s at 1.0 Hz and were significantly better over low frequencies than either the auditory-only (0.54°/s to 2.42°/s at 0.1 and 1.0 Hz, respectively) or vestibular-only (2.00°/s to 0.75°/s at 0.1 and 1.0 Hz, respectively) unisensory conditions. Monaurally presented auditory cues were less effective than binaural cues in lowering multisensory thresholds. Frequency-independent thresholds were derived, assuming that vestibular thresholds depended on a weighted combination of velocity and acceleration cues, whereas auditory thresholds depended on displacement and velocity cues. These results elucidate fundamental mechanisms for the contribution of audition to balance and help explain previous findings, indicating its significance in tasks requiring self-orientation.

NEW & NOTEWORTHY Auditory information can be integrated with visual, proprioceptive, and vestibular signals to improve balance, orientation, and gait, but this process is poorly understood. Here, we show that auditory cues significantly improve sensitivity to self-motion perception below 0.5 Hz, whereas vestibular cues contribute more at higher frequencies. Motion thresholds are determined by a weighted combination of displacement, velocity, and acceleration information. These findings may help understand and treat imbalance, particularly in people with sensory deficits.
Encoding of eye movements explains reward-related activity in cerebellar simple spikes
Authors: Lixenberg Adi , Yarkoni Merav , Botschko Yehudit , Joshua Mati
Published: January 2020

The cerebellum exhibits both motor and reward-related signals. However, it remains unclear whether reward is processed independently from the motor command or might reflect the motor consequences of the reward drive. To test how reward-related signals interact with sensorimotor processing in the cerebellum, we recorded Purkinje cell simple spike activity in the cerebellar floccular complex while monkeys were engaged in smooth pursuit eye movement tasks. The color of the target signaled the size of the reward the monkeys would receive at the end of the target motion. When the tracking task presented a single target, both pursuit and neural activity were only slightly modulated by the reward size. The reward modulations in single cells were rarely large enough to be detected. These modulations were only significant in the population analysis when we averaged across many neurons. In two-target tasks where the monkey learned to select based on the size of the reward outcome, both behavior and neural activity adapted rapidly. In both the single- and two-target tasks, the size of the reward-related modulation matched the size of the effect of reward on behavior. Thus, unlike cortical activity in eye movement structures, the reward-related signals could not be dissociated from the motor command. These results suggest that reward information is integrated with the eye movement command upstream of the Purkinje cells in the floccular complex. Thus reward-related modulations of the simple spikes are akin to modulations found in motor behavior and not to the central processing of the reward value.

NEW & NOTEWORTHY Disentangling sensorimotor and reward signals is only possible if these signals do not completely overlap. We recorded activity in the floccular complex of the cerebellum while monkeys performed tasks designed to separate representations of reward from those of movement. Activity modulation by reward could be accounted for by the coding of eye movement parameters, suggesting that reward information is already integrated into motor commands upstream of the floccular complex.
Increased Tumor Penetration of Single-Domain Antibody–Drug Conjugates Improves In Vivo Efficacy in Prostate Cancer Models
Authors: Nessler Ian , Khera Eshita , Vance Steven , Kopp Anna , Qiu Qifeng , Keating Thomas A. , Abu-Yousif Adnan O. , Sandal Thomas , Legg James , Thompson Lorraine , Goodwin Normann , Thurber Greg M.
Published: January 2020

Targeted delivery of chemotherapeutics aims to increase efficacy and lower toxicity by concentrating drugs at the site-of-action, a method embodied by the seven current FDA-approved antibody–drug conjugates (ADC). However, a variety of pharmacokinetic challenges result in relatively narrow therapeutic windows for these agents, hampering the development of new drugs. Here, we use a series of prostate-specific membrane antigen–binding single-domain (Humabody) ADC constructs to demonstrate that tissue penetration of protein–drug conjugates plays a major role in therapeutic efficacy. Counterintuitively, a construct with lower in vitro potency resulted in higher in vivo efficacy than other protein–drug conjugates. Biodistribution data, tumor histology images, spheroid experiments, in vivo single-cell measurements, and computational results demonstrate that a smaller size and slower internalization rate enabled higher tissue penetration and more cell killing. The results also illustrate the benefits of linking an albumin-binding domain to the single-domain ADCs. A construct lacking an albumin-binding domain was rapidly cleared, leading to lower tumor uptake (%ID/g) and decreased in vivo efficacy. In conclusion, these results provide evidence that reaching the maximum number of cells with a lethal payload dose correlates more strongly with in vivo efficacy than total tumor uptake or in vitro potency alone for these protein–drug conjugates. Computational modeling and protein engineering can be used to custom design an optimal framework for controlling internalization, clearance, and tissue penetration to maximize cell killing.

Significance:

A mechanistic study of protein–drug conjugates demonstrates that a lower potency compound is more effective in vivo than other agents with equal tumor uptake due to improved tissue penetration and cellular distribution.
Statins Limit Coenzyme Q Synthesis and Metabolically Synergize with MEK Inhibition in Pancreatic Tumors
Authors: Cordes Thekla , Metallo Christian M.
Published: January 2020

Tumors frequently increase expression of enzymes in the mevalonate biosynthesis pathway. Statins inhibit flux through this pathway, but if and how such treatments elicit a therapeutic benefit in cancer remains unclear. In this issue of Cancer Research, McGregor and colleagues perform in vivo metabolic tracing to demonstrate that mouse pancreatic ductal adenocarcinoma (PDAC) tumors and human PDAC cell lines require this pathway for coenzyme Q (CoQ) synthesis and redox homeostasis. Simvastatin treatment reduces CoQ synthesis and promotes oxidative stress and apoptosis in tumors when administered in combination with a MEK inhibitor, providing a new mechanism through which statin treatment may impact PDAC growth.

See related article by McGregor et al., p. 175
Medical Financial Hardship Intensity and Financial Sacrifice Associated with Cancer in the United States
Authors: Han Xuesong , Zhao Jingxuan , Zheng Zhiyuan , de Moor Janet S. , Virgo Katherine S. , Yabroff K. Robin
Published: January 2020

Background:

With rising costs of cancer care, this study aims to estimate the prevalence of, and factors associated with, medical financial hardship intensity and financial sacrifices due to cancer in the United States.

Methods:

We identified 963 cancer survivors from the 2016 Medical Expenditures Panel Survey - Experiences with Cancer. Medical financial hardship due to cancer was measured in material (e.g., filed for bankruptcy), psychological (e.g., worry about paying bills and finances), and behavioral (e.g., delaying or forgoing care due to cost) domains. Nonmedical financial sacrifices included changes in spending and use of savings. Multivariable logistic models were used to identify characteristics associated with hardship intensity and sacrifices stratified by age group (18–64 or 65+ years).

Results:

Among cancer survivors ages 18 to 64 years, 53.6%, 28.4%, and 11.4% reported at least one, two, or all three domains of hardship, respectively. Among survivors ages 65+ years, corresponding percentages were 42.0%, 12.7%, and 4.0%, respectively. Moreover, financial sacrifices due to cancer were more common in survivors ages 18 to 64 years (54.2%) than in survivors 65+ years (38.4%; P < 0.001). Factors significantly associated with hardship intensity in multivariable analyses included low income and educational attainment, racial/ethnic minority, comorbidity, lack of private insurance coverage, extended employment change, and recent cancer treatment. Most were also significantly associated with financial sacrifices.

Conclusions:

Medical financial hardship and financial sacrifices are substantial among cancer survivors in the United States, particularly for younger survivors.

Impact:

Efforts to mitigate financial hardship for cancer survivors are warranted, especially for those at high risk.
Feasibility and Acceptability of a Web-Based Dietary Intervention with Text Messages for Colorectal Cancer: A Randomized Pilot Trial
Authors: Van Blarigan Erin L. , Kenfield Stacey A. , Chan June M. , Van Loon Katherine , Paciorek Alan , Zhang Li , Chan Hilary , Savoie Marissa B. , Bocobo Andrea Grace , Liu Vivian N. , Wong Louis X. , Laffan Angela , Atreya Chloe E. , Miaskowski Christine , Fukuoka Yoshimi , Meyerhardt Jeffrey A. , Venook Alan P.
Published: January 2020

Background:

Diet is associated with colorectal cancer survival. Yet, adherence to nutrition guidelines is low among colorectal cancer survivors.

Methods:

We conducted a pilot trial among colorectal cancer survivors to evaluate a 12-week remote dietary intervention. Participants received print materials and were randomized (1:1) to intervention (website, text messages) or wait-list control. Primary outcomes included feasibility and acceptability. We also explored change in diet from 0 to 12 and 24 weeks and change from 0 to 12 weeks in anthropometry and circulating biomarkers (Trial Registration: NCT02965521).

Results:

We randomized 50 colorectal cancer survivors (25 intervention, 25 control). Retention was 90% at 12 weeks and 84% at 24 weeks. Participants had a median age of 55 years and were 66% female, 70% non-Hispanic white, and 96% had a college degree. The intervention arm responded to a median 15 (71%) of 21 text messages that asked for a reply [interquartile range (IQR) = 8, 19] and visited the website a median of 13 (15%) days (IQR = 1, 33) of the 84 study days.

Conclusions:

We developed a Web-based dietary intervention for colorectal cancer survivors. Our pilot results suggest that colorectal cancer survivors may engage more with text messages than a study website. Research to improve tailoring of text messages, while maintaining scalability, is needed.

Impact:

Remote dietary interventions using text messages may be feasible for colorectal cancer survivors.

See all articles in this CEBP Focus section, “Modernizing Population Science.”
Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers
Authors: Parikh Aparna R. , Mojtahed Amikasra , Schneider Jaime L. , Kanter Katie , Van Seventer Emily E. , Fetter Isobel J. , Thabet Ashraf , Fish Madeleine G. , Teshome Bezaye , Fosbenner Kathryn , Nadres Brandon , Shahzade Heather A. , Allen Jill N. , Blaszkowsky Lawrence S. , Ryan David P. , Giantonio Bruce , Goyal Lipika , Nipp Ryan D. , Roeland Eric , Weekes Colin D. , Wo Jennifer Y. , Zhu Andrew X. , Dias-Santagata Dora , Iafrate A. John , Lennerz Jochen K. , Hong Theodore S. , Siravegna Giulia , Horick Nora , Clark Jeffrey W. , Corcoran Ryan B.
Published: January 2020

Purpose:

ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer.

Experimental Design:

A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response.

Results:

A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (P < 0.0001). Four-week change in tumor markers also predicted response (P = 0.0026) and CB (P = 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (P = 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55–7.00; P < 0.0001).

Conclusions:

Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.
Extracellular Vesicle–Mediated In Vitro Transcribed mRNA Delivery for Treatment of HER2+ Breast Cancer Xenografts in Mice by Prodrug CB1954 without General Toxicity
Authors: Forterre Alexis V. , Wang Jing-Hung , Delcayre Alain , Kim Kyuri , Green Carol , Pegram Mark D. , Jeffrey Stefanie S. , Matin A.C.
Published: January 2020

Prodrugs are harmless until activated by a bacterial or viral gene product; they constitute the basis of gene-delivered prodrug therapies called GDEPT, which can kill tumors without major side effects. Previously, we utilized the prodrug CNOB (C16H7CIN2O4; not clinically tested) and enzyme HChrR6 in GDEPT to generate the drug MCHB (C16H9CIN2O2) in tumors. Extracellular vesicles (EVs) were used for directed gene delivery and HChrR6 mRNA as gene. Here, the clinical transfer of this approach is enhanced by: (i) use of CB1954 (tretazicar) for which safe human dose is established; HChrR6 can activate this prodrug. (ii) EVs delivered in vitro transcribed (IVT) HChrR6 mRNA, eliminating the potentially harmful plasmid transfection of EV producer cells we utilized previously; this has not been done before. IVT mRNA loading of EVs required several steps. Naked mRNA being unstable, we ensured its prodrug activating functionality at each step. This was not possible using tretazicar itself; we relied instead on HChrR6′s ability to convert CNOB into MCHB, whose fluorescence is easily visualizable. HChrR6 mRNA-translated product's ability to generate fluorescence from CNOB vicariously indicated its competence for tretazicar activation. (iii) Systemic IVT mRNA–loaded EVs displaying an anti-HER2 single-chain variable fragment (“IVT EXO-DEPTs”) and tretazicar caused growth arrest of human HER2+ breast cancer xenografts in athymic mice. As this occurred without injury to other tissues, absence of off-target mRNA delivery is strongly indicated. Many cancer sites are not amenable for direct gene injection, but current GDEPTs require this. In circumventing this need, a major advance in GDEPT applicability has been accomplished.
Metabolic Profiling Reveals a Dependency of Human Metastatic Breast Cancer on Mitochondrial Serine and One-Carbon Unit Metabolism
Authors: Li Albert M. , Ducker Gregory S. , Li Yang , Seoane Jose A. , Xiao Yiren , Melemenidis Stavros , Zhou Yiren , Liu Ling , Vanharanta Sakari , Graves Edward E. , Rankin Erinn B. , Curtis Christina , Massagué Joan , Rabinowitz Joshua D. , Thompson Craig B. , Ye Jiangbin
Published: January 2020

Breast cancer is the most common cancer among American women and a major cause of mortality. To identify metabolic pathways as potential targets to treat metastatic breast cancer, we performed metabolomics profiling on the breast cancer cell line MDA-MB-231 and its tissue-tropic metastatic subclones. Here, we report that these subclones with increased metastatic potential display an altered metabolic profile compared with the parental population. In particular, the mitochondrial serine and one-carbon (1C) unit pathway is upregulated in metastatic subclones. Mechanistically, the mitochondrial serine and 1C unit pathway drives the faster proliferation of subclones through enhanced de novo purine biosynthesis. Inhibition of the first rate-limiting enzyme of the mitochondrial serine and 1C unit pathway, serine hydroxymethyltransferase (SHMT2), potently suppresses proliferation of metastatic subclones in culture and impairs growth of lung metastatic subclones at both primary and metastatic sites in mice. Some human breast cancers exhibit a significant association between the expression of genes in the mitochondrial serine and 1C unit pathway with disease outcome and higher expression of SHMT2 in metastatic tumor tissue compared with primary tumors. In addition to breast cancer, a few other cancer types, such as adrenocortical carcinoma and kidney chromophobe cell carcinoma, also display increased SHMT2 expression during disease progression. Together, these results suggest that mitochondrial serine and 1C unit metabolism plays an important role in promoting cancer progression, particularly in late-stage cancer.

Implications:

This study identifies mitochondrial serine and 1C unit metabolism as an important pathway during the progression of a subset of human breast cancers.

See interview with Jiangbin Ye, PhD, co-recipient of the 2022 MCR Michael B. Kastan Award for Research Excellence: https://vimeo.com/720728048
AGO2 Mediates MYC mRNA Stability in Hepatocellular Carcinoma
Authors: Zhang Kai , Pomyen Yotsawat , Barry Anna E. , Martin Sean P. , Khatib Subreen , Knight Lucy , Forgues Marshonna , Dominguez Dana A. , Parhar Ravinder , Shah Ashesh P. , Bodzin Adam S. , Wang Xin Wei , Dang Hien
Published: January 2020

Deregulated RNA-binding proteins (RBP), such as Argonaute 2 (AGO2), mediate tumor-promoting transcriptomic changes during carcinogenesis, including hepatocellular carcinoma (HCC). While AGO2 is well characterized as a member of the RNA-induced silencing complex (RISC), which represses gene expression through miRNAs, its role as a bona fide RBP remains unclear. In this study, we investigated AGO2′s role as an RBP that regulates the MYC transcript to promote HCC. Using mRNA and miRNA arrays from patients with HCC, we demonstrate that HCCs with elevated AGO2 levels are more likely to have the mRNA transcriptome deregulated and are associated with poor survival. Moreover, AGO2 overexpression stabilizes the MYC transcript independent of miRNAs. These observations provide a novel mechanism of gene regulation by AGO2 and provide further insights into the potential functions of AGO2 as an RBP in addition to RISC.

Implications:

Authors demonstrate that the RBP Argonaute 2 stabilizes the MYC transcript to promote HCC.
Posterior Variant of Alien Limb Syndrome with Sudden Clinical Onset as Self-Hitting Associated with Thalamic Stroke
Authors: Russo Mirella , Carrarini Claudia , Dono Fedele , Di Stefano Vincenzo , De Angelis Maria Vittoria , Onofrj Marco , Sensi Stefano L.
Published: January 2020

We present a case of sudden postischaemic onset of alien limb syndrome, with unintentional self-injury. Alien limb syndrome is an uncommon neurological disorder featured by uncontrolled and involuntary movements of a limb. Three variants of alien limb syndrome have been described: the anterior, featured by grasping of surrounding objects, the callosal, presenting with intermanual conflict, and the posterior, associated with involuntary levitation of the limb. Our patient suffered from an acute presentation of the posterior variant of the alien limb syndrome, resulting from an isolated thalamic stroke which was documented using 24-h computed tomography brain scan. Only one previous case of alien limb syndrome after thalamic infarct has been reported. Our case enhances the possibility that pure thalamic injury may represent a trigger for this condition.
Role of Peroral Cholangioscopy for Diagnosis and Staging of Biliary Tumors
Authors: Pereira Pedro , Santos Sancha , Morais Rui , Gaspar Rui , Rodrigues-Pinto Eduardo , Vilas-Boas Filipe , Macedo Guilherme
Published: January 2020

Objectives: Peroral cholangioscopy (POC) has shown to be a useful diagnostic procedure in the evaluation of biliary strictures; however, data regarding its role on preoperative staging are scarce. The aim of this study was to evaluate POC role in the diagnosis and preoperative intraductal staging of perihilar cholangiocarcinoma (CCA). Methods: Retrospective study that included all patients who underwent POC with SpyGlassTM Direct Visualization System for the diagnosis of biliary strictures or for preoperative evaluation of extrahepatic biliary tumors, between 2015 and 2019, in a single tertiary center. Results: Forty-three patients were included, 63% male with a median age of 62 years. Thirty-eight (88.3%) underwent POC due to indeterminate biliary strictures, 3 (7%) due to bile duct filling defect, and 2 (4.7%) for intraductal staging of perihilar CCA. In the follow-up, a final diagnosis of malignancy was established in 56% of the patients. Visual impression accuracy with SpyGlass was 95.1% (with 100% sensitivity and 89.5% specificity). SpyBite biopsies accuracy was 80.5% (63.6% sensitivity and 100% specificity). In the 19 patients with a final perihilar CCA diagnosis, intraductal evaluation with SpyGlass altered anatomic classification (Bismuth-Corlette) defined by previous imagiologic findings in 8 (42.1%) patients. Alteration in anatomic classification changed therapeutic approach in 4 (21%). Conclusions: POC use for evaluating intraductal spread in potentially resectable perihilar CCA can detect more extensive and change surgical management. In the future, preoperative staging of perihilar CCA with POC combined with imagiologic evaluation of vascular extension of the lesions may optimize surgical results.
Late-Onset Hepatic Failure in Children: Risk Factors that Determine the Outcome
Authors: Singh Sumit Kumar , Sen Sarma Moinak , Yachha Surender Kumar , Srivastava Anshu , Poddar Ujjal
Published: January 2020

Background: Late-onset hepatic failure (LOHF) is a distinct entity of intractable liver diseases with limited pediatric experience. We aimed to identify the etiology and risk factors that determine the poor outcome (PO) of pediatric LOHF. Methods: LOHF was defined as liver failure occurring 5–24 weeks after onset of jaundice and without any evidence of underlying chronic liver disease. PO (death or liver transplantation within 160 days) was compared with spontaneous recovery (SR; complete normalization of liver functions in the native liver). Pediatric end-stage liver disease (PELD) score and King’s College Criteria (KCC) were applied to investigate their prognostic value. Results: We enrolled 47 children (6 [2–16] years) with LOHF. Hepatitis A was the most common etiology (15, 32%) and 64% complicated with infections. Twelve children (25%) had SR over 6 (1–24) months, while 28 (60%) children had PO. Univariate analysis showed indeterminate etiology, hepatic encephalopathy (HE), infection, acute kidney injury, and high PELD score determined PO. On multivariate regression analysis, only PELD score with a cutoff 32 (area under curve 0.833, sensitivity 68%, specificity 92%) predicted PO. KCC showed a sensitivity of 85.7%, specificity of 41.7% to determine PO in our cohort. Conclusion: Indeterminate etiology, presence of HE, occurrence of infection at any site, and acute kidney injury lead to the PO. PELD score ≥32 can be utilized to optimize the listing for liver transplantation. A significant proportion survives with the native liver.
Left Ventricular Ejection Fraction Recovery in Patients with Heart Failure and Reduced Ejection Fraction Treated with Sacubitril/Valsartan
Authors: Díez-Villanueva Pablo , Vicent Lourdes , de la Cuerda Francisco , Esteban-Fernández Alberto , Gómez-Bueno Manuel , de Juan-Bagudá Javier , Iniesta Ángel Manuel , Ayesta Ana , Rojas-González Antonio , Bover-Freire Ramón , Iglesias Diego , García-Aguado Marcos , Perea-Egido Jesús Ángel , Salamanca Jorge , Martínez-Sellés Manuel
Published: January 2020

Background: A significant number of heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF) experience ventricular function recovery during follow-up. We studied the variables associated with LVEF recovery in patients treated with sacubitril/valsartan (SV) in clinical practice. Methods: We analyzed data from a prospective and multicenter registry including 249 HF outpatients with reduced LVEF who started SV between October 2016 and March 2017. The patients were classified into 2 groups according to LVEF at the end of follow-up (>35%: group R, or ≤35%: group NR). Results: After a mean follow-up of 7 ± 0.1 months, 62 patients (24.8%) had LVEF >35%. They were older (71.3 ± 10.8 vs. 67.5 ± 12.1 years, p = 0.025), and suffered more often from hypertension (83.9 vs. 73.8%, p = 0.096) and higher blood pressure before and after SV (both, p < 0.01). They took more often high doses of beta-blockers (30.6 vs. 27.8%, p = 0.002), with a smaller proportion undergoing cardiac resynchronization therapy (14.8 vs. 29.0%, p = 0.028) and fewer implanted cardioverter defibrillators (ICD; 32.8 vs. 67.9%, p < 0.001), this being the only predictive variable of NR in the multivariate analysis (OR 0.26, 95% CI 0.13–0.47, p < 0.0001). At the end of follow-up, the mean LVEF in group R was 41.9 ± 8.1% (vs. 26.3 ± 4.7% in group NR, p < 0.001), with an improvement compared with the initial LVEF of 14.6 ± 10.8% (vs. 0.8 ± 4.5% in group NR, p < 0.0001). Functional class improved in both groups, mainly in group R (p = 0.035), with fewer visits to the emergency department (11.5 vs. 21.6%, p = 0.07). Conclusions: In patients with LVEF ≤35% treated with SV, not carrying an ICD was independently associated with LVEF recovery, which was related to greater improvement in functional class.
Ganoderic Acid A Inhibits Bleomycin-Induced Lung Fibrosis in Mice
Authors: Wen Gaoyan , Li Tian , He Hua , Zhou Xianmei , Zhu Jia
Published: January 2020

Background: To study the protective effects of ganoderic acid A (GAA) on bleomycin (BLM)-induced pulmonary fibrosis. Methods: ICR mice were intratracheally instilled with BLM to induce pulmonary fibrosis on day 0. Then the mice were orally given GAA (25, 50 mg/kg) or dexamethasone (2 mg/kg). After treatment for 21 days, the mice were sacrificed. Wet dry weight (W/D) ratio of lung was used to detect pulmonary edema. Myeloperoxidase (MPO), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), and superoxide dismutase (SOD) were detected by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining was used to evaluate the pathological changes. The levels of transforming growth factor β (TGF-β), phosphorylated-smad3 (p-smad3), p-IκB, and p-nuclear factor-kappa B (NF-κB) in lung tissue were detected by western blot. Results: GAA treatment significantly improved MPO activity, W/D ratio, and lung histopathology. The protective effect of GAA may be related to downregulation of TNF-α, IL-1β, IL-6, MDA and upregulation of SOD. In addition, GAA significantly decreased the levels of TGF-β, p-smad3, p-IκB, and p-NF-κB, compared with those in BLM group. Conclusion: GAA has protective effect on BLM-induced lung injury, and TGF-β/Smad-3/NF-κB signaling pathway may play an important role in the pathogenesis of BLM-induced lung injury.
Protective Effects of Transforming Growth Factor-β1 Knockdown in Human Umbilical Cord Mesenchymal Stem Cells against Subarachnoid Hemorrhage in a Rat Model
Authors: Chen Hongwei , Chen Li , Xie Dongcheng , Niu Jianxing
Published: January 2020

Background: Emerging evidence indicates a beneficial effect of mesenchymal stem cell (MSC) transplantation in subarachnoid hemorrhage (SAH). Chronic hydrocephalus is a common complication after SAH, which is associated with subarachnoid fibrosis promoted by transforming growth factor-β1 (TGF-β1). This study investigated the effect of human umbilical cord derived MSCs (hUC-MSCs) with TGF-β1 knockdown on chronic hydrocephalus after SAH. Methods: About 0.5 mL autologous blood was injected into the cerebellomedullaris cistern of 6-week SD rats to establish SAH model. hUC-MSCs or hUC-MSCs carrying TGF-β1 knockdown (1 × 105 cells) were intraventricularly transplanted at 1 day before surgery and at P10. Neurological behavior score and water maze test were performed to assess neurological functions. Hydrocephalus was evaluated by Nissl staining. Concentrations of proinflammatory cytokines were measured by enzyme-linked immunosorbent assay. The levels of TGF-β1, p-Smad2/3, and Smad2/3 were measured using western blotting. Results: Intraventricular hUC-MSCs transplantation significantly attenuated SAH-induced chronic hydrocephalus, upregulation of inflammatory cytokines, and behavioral impairment. Knockdown of TGF-β1 in hUC-MSCs enhanced these effects. hUC-MSCs also reduced the upregulation of TGF-β1 levels and Smad2/3 phosphorylation after SAH, and this effect was also enhanced by TGF-β1 knockdown. Conclusion: Transplantation of hUC-MSCs exerts beneficial effect after SAH, possibly be through inhibiting TGF-β1/Smad2/3 signaling pathway. Knockdown of TGF-β1 in hUC-MSCs enhanced these effects.
Preoperative Treatment with Ulipristal Acetate before Outpatient Hysteroscopic Myomectomy
Authors: Ferrero Simone , Scala Carolina , Vellone Valerio Gaetano , Paudice Michele , Vitale Salvatore Giovanni , Cianci Antonio , Barra Fabio
Published: January 2020

Introduction: Nowadays, the resection of submucosal myomas is usually performed by hysteroscopy. No previous study has investigated the use of preoperative hormonal therapy before outpatient hysteroscopic myomectomy. Objective: To compare the usefulness of 3-month preoperative treatment with ulipristal acetate (UPA) before outpatient hysteroscopic myomectomy in patients with FIGO (International Federation of Gynecology and Obstetrics) type 0–1 myomas. Study Design: This prospective patient preference study included women requiring hysteroscopic resection of single FIGO type 0–1 myoma with the largest diameter <2 cm. Patients underwent either preoperative treatment with UPA (5 mg/day) for 3 months or direct surgery. Outpatient myomectomy was performed using the bipolar electrosurgical Versapoint system (Ethicon Gynecare, USA). The primary objective of the study was to compare the rate of complete resections in the 2 study groups. The secondary objective of the study was to compare the operative time and the volume of fluid infused/absorbed. The tertiary objective of the study was to assess the surgical appearance of the myomas in patients treated with UPA. Results: The study included 38 women treated with UPA and 45 women who underwent direct surgery. UPA treatment significantly decreased the volume of uterine myomas (p < 0.001). The percentage of complete resection was higher in patients treated with UPA (89.5%) than in those who underwent direct surgery (68.9%; p = 0.046). Preoperative UPA treatment decreased the operative time (p < 0.001) and the volume of fluid infused (p = 0.016), but it did not significantly affect the volume of fluid absorbed (p = 0.874). The texture of the myoma was not significantly affected by UPA treatment (p = 0.142). Conclusions: Three-month UPA treatment improves the chance of single-step complete outpatient hysteroscopic resection of single FIGO type 0–1 myoma. Future randomized studies with a larger sample size should confirm these preliminary findings.
Family History of Alcohol Abuse Associated with Higher Impulsivity in Patients with Alcohol Use Disorder: A Multisite Study
Authors: Khemiri Lotfi , Kaag Anne Marije , Joos Leen , Dom Geert , Franck Johan , Goudriaan Anna E. , Jayaram-Lindström Nitya
Published: January 2020

Background: Alcohol use disorder (AUD) is to a high degree heritable, and in clinical practice it is common to assert presence of alcohol abuse family history (FH) in treatment-seeking AUD patients. Patients with AUD also exhibit cognitive deficits, including elevated impulsivity and impairments in executive functions (EF), but less is known regarding the relation between FH and these cognitive domains. The aim of the current study was to investigate if alcohol abuse FH in AUD patients is associated with a specific cognitive profile. Methods: Patients with AUD (n = 197) from Sweden (n = 106) and Belgium (n = 91) were recruited. Self-rated impulsivity was assessed by the Barratt Impulsiveness Scale (BIS). EF assessed were response inhibition (stop signal task), attention (rapid visual processing task), and working memory (digit span). A series of linear regression models were run to explore the effect of FH on cognitive outcomes. Results: A FH of alcohol abuse was associated with elevated score in self-rated impulsivity assessed by the BIS, with the greatest effect on the subscale of nonplanning. There was no statistically significant association between FH and any of the other neuropsychological task outcomes. Conclusion: Presence of alcohol abuse FH within AUD patients could be a marker of higher impulsivity, which may have clinical implications regarding diagnostic evaluation and treatment.
Which Staging System Is More Suitable for Gastric Neuroendocrine Cancer and Mixed Adenoneuroendocrine Carcinomas? A Multicenter Cohort Study
Authors: Lin Jianxian  , Zhao YaJun , Zhou Yanbing , Hao Hankun , He Qingliang , Tian Yantao , Zou Bingbing , Zhao Gang , Qiu Xiantu , Jiang Linxin , Li Zhi , Xu Yanchang , Xue Fangqin , Fu Weihua , Xu Zekuan , Li Yongxiang , Li Shuliang , Chen Jinping , Zhou Xiaojun , Zhu Zhenggang , Li Honglang , Li Yong , Li En , Cai Lisheng , Jia Guiqing , Xie Jian-Wei , Li Ping , Zheng Chao-Hui , Huang Chang-Ming
Published: January 2020

Purpose: To evaluate whether the European Neuroendocrine Tumor Society (ENETS) system or the 8th American Joint Committee on Cancer (AJCC) staging manual are suitable for gastric neuroendocrine carcinomas and/or mixed adenoneuroendocrine carcinomas (G-NECs/MANECs). Methods: Patients in a multicentric series with G-NEC/MANEC who underwent curative-intent surgical resection for a primary tumor were included. An optimal staging system was proposed base on analysis of the T and N status and validated by the SEER database. Results: Compared with the ENETS system, the survival curves of the T category and N category in the 8th AJCC system were better separated and distributed in a more balanced way, but the survival curves of T2 vs. T3, N0 vs. N1, and N3a vs. N3b overlapped. For the T category, the 8th AJCC T category was modified by combining T2 and T3, which was consistent with the T category in the 6th AJCC manual for GC. For the N category, the optimal cut-off values of metastatic lymph nodes using X-tile were also similar to those of the N category in the 6th AJCC system. The Kaplan-Meier plots of the 6th AJCC system showed statistically significant differences between individual substages. Compared with the other 2 classifications, the 6th AJCC system also showed superior prognostic stratification. Similar results were obtained in both multicentric and SEER validation sets. Conclusions: Compared to the 8th AJCC and ENETS systems, the 6th AJCC staging system for GC is more suitable for G-NEC/MANEC and can be adopted in clinical practice.
Higher Incidence of Asymptomatic Cerebral Emboli After Atrial Fibrillation Ablation Found With High-Resolution Diffusion-Weighted Magnetic Resonance Imaging
Authors: Yu Yaya , Wang Xuecheng , Li Xiaorong , Zhou Xiujuan , Liao Shengen , Yang Wen , Yu Jinbo , Zhang Fengxiang , Ju Weizhu , Chen Hongwu , Yang Gang , Li Mingfang , Gu Kai , Tang Lijun , Xu Yi , Chan Joseph Yat-Sun , Kojodjojo Pipin , Cao Kejiang , Fan Jie , Yang Bing , Chen Minglong
Published: January 2020

Background:

Asymptomatic cerebral emboli (ACE) are commonly seen on cerebral magnetic resonance imaging (MRI) after atrial fibrillation ablation, but the incidence in previous studies varies widely. No data exists to compare the effects of different diffusion-weighted imaging (DWI) settings on detecting ablation-related ACE. This self-control study sought to compare the incidence and characteristics of ablation-related ACE between high-resolution DWI and conventional DWI.

Methods:

A total of 55 consecutive patients referred for atrial fibrillation ablation between December 2017 and September 2018 were enrolled. Patients underwent high-resolution DWI 1 day before ablation and repeated high-resolution DWI and conventional DWI within 48 hours post-ablation. The incidence, number, size, and location of ACE were compared between 2 DWI settings in the same patients.

Results:

The high-resolution DWI revealed a higher incidence of acute ACE compared with conventional DWI (67.3% versus 41.8% of patients,
P
<0.001) and significantly more ACE (106 versus 45 lesions,
P
=0.001). For ACE seen on both scans, the size measured by high-resolution DWI was larger (5.42 versus 4.21 mm,
P
<0.001). No patients had any impaired neurocognitive performance during follow-up. Impaired left ventricular ejection fraction (
P
=0.012) and low intraoperative activated clotting time (
P
=0.009) level were associated with the occurrence of ACE in a multivariate analysis.

Conclusions:

High-resolution DWI revealed a higher incidence and greater details of post-ablation ACE in patients with atrial fibrillation. MRI settings significantly impact the detection of ACE and should be considered when comparing incidence rates of ACE among different studies.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01761188.
Incidence, Temporal Trends, and Associated Outcomes of Vascular and Bleeding Complications in Patients Undergoing Transfemoral Transcatheter Aortic Valve Replacement
Authors: Sherwood Matthew W. , Xiang Katelyn , Matsouaka Roland , Li Zhuokai , Vemulapalli Sreekanth , Vora Amit N. , Fanaroff Alexander , Harrison J. Kevin , Thourani Vinod H. , Holmes David , Kirtane Ajay , Pineda Andres M. , Peterson Eric D. , Rao Sunil V.
Published: January 2020

Background:

Vascular and bleeding complications were commonly reported in transcatheter aortic valve replacement clinical trials. Little is known about complication rates in contemporary US clinical practice or clinical outcomes associated with these complications.

Methods:

In the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry, we evaluated patients undergoing transcatheter aortic valve replacement from November 1, 2011 to June 30, 2016. The primary outcomes were in-hospital vascular complications and bleeding events. Secondary outcomes included all-cause mortality, stroke, and rehospitalization at 1 year.
P
values for trends were calculated for rates over time, and multivariable logistic regression was used to determine the association between vascular/bleeding complications and in-hospital clinical outcomes.

Results:

Overall, 34 893 patients undergoing transcatheter aortic valve replacement at 445 hospitals were analyzed. Of these, 9.3% (n=3257) experienced a vascular complication while 7.6% (n=2651) had an in-hospital bleeding event. Rates of both vascular complications and bleeding events decreased over time (
P
value for trend test <0.0001); however, there was significant variation in rates across hospital sites (adjusted median rate, 11.4%; IQR, 8.9–14.5). Vascular complications were independently associated with 30-day death (adjusted HR, 2.23 [95% CI, 1.80–2.77]) and death (adjusted HR, 1.17 [95% CI, 1.05–1.30]) and rehospitalization (adjusted HR, 1.14 [95% CI, 1.07–1.22]) at 1 year. Bleeding events were also associated with 30-day death (adjusted HR, 3.71 [95% CI, 2.94–4.69]), and with death (adjusted HR, 1.39 [95% CI, 1.23–1.56]) and hospital readmission (adjusted HR, 1.19 [95% CI, 1.11–1.27]) at 1 year.

Conclusions:

In patients undergoing transcatheter aortic valve replacement in the US, vascular complications and in-hospital bleeding events were common, but rates have declined over time with significant variation in complication rates across hospital sites. Vascular and bleeding complications are both associated with worse short- and long-term clinical outcomes including all-cause mortality. Further innovation to reduce sheath sizes and optimize antithrombotic therapy is necessary to reduce the incidence of these detrimental complications.
A taxonomic revision of Paracanthon Balthasar, 1938 (Coleoptera, Scarabaeidae, Scarabaeinae)
Authors: Pacheco Thaynara L. , Vaz-de-Mello Fernando Z.
Published: January 2020

Paracanthon
Balthasar 1938 includes four nominal species of dung beetles occurring in the Atlantic Forest of northeastern, southeastern and southern Brazil, and Misiones, Argentina. Here we describe twelve new species of Paracanthon: P. arnaudi
sp. n., P. belloi
sp. n., P felipei
sp. n., P genieri
sp. n., P. grossiorum
sp. n., P. laevinotus
sp. n., P. lopesandradei
sp. n., P. marinezae
sp. n., P. millerorum
sp. n., P.monteiroorum
sp. n., P. muriloi
sp. n., P. ocellatopunctatus
sp. n. We propose P. pereirai d’Andretta & Martínez 1957 as a new junior subjective synonym of P. rosinae
Balthasar 1942. In addition, we present new data on the morphology of the hindwings and male genitalia, and an identification key to the species of the genus. Paracanthon is restricted to the Atlantic domain, and we briefly discuss the possible processes that might have led to the diversification of the putative lineages recognized here.