bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

AbstractBackground: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 &lt; 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

Abstract

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

Abstract

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 &lt; 0.0001) and clinical benefit [CB: PR and stable disease (SD), P &lt; 0.0001]. ctDNA decreased by 98% (median) and &gt;30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (P &lt; 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 &lt; 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

Abstract
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

Abstract

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

Abstract

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.
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

<b><i>Objectives:</i></b> 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). <b><i>Methods:</i></b> Retrospective study that included all patients who underwent POC with <i>SpyGlass</i><sup>TM</sup><i> Direct Visualization System</i> for the diagnosis of biliary strictures or for preoperative evaluation of extrahepatic biliary tumors, between 2015 and 2019, in a single tertiary center. <b><i>Results:</i></b> 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%). <b><i>Conclusions:</i></b> 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

<b><i>Background:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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. <b><i>Conclusion:</i></b> 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.
Ganoderic Acid A Inhibits Bleomycin-Induced Lung Fibrosis in Mice
Authors: Wen Gaoyan , Li Tian , He Hua , Zhou Xianmei , Zhu Jia 
Published: January 2020

<b><i>Background:</i></b> To study the protective effects of ganoderic acid A (GAA) on bleomycin (BLM)-induced pulmonary fibrosis. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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. <b><i>Conclusion:</i></b> 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.