bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactions within and between parallel parietal-frontal networks involved in complex motor behaviors in prosimian galagos and a squirrel monkey
Authors: Stepniewska Iwona , Friedman Robert M. , Miller Daniel J. , Kaas Jon H. 
Published: November 2019

Long-train intracortical microstimulation (ICMS) of motor (M1) and posterior parietal cortices (PPC) in primates reveals cortical domains for different ethologically relevant behaviors. How functional domains interact with each other in producing motor behaviors is not known. In this study, we tested our hypothesis that matching domains interact to produce a specific complex movement, whereas connections between nonmatching domains are involved in suppression of conflicting motor outputs to prevent competing movements. In anesthetized galagos, we used 500-ms trains of ICMS to evoke complex movements from a functional domain in M1 or PPC while simultaneously stimulating another mismatched or matched domain. We considered movements of different and similar directions evoked from chosen cortical sites distant or close to each other. Their trajectories and speeds were analyzed and compared with those evoked by simultaneous stimulation. Stimulation of two sites evoking same or complementary movements produced a similar but more pronounced movement or a combined movement, respectively. Stimulation of two sites representing movements of different directions resulted in partial or total suppression of one of these movements. Thus interactions between domains in M1 and PPC were additive when they were functionally matched across fields or antagonistic between functionally conflicting domains, especially in PPC, suggesting that mismatched domains are involved in mutual suppression. Simultaneous stimulation of unrelated domains (forelimb and face) produced both movements independently. Movements produced by the simultaneous stimulation of sites in domains of two cerebral hemispheres were largely independent, but some interactions were observed. NEW & NOTEWORTHY Long trains of electrical pulses applied simultaneously to two sites in motor cortical areas (M1, PPC) have shown that interactions of functionally matched domains (evoking similar movements) within these areas were additive to produce a specific complex movement. Interactions between functionally mismatched domains (evoking different movements) were mostly antagonistic, suggesting their involvement in mutual suppression of conflicting motor outputs to prevent competing movements. Simultaneous stimulation of unrelated domains (forelimb and face) produced both movements independently.
Mirror neurons precede non-mirror neurons during action execution
Authors: Mazurek Kevin A. , Schieber Marc H. 
Published: November 2019

Mirror neurons are thought to represent an individual’s ability to understand the actions of others by discharging as one individual performs or observes another individual performing an action. Studies typically have focused on mirror neuron activity during action observation, examining activity during action execution primarily to validate mirror neuron involvement in the motor act. As a result, little is known about the precise role of mirror neurons during action execution. In this study, during execution of reach-grasp-manipulate movements, we found activity of mirror neurons generally preceded that of non-mirror neurons. Not only did the onset of task-related modulation occur earlier in mirror neurons, but state transitions detected by hidden Markov models also occurred earlier in mirror neuron populations. Our findings suggest that mirror neurons may be at the forefront of action execution. NEW & NOTEWORTHY Mirror neurons commonly are thought to provide a neural substrate for understanding the actions of others, but mirror neurons also are active during action execution, when additional, non-mirror neurons are active as well. Examining the timing of activity during execution of a naturalistic reach-grasp-manipulate task, we found that mirror neuron activity precedes that of non-mirror neurons at both the unit and the population level. Thus mirror neurons may be at the leading edge of action execution.
A Novel Bioengineered miR-127 Prodrug Suppresses the Growth and Metastatic Potential of Triple-Negative Breast Cancer Cells
Authors: Umeh-Garcia Maxine , Simion Catalina , Ho Pui-Yan , Batra Neelu , Berg Anastasia L. , Carraway Kermit L. , Yu Aiming , Sweeney Colleen 
Published: November 2019

Abstract

miR-127 is downregulated in breast cancer, where it has been shown to suppress the proliferation, migration, and invasion of breast cancer cells. In triple-negative breast cancer (TNBC), miR-127 downregulation correlates with decreased disease-free and overall patient survival. Tumor suppressor miRNAs may hold therapeutic promise but progress has been limited by several factors, including the lability and high cost of miRNA mimics. Here, we take a novel approach to produce a miR-127 prodrug (miR-127PD), which we demonstrate is processed to mature, functional miR-127-3p in TNBC tumor cells. miR-127PD decreased the viability and motility of TNBC cells, sensitized TNBC cells to chemotherapy, and restricted the TNBC stem cell population. Furthermore, systemic delivery of miR-127PD suppressed tumor growth of MDA-MB-231 and MDA-MB-468 TNBC cells and spontaneous metastasis of MDA-MB-231 cells. In addition, CERK, NANOS1, FOXO6, SOX11, SOX12, FASN, and SUSD2 were identified as novel, functionally important targets of miR-127. In conclusion, our study demonstrates that miR-127 functions as a tumor and metastasis suppressor in TNBC and that delivery of miR-127 may hold promise as a novel therapy.

Significance:
Exogenous administration of miR-127, which is functionally activated in target cells, inhibits growth and spontaneous metastasis of triple-negative breast cancer.
Epigenetic Aging: More Than Just a Clock When It Comes to Cancer
Authors: Yu Ming , Hazelton William D. , Luebeck Georg E. , Grady William M. 
Published: November 2019

Abstract
The incidence of cancer, adjusted for secular trends, is directly related to age, and advanced chronologic age is one of the most significant risk factors for cancer. Organismal aging is associated with changes at the molecular, cellular, and tissue levels and is affected by both genetic and environmental factors. The specific mechanisms through which these age-associated molecular changes contribute to the increased risk of aging-related disease, such as cancer, are incompletely understood. DNA methylation, a prominent epigenetic mark, also changes over a lifetime as part of an “epigenetic aging” process. Here, we give an update and review of epigenetic aging, in particular, the phenomena of epigenetic drift and epigenetic clock, with regard to its implication in cancer etiology. We discuss the discovery of the DNA methylation–based biomarkers for biological tissue age and the construction of various epigenetic age estimators for human clinical outcomes and health/life span. Recent studies in various types of cancer point to the significance of epigenetic aging in tumorigenesis and its potential use for cancer risk prediction. Future studies are needed to assess the potential clinical impact of strategies focused on lowering cancer risk by preventing premature aging or promoting healthy aging.
MET Inhibition Elicits PGC1α-Dependent Metabolic Reprogramming in Glioblastoma
Authors: Zhang Yiru , Nguyen Trang T.T. , Shang Enyuan , Mela Angeliki , Humala Nelson , Mahajan Aayushi , Zhao Junfei , Shu Chang , Torrini Consuelo , Sanchez-Quintero Maria J. , Kleiner Giulio , Bianchetti Elena , Westhoff Mike-Andrew , Quinzii Catarina M. , Karpel-Massler Georg , Bruce Jeffrey N. , Canoll Peter , Siegelin Markus D. 
Published: November 2019

Abstract

The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-13C-glucose, U-13C-glutamine, and U-13C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species. Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that cAMP response elements binding protein regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and β-oxidation of fatty acids (etomoxir) enhanced the antitumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy.

Significance:
c-MET inhibition causes profound metabolic reprogramming that can be targeted by drug combination therapies.
Adding Indoximod to Hypofractionated Radiotherapy with Anti-PD-1 Checkpoint Blockade Enhances Early NK and CD8+ T-Cell–Dependent Tumor Activity
Authors: Watanabe Tsubasa , Gaedicke Simone , Guffart Elena , Firat Elke , Niedermann Gabriele 
Published: November 2019

AbstractPurpose:There is growing interest in combinations of immunogenic radiotherapy (RT) and immune checkpoint blockade, but clinical responses are still limited. Therefore, we tested the triple therapy with an inhibitor of the indoleamine 2,3-dioxygenase pathway, which like immune checkpoints, downregulates the antitumor immune response.Experimental Design:Triple treatment with hypofractionated RT (hRT) + anti-PD-1 antibody (αPD1) + indoximod was compared with the respective mono- and dual therapies in two syngeneic mouse models.Results:The tumors did not regress following treatment with hRT + αPD1. The αPD1/indoximod combination was not effective at all. In contrast, triple treatment induced rapid, marked tumor regression, even in mice with a large tumor. The effects strongly depended on CD8+ T cells and partly on natural killer (NK) cells. Numbers and functionality of tumor-specific CD8+ T cells and NK cells were increased, particularly early during treatment. However, after 2.5–3 weeks, all large tumors relapsed, which was accompanied by increased apoptosis of tumor-infiltrating lymphocytes associated with a non-reprogrammable state of exhaustion, terminal differentiation, and increased activation-induced cell death, which could not be prevented by indoximod in these aggressive tumor models. Some mice with a smaller tumor were cured. Reirradiation during late regression (day 12), but not after relapse, cured almost all mice with a large B16-CD133 tumor, and strongly delayed relapse in the less immunogenic 4T1 model, depending on CD8+ T cells.Conclusions:Our findings may serve as a rationale for the clinical evaluation of this triple-combination therapy in patients with solitary or oligometastatic tumors in the neoadjuvant or the definitive setting.
Organoid Cultures as Preclinical Models of Non–Small Cell Lung Cancer
Authors: Shi Ruoshi , Radulovich Nikolina , Ng Christine , Liu Ni , Notsuda Hirotsugu , Cabanero Michael , Martins-Filho Sebastiao N. , Raghavan Vibha , Li Quan , Mer Arvind Singh , Rosen Joshua C. , Li Ming , Wang Yu-Hui , Tamblyn Laura , Pham Nhu-An , Haibe-Kains Benjamin , Liu Geoffrey , Moghal Nadeem , Tsao Ming-Sound 
Published: November 2019

Abstract

Purpose:
Non–small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide. There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease.

Experimental Design:
Thirty surgically resected NSCLC primary patient tissue and 35 previously established patient-derived xenograft (PDX) models were processed for organoid culture establishment. Organoids were histologically and molecularly characterized by cytology and histology, exome sequencing, and RNA-sequencing analysis. Tumorigenicity was assessed through subcutaneous injection of organoids in NOD/SCID mice. Organoids were subjected to drug testing using EGFR, FGFR, and MEK-targeted therapies.

Results:
We have identified cell culture conditions favoring the establishment of short-term and long-term expansion of NSCLC organoids derived from primary lung patient and PDX tumor tissue. The NSCLC organoids recapitulated the histology of the patient and PDX tumor. They also retained tumorigenicity, as evidenced by cytologic features of malignancy, xenograft formation, preservation of mutations, copy number aberrations, and gene expression profiles between the organoid and matched parental tumor tissue by whole-exome and RNA sequencing. NSCLC organoid models also preserved the sensitivity of the matched parental tumor to targeted therapeutics, and could be used to validate or discover biomarker–drug combinations.

Conclusions:
Our panel of NSCLC organoids closely recapitulates the genomics and biology of patient tumors, and is a potential platform for drug testing and biomarker validation.
Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study
Authors: Mahalingam Devalingam , Wilkinson Grey A. , Eng Kevin H. , Fields Paul , Raber Patrick , Moseley Jennifer L. , Cheetham Karol , Coffey Matt , Nuovo Gerard , Kalinski Pawel , Zhang Bin , Arora Sukeshi Patel , Fountzilas Christos 
Published: November 2019

AbstractPurpose:Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell–inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Tumor tissues from patients treated with pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab and chemotherapy in patients with PDAC would be safe and effective.Patients and Methods:A phase Ib single-arm study enrolled patients with PDAC who progressed after first-line treatment. Patients received pelareorep, pembrolizumab, and either 5-fluorouracil, gemcitabine, or irinotecan until disease progression or unacceptable toxicity. Study objectives included safety and dose-limiting toxicities, tumor response, evaluation for reovirus replication, and immune analysis in peripheral blood and tumor biopsies.Results:Eleven patients were enrolled. Disease control was achieved in three of the 10 efficacy-evaluable patients. One patient achieved partial response for 17.4 months. Two additional patients achieved stable disease, lasting 9 and 4 months, respectively. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed the creation of new T-cell clones during treatment. High peripheral clonality and changes in the expression of immune genes were observed in patients with clinical benefit.Conclusions:Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy. Further evaluation of pelareorep and anti–PD-1 therapy is ongoing in follow-up studies. This research highlights the potential utility of several pretreatment and on-treatment biomarkers for pelareorep therapy warranting further investigation.
CRISPR Screening Identifies WEE1 as a Combination Target for Standard Chemotherapy in Malignant Pleural Mesothelioma
Authors: Xu Duo , Liang Shun-Qing , Yang Haitang , Bruggmann Rémy , Berezowska Sabina , Yang Zhang , Marti Thomas Michael , Hall Sean Ralph Robert , Gao Yanyun , Kocher Gregor J. , Schmid Ralph A. , Peng Ren-Wang 
Published: November 2019

Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer with dismal prognosis, largely due to poor response rates to and rapid relapse after first-line pemetrexed (MTA)/cisplatin chemotherapy. A better understanding of the molecular mechanisms underlying chemotherapy sensitivity and duration represents a significant but still unmet clinical need. In this study, we reported on a kinome CRISPR/Cas9 knockout screen that identified several G2–M checkpoint kinases, including WEE1, whose loss of function sensitizes MPM cells to standard chemotherapy. We further showed that deregulation of the G2–M checkpoint contributes to chemotherapy resistance, and that WEE1 inhibition synergizes with cisplatin/MTA, leading to enhanced MPM cell death in vitro and potent antitumor effects in vivo. Mechanistically, WEE1 blockage overrides chemotherapy-induced G2–M cell-cycle arrest and promotes premature mitotic entry, which causes DNA damage accumulation and ultimately apoptosis. Our results suggest a new therapeutic combination for MPM, and support the application of CRISPR/Cas9-based functional genomics in identifying novel therapeutic targets to potentiate existing cancer therapies.
Кількісна морфологічна оцінка структурної перебудови артерій яєчка при артеріальній гіпертензії в малому колі кровообігу
Authors: Hnatjuk M. S. , Tatarchuk L. V. , Konovalenko S. O. 
Published: November 2019

Мета роботи: вивчити особливості структурної перебудови артерій яєчків при пострезекційній легеневій артеріальній гіпертензії.
Матеріали і методи. Морфологічними методами досліджено структурну перебудову артерій яєчок 45 щурів, які були розділені на 3 групи. 1-ша група включала 15 інтактних тварин, 2-га – 20 щурів з артеріальною гіпертензією у малому колі кровообігу і компенсованим легеневим серцем, 3-тя – 10 експериментальних тварин з легеневою артеріальною гіпертензією і декомпенсованим легеневим серцем. Пострезекційну легеневу артеріальну гіпертензію і легеневе серце моделювали шляхом виконання у щурів правосторонньої пульмонектомії. Через місяць від початку досліду здійснювали евтаназію щурів кровопусканням в умовах тіопенталового наркозу. Проводили окреме зважування камер серця, їх планіметрію. З яєчок вирізали шматочки, які фіксували в 10 % розчині формаліну, проводили через етилові спирти зростаючої концентрації та поміщали у парафін. Мікротомні зрізи після депарафінізації фарбували різними барвниками. У лівому та правому яєчках вимірювали зовнішній і внутрішній діаметри артерій дрібного калібру, товщину медії, індекс Керногана, висоту ендотеліоцитів, діаметр їх ядер, ядерно-цитоплазматичні відношення в ендотеліоцитах, відносний об’єм ушкоджених клітин. Кількісні показники обробляли статистично.
Результати досліджень та їх обговорення. Морфометрично виявлено, що при декомпенсації пострезекційного легеневого серця просвіт артерій дрібного калібру лівого яєчка зменшився на 12,6 %, індекс Керногана – на 11,7 %, а правого – відповідно на 9,5 та 9,9 %. Відносний об’єм ушкоджених ендотеліоцитів досліджуваних судин у лівому яєчку при правошлуночковій недостатності зріс у 11,6 раза, а правому – у 9,3 раза. Встановлено, що в умовах змодельованої патології виражено потовщується стінка, звужується просвіт досліджуваних артерій, пошкоджуються ендотеліоцити, порушується структурний клітинний гомеостаз, що ускладнюється їх дисфункцією, погіршанням кровопостачання органа, гіпоксією, дистрофічними, некробіотичними змінами клітин і тканин, осередками інфільтрації та склерозу. Структурні зміни артерій переважали у лівому яєчку та при декомпенсації легеневого серця.
Monogenic and Polygenic Contributions to Atrial Fibrillation Risk
Authors: Choi Seung Hoan , Jurgens Sean J. , Weng Lu-Chen , Pirruccello James P. , Roselli Carolina , Chaffin Mark , Lee Christina J.-Y. , Hall Amelia W. , Khera Amit V. , Lunetta Kathryn L. , Lubitz Steven A. , Ellinor Patrick T. 
Published: November 2019

Rationale:

Genome-wide association studies have identified over 100 genetic loci for atrial fibrillation (AF); recent work described an association between loss-of-function (LOF) variants in
TTN
and early-onset AF.

Objective:
We sought to determine the contribution of rare and common genetic variation to AF risk in the general population.

Methods:
The UK Biobank is a population-based study of 500 000 individuals including a subset with genome-wide genotyping and exome sequencing. In this case-control study, we included AF cases and controls of genetically determined white-European ancestry; analyses were performed using a logistic mixed-effects model adjusting for age, sex, the first 4 principal components of ancestry, empirical relationships, and case-control imbalance. An exome-wide, gene-based burden analysis was performed to examine the relationship between AF and rare, high-confidence LOF variants in genes with ≥10 LOF carriers. A polygenic risk score for AF was estimated using the LDpred algorithm. We then compared the contribution of AF polygenic risk score and LOF variants to AF risk.

Results:

The study included 1546 AF cases and 41 593 controls. In an analysis of 9099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene,
TTN
(odds ratio, 2.71,
P
=2.50×10
−8
). The association with AF was more significant (odds ratio, 6.15,
P
=3.26×10
−14
) when restricting to LOF variants located in exons highly expressed in cardiac tissue (
TTN
LOF
). Overall, 0.44% of individuals carried
TTN
LOF
variants, of whom 14% had AF. Among individuals in the highest 0.44% of the AF polygenic risk score only 9.3% had AF. In contrast, the AF polygenic risk score explained 4.7% of the variance in AF susceptibility, while
TTN
LOF
variants only accounted for 0.2%.

Conclusions:

Both monogenic and polygenic factors contribute to AF risk in the general population. While rare
TTN
LOF
variants confer a substantial AF penetrance, the additive effect of many common variants explains a larger proportion of genetic susceptibility to AF.