bluuebunny/crossref_metadata_2025_split huggingface dataset:
N6-methyladenosine mRNA methylation of PIK3CB regulates AKT signalling to promote PTEN-deficient pancreatic cancer progression
Authors: Tian Jianbo , Zhu Ying , Rao Meilin , Cai Yimin , Lu Zequn , Zou Danyi , Peng Xiating , Ying Pingting , Zhang Ming , Niu Siyuan , Li Yue , Zhong Rong , Chang Jiang , Miao Xiaoping 
Published: April 2020

ObjectivePancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N6-methyladenosine (m6A) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear.DesignWe first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene PIK3CB underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth.ResultsWe identified a missense variant rs142933486 in PIK3CB that is significantly associated with the overall survival of PDAC by reducing the PIK3CB m6A level, which facilitated its mRNA and protein expression levels mediated by the m6A ‘writer’ complex (METTL13/METTL14/WTAP) and the m6A ‘reader’ YTHDF2. The upregulation of PIK3CB is widely found in PDAC tumour tissues and significantly correlated with the poor prognosis of PDAC, especially in PTEN-deficient patients. We further demonstrated that PIK3CB overexpression substantially enhanced the proliferation and migration abilities of PTEN-deficient PDAC cells and activated AKT signalling pathway. Remarkably, KIN-193, a PIK3CB-selective inhibitor, is shown to serve as an effective anticancer agent for blocking PTEN-deficient PDAC.ConclusionsThese findings demonstrate aberrant m6A homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of PIK3CB as a therapeutic target for this disease.
SMARCAfamily of genes
Authors: Chetty Runjan , Serra Stefano 
Published: April 2020

TheSMARCAsubgroup of genes belong to the SWI1/SNF1 family that are responsible chromatin remodelling and repair. Inactivating mutations in the mainSMARCAgenesA2andA4lead to loss of expression of their respective proteins within the nucleus and, as such have characterised a set of malignancies that are underpinned by SMARCA-deficiency.The morphology of these tumours ranges from small to large epithelioid cells, giant cells and rhabdoid cells. The rhabdoid cells are frequently present in these tumours but are not a sine qua non for the diagnosis. Most of these tumours are undifferentiated or dedifferentiated, high-grade pleomorphic carcinomas. Focally, areas of better differentiation can be seen. The initial description of a SMARCA4-deficient malignancy was the small cell carcinoma of the ovary, hypercalcaemic type. Subsequently, tumours fitting this characteristic morphology and immunophenotype have been described in the lung, thoracic cavity, endometrium and sinonasal tract, gastrointestinal tract and kidney. Immunohistochemical loss of SMARCA2 and SMARCA4 may occur concomitantly or independently of each other.SMARCA-deficient malignant tumours represent a unique subset of tumours with typical morphological and immunohistochemical findings.
Central nervous system complications associated with immune checkpoint inhibitors
Authors: Vogrig Alberto , Muñiz-Castrillo Sergio , Joubert Bastien , Picard Geraldine , Rogemond Veronique , Marchal Cécile , Chiappa Anne Marie , Chanson Eve , Skowron François , Leblanc Amelie , Ducray François , Honnorat Jerome 
Published: April 2020

ObjectiveTo describe the spectrum and outcome of central nervous system complications associated with immune checkpoint inhibitors (CNS-ICI).MethodsPatients with CNS-ICI were identified and their characteristics compared with ICI-related peripheral neuropathy (PN-ICI).ResultsWe identified 19 patients with CNS-ICI. The patients were receiving nivolumab (n=8), pembrolizumab (n=6), a combination of ipilimumab-nivolumab (n=3), ipilimumab-durvalumab (n=1), or atezolizumab (n=1). Underlying malignancies included non-small-cell lung cancer (n=8), melanoma (n=3), and other less common tumours (n=8). Neurological phenotypes were limbic encephalitis (n=8), meningoencephalitis (n=4) and cerebellitis (n=4). Two patients developed isolated confusion and one parkinsonism. Associated autoantibodies included onconeural (Ma2, n=7; Hu, n=1), astrocytic (glial fibrillar acidic protein, n=2) and neuronal surface (contactin-associated protein-like 2, n=1) specificities. ICIs were withheld and corticosteroid treatment was given in all cases. Five patients received intravenous immunoglobulin, two rituximab, one plasmapheresis and one infliximab. Overall, six patients died. Readministration of ICI was attempted in three patients, without further relapses. Non-small-cell lung cancer was significantly more frequent in patients with CNS-ICI (p<0.01), while melanoma and ipilimumab treatment were more common in PN-ICI (p<0.01 and p=0.01). Conversely, CNS-ICI cases were more frequently antibody-positive than PN-ICI (p<0.01) and showed a strong trend towards poorer outcome (p=0.053).ConclusionThree main clinical phenotypes characterise CNS complications of ICIs, each with distinct immunological background, disease course and response to treatment. Other clinical manifestations (including parkinsonism and steroid-responsive confusion) are also possible. Underlying cancers, antibody prevalence and outcome appear different from those of patients with PN-ICI.
Bound on Lyapunov exponent in $$c=1$$ matrix model
Authors: Morita Takeshi 
Published: April 2020

AbstractClassical particle motions in an inverse harmonic potential show the exponential sensitivity to initial conditions, where the Lyapunov exponent $$\lambda _L$$λL is uniquely fixed by the shape of the potential. Hence, if we naively apply the bound on the Lyapunov exponent $$\lambda _L \le 2\pi T/ \hbar $$λL≤2πT/ħ to this system, it predicts the existence of the bound on temperature (the lowest temperature) $$T \ge \hbar \lambda _L/ 2\pi $$T≥ħλL/2π and the system cannot be taken to be zero temperature when $$\hbar \ne 0$$ħ≠0. This seems a puzzle because particle motions in an inverse harmonic potential should be realized without introducing any temperature but this inequality does not allow it. In this article, we study this problem in N non-relativistic free fermions in an inverse harmonic potential ($$c=1$$c=1 matrix model). We find that thermal radiation is induced when we consider the system in a semi-classical regime even though the system is not thermal at the classical level. This is analogous to the thermal radiation of black holes, which are classically non-thermal but behave as thermal baths quantum mechanically. We also show that the temperature of the radiation in our model saturates the inequality, and thus, the system saturates the bound on the Lyapunov exponent, although the system is free and integrable. Besides, this radiation is related to acoustic Hawking radiation of the fermi fluid.
Volkov–Akulov–Starobinsky supergravity revisited
Authors: Aldabergenov Yermek 
Published: April 2020

AbstractWe find new realizations of Volkov–Akulov–Starobinsky supergravity, i.e. Starobinsky inflationary models in supergravity coupled to a nilpotent superfield describing Volkov–Akulov goldstino. Our constructions are based on the no-scale Kähler potential $$K=-3\log (T+\overline{T})$$K=-3log(T+T¯) for the inflaton field, and can describe de Sitter vacuum after inflation where supersymmetry is broken by the goldstino auxiliary component. In fact, we show that a more general class of models with $$K=-\alpha \log (T+\overline{T})$$K=-αlog(T+T¯) for $$3\le \alpha \lesssim 6.37$$3≤α≲6.37 can accomodate Starobinsky-like inflation with the universal prediction $$n_s\simeq 1-\frac{2}{N_e}$$ns≃1-2Ne and $$r\simeq \frac{4\alpha }{(\alpha -2)^2N_e^2}$$r≃4α(α-2)2Ne2, while for $$6.37\lesssim \alpha \lesssim 7.23$$6.37≲α≲7.23 viable hilltop inflation is possible (with $$n_s$$ns and r close to the above expressions). We derive the full component action and the masses of sinflaton, gravitino, and inflatino that are generally around the inflationary Hubble scale. Finally, we show that one of our models can be dualized into higher-derivative supergravity with constrained chiral curvature superfield.
Particle event generator: a simple-in-use system PEGASUS version 1.0
Authors: Lipatov A. V. , Malyshev M. A. , Baranov S. P. 
Published: April 2020

Abstractpegasusis a parton-level Monte-Carlo event generator designed to calculate cross sections for a wide range of hard QCD processes at high energyppand$$p\bar{p}$$pp¯collisions, which incorporates the dynamics of transverse momentum dependent (TMD) parton distributions in a proton. Being supplemented with off-shell production amplitudes for a number of partonic subprocesses and provided with necessary TMD gluon density functions, it produces weighted or unweighted event records which can be saved as a plain data file or a file in a commonly used Les Houches Event format. A distinctive feature of thepegasusis an intuitive and extremely user friendly interface, allowing one to easily implement various kinematical cuts into the calculations. Results can be also presented “on the fly” with built-in toolpegasus plotter. A short theoretical basis is presented and detailed program description is given.
MTH1 Inhibitor TH588 Disturbs Mitotic Progression and Induces Mitosis-Dependent Accumulation of Genomic 8-oxodG
Authors: Rudd Sean G. , Gad Helge , Sanjiv Kumar , Amaral Nuno , Hagenkort Anna , Groth Petra , Ström Cecilia E. , Mortusewicz Oliver , Berglund Ulrika Warpman , Helleday Thomas 
Published: April 2020

Abstract

Reactive oxygen species (ROS) oxidize nucleotide triphosphate pools (e.g., 8-oxodGTP), which may kill cells if incorporated into DNA. Whether cancers avoid poisoning from oxidized nucleotides by preventing incorporation via the oxidized purine diphosphatase MTH1 remains under debate. Also, little is known about DNA polymerases incorporating oxidized nucleotides in cells or how oxidized nucleotides in DNA become toxic. Here we show that replacement of one of the main DNA replicases in human cells, DNA polymerase delta (Pol δ), with an error-prone variant allows increased 8-oxodG accumulation into DNA following treatment with TH588, a dual MTH1 inhibitor and microtubule targeting agent. The resulting elevated genomic 8-oxodG correlated with increased cytotoxicity of TH588. Interestingly, no substantial perturbation of replication fork progression was observed, but rather mitotic progression was impaired and mitotic DNA synthesis triggered. Reducing mitotic arrest by reversin treatment prevented accumulation of genomic 8-oxodG and reduced cytotoxicity of TH588, in line with the notion that mitotic arrest is required for ROS buildup and oxidation of the nucleotide pool. Furthermore, delayed mitosis and increased mitotic cell death was observed following TH588 treatment in cells expressing the error-prone but not wild-type Pol δ variant, which is not observed following treatments with antimitotic agents. Collectively, these results link accumulation of genomic oxidized nucleotides with disturbed mitotic progression.

Significance:
These findings uncover a novel link between accumulation of genomic 8-oxodG and perturbed mitotic progression in cancer cells, which can be exploited therapeutically using MTH1 inhibitors.
See related commentary by Alnajjar and Sweasy, p. 3459
Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients withAKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer
Authors: Smyth Lillian M. , Tamura Kenji , Oliveira Mafalda , Ciruelos Eva M. , Mayer Ingrid A. , Sablin Marie-Paule , Biganzoli Laura , Ambrose Helen J. , Ashton Jack , Barnicle Alan , Cashell Des D. , Corcoran Claire , de Bruin Elza C. , Foxley Andrew , Hauser Joana , Lindemann Justin P.O. , Maudsley Rhiannon , McEwen Robert , Moschetta Michele , Pass Martin , Rowlands Vicky , Schiavon Gaia , Banerji Udai , Scaltriti Maurizio , Taylor Barry S. , Chandarlapaty Sarat , Baselga José , Hyman David M. 
Published: April 2020

AbstractPurpose:The activating mutation AKT1E17K occurs in approximately 7% of estrogen receptor–positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1E17K-mutant ER+ MBC.Patients and Methods:Patients with an AKT1E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort.Results:From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)].Conclusions:Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.
Adapting to a Pandemic — Conducting Oncology Trials during the SARS-CoV-2 Pandemic
Authors: Tan Aaron C. , Ashley David M. , Khasraw Mustafa 
Published: April 2020

AbstractThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has necessitated changes in cancer care delivery as resources are reallocated. Clinical trials and other research activities are inevitably impacted. Start-up activities for new trials may be deferred and recruitment suspended. For patients already enrolled however, there are challenges in continuing treatment on trial. Regulatory bodies have issued guidance on managing clinical trials during the pandemic, including contingency measures for remote study visits, delivery of investigational product, and site monitoring visits. New cancer clinical trial practices during the SARS-CoV-2 pandemic include new risk assessment strategies, decentralized and remote trial coordination, data collection, and delegation of specific therapeutic activities. This experience could provide evidence of more feasible and cost-effective methods for future clinical trial conduct.
Polycomb-like Protein 3 Induces Proliferation and Drug Resistance in Multiple Myeloma and Is Regulated by miRNA-15a
Authors: Yu Tengteng , Du Chenxing , Ma Xiaoke , Sui Weiwei , Yu Zhen , Liu Lanting , Zhao Lei , Li Zhongqing , Xu Jie , Wei Xiaojing , Zhou Wen , Deng Shuhui , Zou Dehui , An Gang , Tai Yu-Tzu , Tricot Guido , Anderson Kenneth C. , Qiu Lugui , Zhan Fenghuang , Hao Mu 
Published: April 2020

Abstract

Multiple myeloma remains incurable due to the persistence of a minor population of multiple myeloma cells that exhibit drug resistance, which leads to relapsed and/or refractory multiple myeloma. Elucidating the mechanism underlying drug resistance and developing an effective treatment are critical for clinical management of multiple myeloma. Here we showed that promoting expression of the gene for polycomb-like protein 3 (PHF19) induced multiple myeloma cell growth and multidrug resistance in vitro and in vivo. PHF19 was overexpressed in high-risk and drug-resistant primary cells from patients. High levels of PHF19 were correlated with inferior survival of patients with multiple myeloma, in the Total Therapy 2 cohort and in the Intergroup Francophone du Myeloma (IFM) cohort. Enhancing PHF19 expression levels increased Bcl-xL, Mcl-1, and HIF-1a expression in multiple myeloma cells. PHF19 also bound directly with EZH2 and promoted the phosphorylation of EZH2 through PDK1/AKT signaling. miR-15a is a small noncoding RNA that targeted the 3′UTR of PHF19. We found that downregulation of miR-15a led to high levels of PHF19 in multiple myeloma cells. These findings revealed that PHF19 served a crucial role in multiple myeloma proliferation and drug resistance and suggested that the miR-15a/PHF19/EZH2 pathway made a pivotal contribution to multiple myeloma pathogenesis, offering a promising approach to multiple myeloma treatment.

Implications:
Our findings identify that PHF19 mediates EZH2 phosphorylation as a mechanism of myeloma cell drug resistance, providing a rationale to explore therapeutic potential of targeting PHF19 in relapsed or refractory patients with multiple myeloma.
Maternal Obesity and Diabetes Mellitus as Risk Factors for Congenital Heart Disease in the Offspring
Authors: Helle Emmi , Priest James R. 
Published: April 2020

Abstract
Congenital heart disease (CHD) is the most common anatomical malformation occurring live‐born infants and an increasing cause of morbidity and mortality across the lifespan and throughout the world. Population‐based observations have long described associations between maternal cardiometabolic disorders and the risk of CHD in the offspring. Here we review the epidemiological evidence and clinical observations relating maternal obesity and diabetes mellitus to the risk of CHD offspring with particular attention to mechanistic models of maternal‐fetal risk transmission and first trimester disturbances of fetal cardiac development. A deeper understanding of maternal risk factors holds the potential to improve both prenatal detection of CHD by identifying at‐risk pregnancies, along with primary prevention of disease by improving preconception and prenatal treatment of at‐risk mothers.
A Feature-Based Approach to Classifying Summertime Potential Vorticity Streamers Linked to Rossby Wave Breaking in the North Atlantic Basin
Authors: Papin Philippe P. , Bosart Lance F. , Torn Ryan D. 
Published: April 2020

AbstractThis study examines climatological potential vorticity streamer (PVS) activity associated with Rossby wave breaking (RWB), which can impact TC activity in the subtropical North Atlantic (NATL) basin via moisture and wind anomalies. PVSs are identified along the 2-PVU (1 PVU = 10−6 K kg−1 m2 s−1) contour on the 350-K isentropic surface, using a unique identification technique that combines previous methods. In total, 21 149 individual PVS instances are identified from the ERA-Interim (ERAI) climatology during June–November over 1979–2015 with a peak in July–August. The total number of PVSs identified in this study is more than previous PVS climatologies for this region, since the new technique identifies a wider range of cases. Variations in PVS size and intensity prompt the development of a new PVS activity index (PVSI), which provides an integrated measure of PVS activity that can improve comparisons with TC activity. For instance, PVSI has a stronger negative correlation with seasonal TC activity (r = −0.55) relative to PVS frequency, size, or intensity alone. PVSI in June–July is also positively correlated with PVSI in August–November (r = 0.67), suggesting predictive capability. Compared to the ERAI and Japan Meteorological Agency 55-Year Reanalysis (JRA-55) climatology, there are more PVSs in the Climate Forecast System Reanalysis (CFSR) but these have weaker average intensity overall. While no long-term trend in PVSI is observed in the ERAI or JRA-55 climatologies, a negative trend is observed in CFSR, which could be related to differences in near tropopause static stability early in the climatological period (1979–86) between the CFSR and ERAI datasets.
Polydrug Use During Pregnancy and Preterm Birth in a Low-Income, Multiethnic Birth Cohort, Boston, 1998-2018
Authors: Garrison-Desany Henri M. , Nawa Nobutoshi , Kim Yoona , Ji Yuelong , (Susan) Chang Hsing-Yuan , Hong Xiumei , Wang Guoying , Pearson Colleen , Zuckerman Barry S. , Wang Xiaobin , Surkan Pamela J. 
Published: April 2020

Objective The opioid epidemic in the United States increasingly affects women of reproductive age and has resulted in a rise in concurrent polydrug use. The objective of this study was to investigate the effect of this polydrug use on preterm birth in a multiethnic birth cohort. Methods We analyzed data from 8261 mothers enrolled in the Boston Birth Cohort from 1998 to 2018 in Boston, Massachusetts. We grouped substances used during pregnancy based on their primary effects (stimulant or depressant) and assessed independent and combined associations with smoking on preterm birth. Results Of 8261 mothers, 131 used stimulant drugs and 193 used depressant drugs during pregnancy. The preterm birth rate was 27.5% (2271 of 8261) in the sample. Mothers who smoked had 35% increased odds of preterm birth across adjusted models. Mothers who used stimulant drugs without smoking were not at increased risk of preterm delivery compared with mothers who used neither (odds ratio [OR] = 0.69; 95% confidence interval [CI], 0.19-1.98), whereas mothers who used depressant drugs without smoking had more than twice the odds of having preterm delivery (OR = 2.31; 95% CI, 1.19-4.44), and infants were at risk of a 1-week reduction in gestational age (OR = −1.05; 95% CI, −2.07 to −0.03). Concurrently smoking and using depressant drugs was associated with increased odds of preterm birth (OR = 1.83; 95% CI, 1.28-2.61), as was concurrently smoking and using stimulant drugs (OR = 1.73; 95% CI, 1.14-2.59). Conclusions Using stimulant drugs and depressant drugs during pregnancy is a risk factor for preterm birth. The individual and combined effects of using these drugs with smoking must be considered together to reduce the risk of preterm birth in the United States.