bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic Targeting of Nemo-like Kinase in Primary and Acquired Endocrine-resistant Breast Cancer
Authors: Wang Xian , Veeraraghavan Jamunarani , Liu Chia-Chia , Cao Xixi , Qin Lanfang , Kim Jin-Ah , Tan Ying , Loo Suet Kee , Hu Yiheng , Lin Ling , Lee Sanghoon , Shea Martin J. , Mitchell Tamika , Li Shunqiang , Ellis Matthew J. , Hilsenbeck Susan G. , Schiff Rachel , Wang Xiao-Song 
Published: February 2021

Abstract

Purpose:
Endocrine resistance remains a major clinical challenge in estrogen receptor (ER)–positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There is an unmet need to discover new drug targets in the unknown escape pathways. Here, we report Nemo-like kinase (NLK) as a new actionable kinase target that endows previously uncharacterized survival signaling in endocrine-resistant breast cancer.

Experimental Design:
The effects of NLK inhibition on the viability of endocrine-resistant breast cancer cell lines were examined by MTS assay. The effect of VX-702 on NLK activity was verified by kinase assay. The modulation of ER and its coactivator, SRC-3, by NLK was examined by immunoprecipitation, kinase assay, luciferase assay, and RNA sequencing. The therapeutic effects of VX-702 and everolimus were tested on cell line- and patient-derived xenograft (PDX) tumor models.

Results:
NLK overexpression endows reduced endocrine responsiveness and is associated with worse outcome of patients treated with tamoxifen. Mechanistically, NLK may function, at least in part, via enhancing the phosphorylation of ERα and its key coactivator, SRC-3, to modulate ERα transcriptional activity. Through interrogation of a kinase profiling database, we uncovered and verified a highly selective dual p38/NLK inhibitor, VX-702. Coadministration of VX-702 with the mTOR inhibitor, everolimus, demonstrated a significant therapeutic effect in cell line-derived xenograft and PDX tumor models of acquired or de novo endocrine resistance.

Conclusions:
Together, this study reveals the potential of therapeutic modulation of NLK for the management of the endocrine-resistant breast cancers with active NLK signaling.
ONC201 Shows Potent Anticancer Activity Against Medullary Thyroid Cancer via Transcriptional Inhibition of RET, VEGFR2, and IGFBP2
Authors: Bagheri-Yarmand Rozita , Dadu Ramona , Ye Lei , Shiny Jebaraj Yaashmin , Martinez Jade A. , Ma Junsheng , Tarapore Rohinton S. , Allen Joshua E. , Sherman Steven I. , Williams Michelle D. , Gagel Robert F. 
Published: February 2021

Abstract
Gain-of-function point mutations in the receptor tyrosine kinase RET, a driver oncogene in medullary thyroid carcinoma (MTC), prevent apoptosis through inhibition of ATF4, a critical transcriptional regulator of endoplasmic reticulum stress. However, the critical regulatory mechanisms driving RET-dependent oncogenesis remain elusive, and there is a clinical need to identify a transcriptional RET inhibitor. Here, we found that RET depletion decreased IGFBP2 and VEGFR2 mRNA and protein expression in MTC cells. IGFBP2 knockdown decreased cell survival and migration of MTC cells. In patients, IGFBP2 expression increased in metastatic MTC, and high IGFBP2 associated with poor overall survival. VEGFR2 protein levels were positively associated with RET expression in primary tumors, and VEGF-mediated increased cell viability was RET dependent. The small-molecule ONC201 treatment of MTC cells caused apoptotic cell death, decreased transcription of RET, VEGFR2, IGFBP2, increased mRNA levels of ATF4, and ATF4 target genes including DDIT3, BBC3, DUSP8, MKNK2, KLF9, LZTFL1, and SESN2. Moreover, IGFBP2 depletion increased ONC201-induced cell death. ONC201 inhibited tumor growth at a well-tolerated dose of 120 mg/kg/week administered by oral gavage and decreased MTC xenograft cell proliferation and angiogenesis. The protein levels of RET, IGFBP2, and VEGFR2 were decreased in ONC201-treated xenografts. Our study uncovered a novel ONC201 mechanism of action through regulation of RET and its targets, VEGFR2 and IGFBP2; this mechanism could be translated into the clinic and represent a promising strategy for the treatment of all patients with MTC, including those with TKI-refractory disease and other cancer with RET abnormalities.
Anti-LYPD1/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Ovarian Cancer
Authors: Lo Amy A. , Johnston Jennifer , Li Ji , Mandikian Danielle , Hristopoulos Maria , Clark Robyn , Nickles Dorothee , Liang Wei-Ching , Hötzel Kathy , Dunlap Debra , Pham Thinh , Cai Hao , Ovacik Meric , Bravo-Perez Daniel , Mai Elaine , Slaga Dionysos , Ellerman Diego , Ziai James , Totpal Klara , Lee Genee , Boswell C. Andrew , Payandeh Jian , Wu Yan , Junttila Teemu T. 
Published: February 2021

Abstract
Ovarian cancer is a diverse class of tumors with very few effective treatment options and suboptimal response rates in early clinical studies using immunotherapies. Here we describe LY6/PLAUR domain containing 1 (LYPD1) as a novel target for therapeutic antibodies for the treatment of ovarian cancer. LYPD1 is broadly expressed in both primary and metastatic ovarian cancer with ∼70% prevalence in the serous cancer subset. Bispecific antibodies targeting CD3 on T cells and a tumor antigen on cancer cells have demonstrated significant clinical activity in hematologic cancers. We have developed an anti-LYPD1/CD3 T-cell-dependent bispecific antibody (TDB) to redirect T-cell responses to LYPD1 expressing ovarian cancer. Here we characterize the nonclinical pharmacology of anti-LYPD1/CD3 TDB and show induction of a robust polyclonal T-cell activation and target dependent killing of LYPD1 expressing ovarian cancer cells resulting in efficient in vivo antitumor responses in PBMC reconstituted immune-deficient mice and human CD3 transgenic mouse models. Anti-LYPD1/CD3 TDB is generally well tolerated at high-dose levels in mice, a pharmacologically relevant species, and showed no evidence of toxicity or damage to LYPD1 expressing tissues.
ERK Inhibitor LY3214996-Based Treatment Strategies forRAS-Driven Lung Cancer
Authors: Köhler Jens , Zhao Yutong , Li Jiaqi , Gokhale Prafulla C. , Tiv Hong L. , Knott Aine R. , Wilkens Margaret K. , Soroko Kara M. , Lin Mika , Ambrogio Chiara , Musteanu Monica , Ogino Atsuko , Choi Jihyun , Bahcall Magda , Bertram Arrien A. , Chambers Emily S. , Paweletz Cloud P. , Bhagwat Shripad V. , Manro Jason R. , Tiu Ramon V. , Jänne Pasi A. 
Published: February 2021

AbstractRAS gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them the MAPK, PI3K, and RB pathways. Within the MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals and activating cytoplasmic and nuclear targets. In view of disappointing antitumor activity and toxicity of continuously applied MEK inhibitors in patients with KRAS-mutant lung cancer, research has recently focused on ERK1/2 proteins as therapeutic targets and on ERK inhibitors for their ability to prevent bypass and feedback pathway activation. Here, we show that intermittent application of the novel and selective ATP-competitive ERK1/2 inhibitor LY3214996 exerts single-agent activity in patient-derived xenograft (PDX) models of RAS-mutant lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and—equally important—to identify biomarkers for patient stratification.
Isoform- and Phosphorylation-specific Multiplexed Quantitative Pharmacodynamics of Drugs Targeting PI3K and MAPK Signaling in Xenograft Models and Clinical Biopsies
Authors: Herrick William G. , Kilpatrick Casey L. , Hollingshead Melinda G. , Esposito Dominic , O'Sullivan Coyne Geraldine , Gross Andrea M. , Johnson Barry C. , Chen Alice P. , Widemann Brigitte C. , Doroshow James H. , Parchment Ralph E. , Srivastava Apurva K. 
Published: February 2021

Abstract
Ras/Raf/MEK/ERK (MAPK) and PI3K/AKT signaling pathways influence several cell functions involved in oncogenesis, making them attractive drug targets. We describe a novel multiplex immunoassay to quantitate isoform-specific phosphorylation of proteins in the PI3K/AKT and MAPK pathways as a tool to assess pharmacodynamic changes. Isoform-specific assays measuring total protein and site-specific phosphorylation levels of ERK1/2, MEK1/2, AKT1/2/3, and rpS6 were developed on the Luminex platform with validated antibody reagents. The multiplex assay demonstrated satisfactory analytic performance. Fit-for-purpose validation was performed with xenograft models treated with selected agents. In PC3 and HCC70 xenograft tumors, the PI3Kβ inhibitor AZD8186 suppressed phosphorylation of AKT1, AKT2, and rpS6 for 4 to 7 hours post single dose, but levels returned to baseline by 24 hours. AKT3 phosphorylation was suppressed in PC3 xenografts at all doses tested, but only at the highest dose in HCC70. The AKT inhibitor MK-2206 reduced AKT1/2/3 phosphorylation in SW620 xenograft tumors 2 to 4 hours postdose, and the MEK inhibitor selumetinib reduced MEK1/2 and ERK1/2 phosphorylation by up to 50% and &gt;90%, respectively. Clinical utility was demonstrated by analyzing biopsies from untreated patients with plexiform neurofibromas enrolled in a clinical trial of selumetinib (NCT02407405). These biopsies showed MEK and ERK phosphorylation levels sufficient for measuring up to 90% inhibition, and low AKT and rpS6 phosphorylation. This validated multiplex immunoassay demonstrates the degree and duration of phosphorylation modulation for three distinct classes of drugs targeting the PI3K/AKT and MAPK pathways.
Clinical and Biological Subtypes of B-cell Lymphoma Revealed by Microenvironmental Signatures
Authors: Kotlov Nikita , Bagaev Alexander , Revuelta Maria V. , Phillip Jude M. , Cacciapuoti Maria Teresa , Antysheva Zoya , Svekolkin Viktor , Tikhonova Ekaterina , Miheecheva Natalia , Kuzkina Natalia , Nos Grigorii , Tabbo Fabrizio , Frenkel Felix , Ghione Paola , Tsiper Maria , Almog Nava , Fowler Nathan , Melnick Ari M. , Leonard John P. , Inghirami Giorgio , Cerchietti Leandro 
Published: February 2021

AbstractDiffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment.Significance:In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies.This article is highlighted in the In This Issue feature, p. 1307
Record of the non-indigenous species Sternaspis aff. nana Zhadan, Tzetlin & Salazar-Vallejo, 2017 (Annelida: Sternaspidae) in the Southwest Atlantic Ocean
Authors: Craveiro Nykon , Rosa Filho José Souto 
Published: February 2021

The introduction of non-indigenous marine species in new habitats is generally associated with ships arriving at ports, driven by species transported in ballast water and sediment and biofouling communities on ship hulls, drifting object and underwater surfaces in dock areas. The present paper reports the record of the specie Sternaspis aff. nana in the Atlantic Ocean, discussing its possible conservation status and method of arrival to Brazil. Sediments samples were collected in the external area (11 m depth) of the Suape Harbor (Brazil) in February 2018. Two individuals of Sternaspis aff. nana were recorded, representing the first record of this species in the Southwest Atlantic Ocean. The way S. aff. nana arrived in Brazilian waters cannot be easily determined, the short-lived lecithotrophic larvae of sternaspids suggest that the specimens found in Suape have arrived in ballast sediment. An increase in trade between Brazil and Asian countries since the 2000s has led to that more ships coming from China having arrived in Brazilian harbors. The arrival of S. aff. nana, originally described in the South China Sea, in the Suape harbor area may have resulted from this intense movement of ships between China and Brazil.
Biological and morphological aspects of Plectris aliena (Coleoptera: Melolonthidae) in sugarcane in Brazil
Authors: Gomes Elias Soares , Ávila Crébio José , Cherman Mariana Alejandra 
Published: February 2021

Plectris aliena (Coleoptera, Melolonthidae) Chapin is a species already recorded causing serious damage to various cultures in North America and Australia. Although its occurrence has recently been reported in Brazil, information about its distribution, taxonomy, and biology is limited. Thus, this study aims to report this new occurrence of P. aliena in Deodápolis (Mato Grosso do Sul, Brazil), as well as to present bioecological and morphological aspects of this species. In this way, the seasonal distribution and the life cycle was studied in the years 2017 and 2018. The larvae were sampled through trenches made in the soil and reared in the laboratory. Adults were captured using “Luiz de Queiroz” light traps. Adults have body with dense white hairs, antennae with 10 antenomeres; they measure approximately 12 mm in length, and their antennal lamellae are larger for males than females. The larvae reach 30 mm in length in the third stage and pupae show about 19 mm in length. The life cycle of this species is univoltine. Due to the great diversity of Plectris and the scarce information available about this species in South America, this study will facilitate its identification in the field and indicate the best time for monitoring in sugarcane crop.
Contribution to the knowledge of Atrichobrunettia Satchel, 1953 (Diptera, Psychodidae) from Brazil
Authors: Araújo Maíra Xavier , Bravo Freddy 
Published: February 2021

A new species of moth-fly, Atrichobrunettia (Polibrunettia) longipalpis sp. nov. (Psychodinae, Psychodidae), from the Brazilian Atlantic Rain Forest is described. It can be distinguished from other species of the subgenus mainly by the length of palpus that is longer and by the dentate distal margin of hypandrium. Here the distribution of A. angelae Bravo, 2006 and A. paranaensis Bravo, 2005 is reviewed and morphological data to A. paranaensis Bravo, 2006 is given to complement the original description of the species.
New Insight Into Metformin-Induced Cholesterol-Lowering Effect Crosstalk Between Glucose and Cholesterol Homeostasis via ChREBP (Carbohydrate-Responsive Element-Binding Protein)-Mediated PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Regulation
Authors: Hu Die , Guo Yanhong , Wu Renrong , Shao Tiannan , Long Junke , Yu Bilian , Wang Huilun , Luo Yonghong , Lu Haocheng , Zhang Jifeng , Chen Y. Eugene , Peng Daoquan 
Published: February 2021

Objective:
Metformin, a first-line drug for treating individuals with type 2 diabetes, exerts beneficial effects on cholesterol-lowering, yet its precise mechanism has not been established.

Approach and Results:
In 2 dyslipidemia mouse models, administration of metformin significantly decreased serum cholesterol and PCSK9 (proprotein convertase subtilisin/kexin type 9) levels, accompanied by decreased expression of PCSK9 in both mRNA and protein levels resulting in a 3-fold increase of LDLR (low-density lipoprotein receptor) in the liver. In human hepatocytes, metformin treatment suppressed the PCSK9 transcription. Depressed transcription was driven by a glucose sensor, the ChREBP (carbohydrate-responsive element-binding protein) but not by the intracellular cholesterol sensor, the SREBP2 (sterol regulatory element-binding protein 2). We further identified PCSK9 as a novel target gene of ChREBP. Metformin decreased the expression of ChREBP and inhibited its transcriptional activity by blocking its nuclear translocation attributed to the decreased intracellular glucose and glucose metabolites levels. Moreover, metformin treatment significantly decreased serum low-density lipoprotein cholesterol and PCSK9 levels in nondiabetic individuals.

Conclusions:
Collectively, we revealed a new mechanism of action of metformin in cholesterol-lowering and identified a novel crosstalk signal between glucose and cholesterol homeostasis via ChREBP-mediated PCSK9 regulation.
Molecular Mechanisms of Diaphragm Myopathy in Humans With Severe Heart Failure
Authors: Mangner Norman , Garbade Jens , Heyne Estelle , van den Berg Marloes , Winzer Ephraim B. , Hommel Jennifer , Sandri Marcus , Jozwiak-Nozdrzykowska Joanna , Meyer Anna L. , Lehmann Sven , Schmitz Clara , Malfatti Edoardo , Schwarzer Michael , Ottenheijm Coen A.C. , Bowen T. Scott , Linke Axel , Adams Volker 
Published: February 2021

Rationale:
Diaphragm weakness impairs quality of life, exercise capacity, and survival in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction. However, the underlying cellular mechanisms responsible in humans remain poorly resolved.

Objectives:
We prospectively evaluated clinical, functional (in vivo/in vitro), histological/ultrastructural, and molecular alterations of the diaphragm from patients with CHF receiving a left ventricular assist device compared with patients without CHF undergoing elective coronary bypass grafting (control) in the observational LIPAMUS-HF (Lipsia Diaphragm And Muscle Heart Failure).

Methods and Results:
Participants (controls=21, CHF=18) underwent cardiopulmonary exercise and spirometry/respiratory muscle testing alongside diaphragm and cardiac imaging. Diaphragm biopsies were phenotyped for mitochondrial respiration, muscle fiber function, histology/ultrastructure, and protein expression.

In vivo respiratory muscle function and diaphragm thickness were reduced in CHF by 38% and 23%. Diaphragm biopsies revealed a fiber-type shift and severe fiber atrophy in CHF alongside elevated proteasome-dependent proteolysis (ie, MuRF1 [muscle-specific RING finger protein 1] expression, ubiquitination, ubiquitin-proteasome activity) and myofibrillar protein oxidation, which corresponded to upregulated Nox (NADPH [nicotinamide adenine dinucleotide phosphate oxidase] oxidase; Nox2/Nox4) signaling. Mitochondria demonstrated severe intrinsic functional and ultrastructural abnormalities in CHF characterized by accumulation of small mitochondria and inhibited autophagy/mitophagy. Single muscle fiber contractile function revealed reduced Ca
2+
sensitivity in CHF and there was evidence of RyR1 (ryanodine receptor 1) dysfunction indicating Ca
2+
leak from the sarcoplasmic reticulum. Mitochondrial and Ca
2+
measures corresponded to upregulated Nox4 isoform NADPH oxidase expression. Molecular markers correlated to whole-body exercise intolerance and diaphragm dysfunction/wasting.

Conclusions:

Patients with CHF demonstrate an obvious diaphragm myopathy independent of disuse or other confounding factors, such as aging, obesity, or hypertension. Diaphragm weakness in CHF was associated with intracellular abnormalities characterized by fiber atrophy, oxidative stress, mitochondrial dysfunction, impaired Ca
2+
homeostasis, elevated proteasome-dependent proteolysis, but inhibited autophagy/mitophagy, which we speculate offers a novel therapeutic molecular target regulated by a Nox-MuRF1/ubiquitin-proteasome-mitochondria-RyR1/Ca
2+
signaling axis.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02663115.
Intracerebral Hemorrhage in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
Authors: Liao Yi-Chu , Hu Yu-Chen , Chung Chih-Ping , Wang Yen-Feng , Guo Yuh-Cherng , Tsai Yu-Shuen , Lee Yi-Chung 
Published: February 2021

Background and Purpose:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic cerebral small vessel disease. The role of intracerebral hemorrhage (ICH) in CADASIL remains elusive. The present study aims to investigate the prevalence, characteristics, and risk factors for ICH in CADASIL.

Methods:
This retrospective cross-sectional study investigated ICH and cerebral microbleeds (CMBs) in brain susceptibility-weighted imaging or T2*-weighted gradient-recalled echo images of 127 Taiwanese patients with genetically confirmed CADASIL. We analyzed CMBs, lacunes, white matter hyperintensity, and perivascular space. The total small vessel disease score (range, 0–4) was calculated to estimate the overall magnetic resonance imaging burden of small vessel disease. Multivariate regression analysis was performed to identify factors related to ICH lesions in CADASIL.

Results:
Thirty-seven ICH lesions, including 15 symptomatic and 22 asymptomatic lesions, were found in 27 (21.3% [95% CI, 14.0%–30.9%]) of the 127 patients with CADASIL. The thalamus and lobar regions were the most common ICH locations, and 72.7% of the lobar hemorrhages occurred silently. Patients with CADASIL with ICH lesions more often had hypertension and a higher total small vessel disease score than those without ICH (odds ratio [95% CI]: 3.22 [1.25–8.30] and 3.79 [1.51–9.51]). The presence of CMBs in the brain stem and a total CMB count >10 were independently associated with ICH lesions in patients with CADASIL, with odds ratio (95% CI) of 5.82 (1.80–18.80) and 3.83 (1.08–13.67), respectively.

Conclusions:
ICH is an underestimated but important manifestation of CADASIL. The location and number of CMBs are associated with the presence of ICH lesions in patients with CADASIL.