bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Predictors of Circulating 25-Hydroxyvitamin D and Prognosis after Colorectal Cancer
Authors: Neumeyer Sonja , Butterbach Katja , Banbury Barbara L. , Berndt Sonja I. , Campbell Peter T. , Chlebowski Rowan T. , Chan Andrew T. , Giovannucci Edward L. , Joshi Amit D. , Ogino Shuji , Song Mingyang , McCullough Marjorie L. , Maalmi Haifa , Manson JoAnn E. , Sakoda Lori C. , Schoen Robert E. , Slattery Martha L. , White Emily , Win Aung K. , Figueiredo Jane C. , Hopper John L. , Macrae Finlay A. , Peters Ulrike , Brenner Hermann , Hoffmeister Michael , Newcomb Polly A. , Chang-Claude Jenny 
Published: March 2020

Abstract

Background:
Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer–specific survival.

Methods:
Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer–specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer.

Results:
The 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D–binding protein) was associated with poorer colorectal cancer–specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86–2.78] and colorectal cancer–specific mortality (HR = 1.76; 95% CI, 0.86–3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45–7.33; Pheterogeneity = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50–11.43, Pheterogeneity = 0.02).

Conclusions:
Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer–specific survival, although power might have been an issue.

Impact:
Further studies are warranted to investigate the association in specific subgroups.
Type I IFN, Ly6C+ cells, and Phagocytes Support Suppression of Peritoneal Carcinomatosis Elicited by a TLR and CLR Agonist Combination
Authors: Dyevoich Allison M. , Haas Karen M. 
Published: March 2020

AbstractMetastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Our previous study demonstrated a Toll-like receptor and C-type lectin receptor agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6′-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development following TA3-Ha and EL4 challenge through a mechanism dependent on B-1a cell–produced natural IgM and complement. In this study, we investigated additional players in the MPL/TDCM-elicited response. MPL/TDCM treatment rapidly increased type I IFN levels in the peritoneal cavity along with myeloid cell numbers, including macrophages and Ly6Chi monocytes. Type I IFN receptor (IFNAR1−/−) mice produced tumor-reactive IgM following MPL/TDCM treatment, but failed to recruit Ly6C+ monocytes and were not afforded protection during tumor challenges. Clodronate liposome depletion of phagocytic cells, as well as targeted depletion of Ly6C+ cells, also ablated MPL/TDCM-induced protection. Cytotoxic mediators known to be produced by these cells were required for effects. TNFα was required for effective TA3-Ha killing and nitric oxide was required for EL4 killing. Collectively, these data reveal a model whereby MPL/TDCM-elicited antitumor effects strongly depend on innate cell responses, with B-1a cell–produced tumor-reactive IgM and complement pairing with myeloid cell–produced cytotoxic mediators to effectively eradicate tumors in the peritoneal cavity.
Global Regulation of the Histone Mark H3K36me2 Underlies Epithelial Plasticity and Metastatic Progression
Authors: Yuan Salina , Natesan Ramakrishnan , Sanchez-Rivera Francisco J. , Li Jinyang , Bhanu Natarajan V. , Yamazoe Taiji , Lin Jeffrey H. , Merrell Allyson J. , Sela Yogev , Thomas Stacy K. , Jiang Yanqing , Plesset Jacqueline B. , Miller Emma M. , Shi Junwei , Garcia Benjamin A. , Lowe Scott W. , Asangani Irfan A. , Stanger Ben Z. 
Published: March 2020

Abstract

Epithelial plasticity, reversible modulation of a cell's epithelial and mesenchymal features, is associated with tumor metastasis and chemoresistance, leading causes of cancer mortality. Although different master transcription factors and epigenetic modifiers have been implicated in this process in various contexts, the extent to which a unifying, generalized mechanism of transcriptional regulation underlies epithelial plasticity remains largely unknown. Here, through targeted CRISPR/Cas9 screening, we discovered two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial-to-mesenchymal identity, tumor differentiation, and metastasis. Using a lysine-to-methionine histone mutant to directly inhibit H3K36me2, we found that global modulation of the mark is a conserved mechanism underlying the mesenchymal state in various contexts. Mechanistically, regulation of H3K36me2 reprograms enhancers associated with master regulators of epithelial-to-mesenchymal state. Our results thus outline a unifying epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity and metastasis in cancer.

Significance:
Although epithelial plasticity contributes to cancer metastasis and chemoresistance, no strategies exist for pharmacologically inhibiting the process. Here, we show that global regulation of a specific histone mark, H3K36me2, is a universal epigenome-wide mechanism that underlies epithelial-to-mesenchymal transition and mesenchymal-to-epithelial transition in carcinoma cells. These results offer a new strategy for targeting epithelial plasticity in cancer.
This article is highlighted in the In This Issue feature, p. 747
Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization
Authors: Liu Zhaoqi , Yoshimi Akihide , Wang Jiguang , Cho Hana , Chun-Wei Lee Stanley , Ki Michelle , Bitner Lillian , Chu Timothy , Shah Harshal , Liu Bo , Mato Anthony R. , Ruvolo Peter , Fabbri Giulia , Pasqualucci Laura , Abdel-Wahab Omar , Rabadan Raul 
Published: March 2020

Abstract

Although mutations in the gene encoding the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here, we characterize 98 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3′ splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most common SF3B1 mutation activates MYC via effects conserved across human and mouse cells. SF3B1 mutations promote decay of transcripts encoding the protein phosphatase 2A (PP2A) subunit PPP2R5A, increasing MYC S62 and BCL2 S70 phosphorylation which, in turn, promotes MYC protein stability and impair apoptosis, respectively. Genetic PPP2R5A restoration or pharmacologic PP2A activation impaired SF3B1-mutant tumorigenesis, elucidating a therapeutic approach to aberrant splicing by mutant SF3B1.

Significance:
Here, we identify that mutations in SF3B1, the most commonly mutated splicing factor gene across cancers, alter splicing of a specific subunit of the PP2A serine/threonine phosphatase complex to confer post-translational MYC and BCL2 activation, which is therapeutically intervenable using an FDA-approved drug.
See related commentary by O'Connor and Narla, p. 765.
This article is highlighted in the In This Issue feature, p. 747
HuR (Human Antigen R) Regulates the Contraction of Vascular Smooth Muscle and Maintains Blood Pressure
Authors: Liu Shanshan , Jiang Xiuxin , Lu Hanlin , Xing Mengdan , Qiao Yanning , Zhang Cheng , Zhang Wencheng 
Published: March 2020

Objective:
HuR (human antigen R)—an RNA-binding protein—is involved in regulating mRNA stability by binding adenylate-uridylate–rich elements. This study explores the role of HuR in the regulation of smooth muscle contraction and blood pressure.

Approach and Results:

Vascular HuR
SMKO
(smooth muscle–specific HuR knockout) mice were generated by crossbreeding HuR
flox/flox
mice with α-SMA (α-smooth muscle actin)-Cre mice. As compared with CTR (control) mice, HuR
SMKO
mice showed hypertension and cardiac hypertrophy. HuR levels were decreased in aortas from hypertensive patients and SHRs (spontaneously hypertensive rats), and overexpression of HuR could lower the blood pressure of SHRs. Contractile response to vasoconstrictors was increased in mesenteric artery segments isolated from HuR
SMKO
mice. The functional abnormalities in HuR
SMKO
mice were attributed to decreased mRNA and protein levels of RGS (regulator of G-protein signaling) protein(s) RGS2, RGS4, and RGS5, which resulted in increased intracellular calcium increase. Consistently, the degree of intracellular calcium ion increase in HuR-deficient smooth muscle cells was reduced by overexpression of RGS2, RGS4, or RGS5. Finally, administration of RGS2 and RGS5 reversed the elevated blood pressure in HuR
SMKO
mice.

Conclusions:
Our findings indicate that HuR regulates vascular smooth muscle contraction and maintains blood pressure by modulating RGS expression.
Myristoylation of LMCD1 Leads to Its Species-Specific Derepression of E2F1 and NFATc1 in the Modulation of CDC6 and IL-33 Expression During Development of Vascular Lesions
Authors: Govatati Suresh , Pichavaram Prahalathan , Janjanam Jagadeesh , Guo Liang , Virmani Renu , Rao Gadiparthi N. 
Published: March 2020

Objective:
In view of our previous observations on differential expression of LMCD1 (LIM and cysteine-rich domains 1) in human versus rodents, we asked the question whether LMCD1 plays a species-specific role in the development of vascular lesions.

Approach and Results:
A combination of genetic, molecular, cellular, and disease models were used to test species-specific role of LMCD1 in the pathogenesis of vascular lesions. Here, we report species-specific regulation of LMCD1 expression in mediating vascular smooth muscle cell proliferation and migration during vascular wall remodeling in humans versus mice. Thrombin induced LMCD1 expression in human aortic smooth muscle cells but not mouse aortic smooth muscle cells via activation of Par1 (protease-activated receptor 1)-Gαq/11 (Gα protein q/11)-PLCβ3 (phospholipase Cβ3)-NFATc1 (nuclear factor of activated T cells 1) signaling. Furthermore, although LMCD1 mediates thrombin-induced proliferation and migration of both human aortic smooth muscle cells and mouse aortic smooth muscle cells via influencing E2F1 (E2F transcription factor 1)-mediated CDC6 (cell division cycle 6) expression and NFATc1-mediated IL (interleukin)-33 expression, respectively, in humans, it acts as an activator, and in mice, it acts as a repressor of these transcriptional factors. Interestingly, LMCD1 repressor activity was nullified by N-myristoyltransferase 2–mediated myristoylation in mouse. Besides, we found increased expression of LMCD1 in human stenotic arteries as compared to nonstenotic arteries. On the other hand, LMCD1 expression was decreased in neointimal lesions of mouse injured arteries as compared to noninjured arteries.

Conclusions:
Together, these observations reveal that LMCD1 acts as an activator and repressor of E2F1 and NFATc1 in humans and mice, respectively, in the induction of CDC6 and IL-33 expression during development of vascular lesions. Based on these findings, LMCD could be a potential target for drug development against restenosis and atherosclerosis in humans.
Crystal Clots as Therapeutic Target in Cholesterol Crystal Embolism
Authors: Shi Chongxu , Kim Tehyung , Steiger Stefanie , Mulay Shrikant R. , Klinkhammer Barbara M. , Bäuerle Tobias , Melica Maria Elena , Romagnani Paola , Möckel Diana , Baues Maike , Yang Luying , Brouns Sanne L.N. , Heemskerk Johan W. M. , Braun Attila , Lammers Twan , Boor Peter , Anders Hans-Joachim 
Published: March 2020

Rationale:
Cholesterol crystal embolism can be a life-threatening complication of advanced atherosclerosis. Pathophysiology and molecular targets for treatment are largely unknown.

Objective:
We aimed to develop a new animal model of cholesterol crystal embolism to dissect the molecular mechanisms of cholesterol crystal (CC)–driven arterial occlusion, tissue infarction, and organ failure.

Methods and Results:
C57BL/6J mice were injected with CC into the left kidney artery. Primary end point was glomerular filtration rate (GFR). CC caused crystal clots occluding intrarenal arteries and a dose-dependent drop in GFR, followed by GFR recovery within 4 weeks, that is, acute kidney disease. In contrast, the extent of kidney infarction was more variable. Blocking necroptosis using mixed lineage kinase domain–like deficient mice or necrostatin-1s treatment protected from kidney infarction but not from GFR loss because arterial obstructions persisted, identifying crystal clots as a primary target to prevent organ failure. CC involved platelets, neutrophils, fibrin, and extracellular DNA. Neutrophil depletion or inhibition of the release of neutrophil extracellular traps had little effects, but platelet P2Y12 receptor antagonism with clopidogrel, fibrinolysis with urokinase, or DNA digestion with recombinant DNase I all prevented arterial occlusions, GFR loss, and kidney infarction. The window-of-opportunity was <3 hours after CC injection. However, combining Nec-1s (necrostatin-1s) prophylaxis given 1 hour before and DNase I 3 hours after CC injection completely prevented kidney failure and infarcts. In vitro, CC did not directly induce plasmatic coagulation but induced neutrophil extracellular trap formation and DNA release mainly from kidney endothelial cells, neutrophils, and few from platelets. CC induced ATP release from aggregating platelets, which increased fibrin formation in a DNase-dependent manner.

Conclusions:
CC embolism causes arterial obstructions and organ failure via the formation of crystal clots with fibrin, platelets, and extracellular DNA as critical components. Therefore, our model enables to unravel the pathogenesis of the CC embolism syndrome as a basis for both prophylaxis and targeted therapy.
The Noonan Syndrome Gene
Lztr1
Controls Cardiovascular Function by Regulating Vesicular Trafficking
Authors: Sewduth Raj Nayan , Pandolfi Silvia , Steklov Mikhail , Sheryazdanova Aidana , Zhao Peihua , Criem Nathan , Baietti Maria F. , Lechat Benoit , Quarck Rozeen , Impens Francis , Sablina Anna A. 
Published: March 2020

Rationale:
Noonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in patients with NS indicates an urgent need for new therapeutic approaches.

Objective:
Bleeding disorders have recently been described in patients with NS harboring mutations of LZTR1 (leucine zipper-like transcription regulator 1), an adaptor for CUL3 (CULLIN3) ubiquitin ligase complex. Here, we assessed the pathobiology of LZTR1-mediated bleeding disorders.

Methods and Results:

Whole-body and vascular specific knockout of
Lztr1
results in perinatal lethality due to cardiovascular dysfunction.
Lztr1
deletion in blood vessels of adult mice leads to abnormal vascular leakage. We found that defective adherent and tight junctions in
Lztr1
-depleted endothelial cells are caused by dysregulation of vesicular trafficking. LZTR1 affects the dynamics of fusion and fission of recycling endosomes by controlling ubiquitination of the ESCRT-III (endosomal sorting complex required for transport III) component CHMP1B (charged multivesicular protein 1B), whereas NS-associated
LZTR1
mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2 (vascular endothelial growth factor receptor 2) and decreases blood levels of soluble VEGFR2 in
Lztr1
haploinsufficient mice. Inhibition of VEGFR2 activity by cediranib rescues vascular abnormalities observed in
Lztr1
knockout mice

Conclusions:

Lztr1
deletion phenotypically overlaps with bleeding diathesis observed in patients with NS. ELISA screening of soluble VEGFR2 in the blood of
LZTR1
-mutated patients with NS may predict both the severity of NS phenotypes and potential responders to anti-VEGF therapy. VEGFR inhibitors could be beneficial for the treatment of bleeding disorders in patients with NS.
PTH/PTHrP Receptor Signaling Restricts Arterial Fibrosis in Diabetic LDLR
−/−
Mice by Inhibiting Myocardin-Related Transcription Factor Relays
Authors: Behrmann Abraham , Zhong Dalian , Li Li , Cheng Su-Li , Mead Megan , Ramachandran Bindu , Sabaeifard Parastoo , Goodarzi Mohammad , Lemoff Andrew , Kronenberg Henry M. , Towler Dwight A. 
Published: March 2020

Rationale:

The PTH1R (PTH [parathyroid hormone]/PTHrP [PTH-related protein] receptor) is expressed in vascular smooth muscle (VSM) and increased VSM PTH1R signaling mitigates diet-induced arteriosclerosis in LDLR
−/−
mice.

Objective:

To study the impact of VSM PTH1R deficiency, we generated mice SM22-Cre:PTH1R(fl/fl);LDLR
−/−
mice (PTH1R-VKO) and Cre-negative controls.

Methods and Results:

Immunofluorescence and Western blot confirmed PTH1R expression in arterial VSM that was reduced by Cre-mediated knockout. PTH1R-VKO cohorts exhibited increased aortic collagen accumulation in vivo, and VSM cultures from PTH1R-VKO mice elaborated more collagen (2.5-fold;
P
=0.01) with elevated
Col3a1
and
Col1a1
expression. To better understand these profibrotic responses, we performed mass spectrometry on nuclear proteins extracted from Cre-negative controls and PTH1R-VKO VSM. PTH1R deficiency reduced Gata6 but upregulated the MADS (MCM1, Agamous, Deficiens, and Srf DNA-binding domain)-box transcriptional co-regulator, Mkl-1 (megakaryoblastic leukemia [translocation] 1). Co-transfection assays (
Col3a1
promoter-luciferase reporter) confirmed PTH1R-mediated inhibition and Mkl-1-mediated activation of
Col3a1
transcription. Regulation mapped to a conserved hybrid CT(A/T)
6
GG MADS-box cognate in the
Col3a1
promoter. Mutations of C/G in this motif markedly reduced
Col3a1
transcriptional regulation by PTH1R and Mkl-1. Upregulation of
Col3a1
and
Col1a1
in PTH1R-VKO VSM was inhibited by small interfering RNA targeting
Mkl1
and by treatment with the Mkl-1 antagonist CCG1423 or the Rock (Rho-associated coiled-coil containing protein kinase)-2 inhibitor KD025. Chromatin precipitation demonstrated that VSM PTH1R deficiency increased Mkl-1 binding to
Col3a1 and Col1a1
, but not
TNF
, promoters. Proteomic studies of plasma extracellular vesicles and VSM from PTH1R-VKO mice identified C1r (complement component 1, r) and C1s (complement component 1, s), complement proteins involved in vascular collagen metabolism, as potential biomarkers. VSM C1r protein and
C1r
message were increased with PTH1R deficiency, mediated by Mkl-1-dependent transcription and inhibited by CCG1423 or KD025.

Conclusions:
PTH1R signaling restricts collagen production in the VSM lineage, in part, via Mkl-1 regulatory circuits that control collagen gene transcription. Strategies that maintain homeostatic VSM PTH1R signaling, as reflected in extracellular vesicle biomarkers of VSM PTH1R/Mkl-1 action, may help mitigate arteriosclerosis and vascular fibrosis.
EHD1 Modulates Cx43 Gap Junction Remodeling Associated With Cardiac Diseases
Authors: Martins-Marques Tania , Catarino Steve , Gonçalves Alexandre , Miranda-Silva Daniela , Gonçalves Lino , Antunes Pedro , Coutinho Gonçalo , Leite Moreira Adelino , Falcão Pires Inês , Girão Henrique 
Published: March 2020

Rationale:
Efficient communication between heart cells is vital to ensure the anisotropic propagation of electrical impulses, a function mainly accomplished by gap junctions (GJ) composed of Cx43 (connexin 43). Although the molecular mechanisms remain unclear, altered distribution and function of gap junctions have been associated with acute myocardial infarction and heart failure.

Objective:
A recent proteomic study from our laboratory identified EHD1 (Eps15 [endocytic adaptor epidermal growth factor receptor substrate 15] homology domain-containing protein 1) as a novel interactor of Cx43 in the heart.

Methods and Results:
In the present work, we demonstrate that knockdown of EHD1 impaired the internalization of Cx43, preserving gap junction-intercellular coupling in cardiomyocytes. Interaction of Cx43 with EHD1 was mediated by Eps15 and promoted by phosphorylation and ubiquitination of Cx43. Overexpression of wild-type EHD1 accelerated internalization of Cx43 and exacerbated ischemia-induced lateralization of Cx43 in isolated adult cardiomyocytes. In addition, we show that EHDs associate with Cx43 in human and murine failing hearts.

Conclusions:
Overall, we identified EHDs as novel regulators of endocytic trafficking of Cx43, participating in the pathological remodeling of gap junctions, paving the way to innovative therapeutic strategies aiming at preserving intercellular communication in the heart.
Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden Death
Authors: Basso Cristina , Iliceto Sabino , Thiene Gaetano , Perazzolo Marra Martina 
Published: March 2020

Despite a 2% to 3% prevalence of echocardiographically defined mitral valve prolapse (MVP) in the general population, the actual burden, risk stratification, and treatment of the so-called arrhythmic MVP are unknown. The clinical profile is characterized by a patient, usually female, with mostly bileaflet myxomatous disease, mid-systolic click, repolarization abnormalities in the inferior leads, and complex ventricular arrhythmias with polymorphic/right bundle branch block morphology, without significant regurgitation. Among the various pathophysiologic mechanisms of electrical instability, left ventricular fibrosis in the papillary muscles and inferobasal wall, mitral annulus disjunction, and systolic curling have been recently described by pathological and cardiac magnetic resonance studies in sudden death victims and patients with arrhythmic MVP. In addition, premature ventricular beats arising from the Purkinje tissue as ventricular fibrillation triggers have been documented by electrophysiologic studies in MVP patients with aborted sudden death.
The genesis of malignant ventricular arrhythmias in MVP probably recognizes the combination of the substrate (regional myocardial hypertrophy and fibrosis, Purkinje fibers) and the trigger (mechanical stretch) eliciting premature ventricular beats because of a primary morphofunctional abnormality of the mitral valve annulus.
The main clinical challenge is how to identify patients with arrhythmic MVP (which imaging technique and in which patient) and how to treat them to prevent sudden death. Thus, there is a necessity for prospective multicenter studies focusing on the prognostic role of cardiac magnetic resonance and electrophysiologic studies and on the therapeutic efficacy of targeted catheter ablation and mitral valve surgery in reducing the risk of life-threatening arrhythmias, as well as the role of implantable cardioverter defibrillators for primary prevention.