bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of CXCR4 in Cell-Cell Fusion and Infection of Monocyte-Derived Macrophages by Primary Human Immunodeficiency Virus Type 1 (HIV-1) Strains: Two Distinct Mechanisms of HIV-1 Dual Tropism
Authors: Yi Yanjie , Isaacs Stuart N. , Williams Darlisha A. , Frank Ian , Schols Dominique , De Clercq Erik , Kolson Dennis L. , Collman Ronald G. 
Published: December 2019

ABSTRACTDual-tropic human immunodeficiency virus type 1 (HIV-1) strains infect both primary macrophages and transformed T-cell lines. Prototype T-cell line-tropic (T-tropic) strains use CXCR4 as their principal entry coreceptor (X4 strains), while macrophagetropic (M-tropic) strains use CCR5 (R5 strains). Prototype dual tropic strains use both coreceptors (R5X4 strains). Recently, CXCR4 expressed on macrophages was found to support infection by certain HIV-1 isolates, including the dual-tropic R5X4 strain 89.6, but not by T-tropic X4 prototypes like 3B. To better understand the cellular basis for dual tropism, we analyzed the macrophage coreceptors used for Env-mediated cell-cell fusion as well as infection by several dual-tropic HIV-1 isolates. Like 89.6, the R5X4 strain DH12 fused with and infected both wild-type and CCR5-negative macrophages. The CXCR4-specific inhibitor AMD3100 blocked DH12 fusion and infection in macrophages that lacked CCR5 but not in wild-type macrophages. This finding indicates two independent entry pathways in macrophages for DH12, CCR5 and CXCR4. Three primary isolates that use CXCR4 but not CCR5 (tybe, UG021, and UG024) replicated efficiently in macrophages regardless of whether CCR5 was present, and AMD3100 blocking of CXCR4 prevented infection in both CCR5 negative and wild-type macrophages. Fusion mediated by UG021 and UG024 Envs in both wild-type and CCR5-deficient macrophages was also blocked by AMD3100. Therefore, these isolates use CXCR4 exclusively for entry into macrophages. These results confirm that macrophage CXCR4 can be used for fusion and infection by primary HIV-1 isolates and indicate that CXCR4 may be the sole macrophage coreceptor for some strains. Thus, dual tropism can result from two distinct mechanisms: utilization of both CCR5 and CXCR4 on macrophages and T-cell lines, respectively (dual-tropic R5X4), or the ability to efficiently utilize CXCR4 on both macrophages and T-cell lines (dual-tropic X4).
Functionally Heterogeneous CD8+T-Cell Memory Is Induced by Sendai Virus Infection of Mice
Authors: Usherwood Edward J. , Hogan Robert J. , Crowther Graham , Surman Sherri L. , Hogg Twala L. , Altman John D. , Woodland David L. 
Published: December 2019

ABSTRACTIt has recently been established that memory CD8+T cells induced by viral infection are maintained at unexpectedly high frequencies in the spleen. While it has been established that these memory cells are phenotypically heterogeneous, relatively little is known about the functional status of these cells. Here we investigated the proliferative potential of CD8+memory T cells induced by Sendai virus infection. High frequencies of CD8+T cells specific for both dominant and subdominant Sendai virus epitopes persisted for many weeks after primary infection, and these cells were heterogeneous with respect to CD62L expression (approximately 20% CD62Lhiand 80% CD62Llo). Reactivation of these cells with the antigenic peptide in vitro induced strong proliferation of antigen-specific CD8+T cells. However, approximately 20% of the cells failed to proliferate in vitro in response to a cognate peptide but nevertheless differentiated into effector cells and acquired full cytotoxic potential. These cells also expressed high levels of CD62L (in marked contrast to the CD62Llostatus of the proliferating cells in the culture). Direct isolation of CD62Lhiand CD62LloCD8+T cells from memory mice confirmed the correlation of this marker with proliferative potential. Taken together, these data demonstrate that Sendai virus infection induces high frequencies of memory CD8+T cells that are highly heterogeneous in terms of both their phenotype and their proliferative potential.
Identification of Amino Acid Residues of Influenza Virus Nucleoprotein Essential for RNA Binding
Authors: Elton Debra , Medcalf Liz , Bishop Konrad , Harrison Deborah , Digard Paul 
Published: December 2019

ABSTRACT
The influenza virus nucleoprotein (NP) is a single-strand-RNA-binding protein associated with genome and antigenome RNA and is one of the four virus proteins necessary for transcription and replication of viral RNA. To better characterize the mechanism by which NP binds RNA, we undertook a physical and mutational analysis of the polypeptide, with the strategy of identifying first the regions in direct contact with RNA, then the classes of amino acids involved, and finally the crucial residues by mutagenesis. Chemical fragmentation and amino acid sequencing of NP that had been UV cross linked to radiolabelled RNA showed that protein-RNA contacts occur throughout the length of the polypeptide. Chemical modification experiments implicated arginine but not lysine residues as important for RNA binding, while RNA-dependent changes in the intrinsic fluorescence spectrum of NP suggested the involvement of tryptophan residues. Supporting these observations, single-codon mutagenesis identified five tryptophan, one phenylalanine, and two arginine residues as essential for high-affinity RNA binding at physiological temperature. In addition, mutants unable to bind RNA in vitro were unable to support virus gene expression in vivo. The mutationally sensitive residues are not localized to any particular region of NP but instead are distributed throughout the protein. Overall, these data are inconsistent with previous models suggesting that the NP-RNA interaction is mediated by a discrete N-terminal domain. Instead, we propose that high-affinity binding of RNA by NP requires the concerted interaction of multiple regions of the protein with RNA and that the individual protein-RNA contacts are mediated by a combination of electrostatic interactions between positively charged residues and the phosphate backbone and planar interactions between aromatic side chains and bases.
Cytoplasmic Polyadenylation in Development and Beyond
Authors: Richter Joel D. 
Published: December 2019

SUMMARY
Maternal mRNA translation is regulated in large part by cytoplasmic polyadenylation. This process, which occurs in both vertebrates and invertebrates, is essential for meiosis and body patterning. In spite of the evolutionary conservation of cytoplasmic polyadenylation, many of the cis elements and trans-acting factors appear to have some species specificity. With the recent isolation and cloning of factors involved in both poly(A) elongation and deadenylation, the underlying biochemistry of these reactions is beginning to be elucidated. In addition to early development, cytoplasmic polyadenylation is now known to occur in the adult brain, and there is circumstantial evidence that this process occurs at synapses, where it could mediate the long-lasting phase of long-term potentiation, which is probably the basis of learning and memory. Finally, there may be multiple mechanisms by which polyadenylation promotes translation. Important questions yet to be answered in the field of cytoplasmic polyadenylation are addressed.
PAS Domains: Internal Sensors of Oxygen, Redox Potential, and Light
Authors: Taylor Barry L. , Zhulin Igor B. 
Published: December 2019

SUMMARY
PAS domains are newly recognized signaling domains that are widely distributed in proteins from members of the Archaea and Bacteria and from fungi, plants, insects, and vertebrates. They function as input modules in proteins that sense oxygen, redox potential, light, and some other stimuli. Specificity in sensing arises, in part, from different cofactors that may be associated with the PAS fold. Transduction of redox signals may be a common mechanistic theme in many different PAS domains. PAS proteins are always located intracellularly but may monitor the external as well as the internal environment. One way in which prokaryotic PAS proteins sense the environment is by detecting changes in the electron transport system. This serves as an early warning system for any reduction in cellular energy levels. Human PAS proteins include hypoxia-inducible factors and voltage-sensitive ion channels; other PAS proteins are integral components of circadian clocks. Although PAS domains were only recently identified, the signaling functions with which they are associated have long been recognized as fundamental properties of living cells.
How a strong low-angle normal fault formed: The Whipple detachment, southeastern California
Authors: Axen Gary J. 
Published: December 2019

AbstractMany low-angle normal faults (dip ≤30°) accommodate tens of kilometers of crustal extension, but their mechanics remain contentious. Most models for low-angle normal fault slip assume vertical maximum principal stress σ1, leading many authors to conclude that low-angle normal faults are poorly oriented in the stress field (≥60° from σ1) and weak (low friction). In contrast, models for low-angle normal fault formation in isotropic rocks typically assume Coulomb failure and require inclined σ1 (no misorientation). Here, a data-based, mechanical-tectonic model is presented for formation of the Whipple detachment fault, southeastern California. The model honors local and regional geologic and tectonic history and laboratory friction measurements. The Whipple detachment fault formed progressively in the brittle-plastic transition by linking of “minidetachments,” which are small-scale analogs (meters to kilometers in length) in the upper footwall.Minidetachments followed mylonitic anisotropy along planes of maximum shear stress (45° from the maximum principal stress), not Coulomb fractures. They evolved from mylonitic flow to cataclasis and frictional slip at 300–400 °C and ∼9.5 km depth, while fluid pressure fell from lithostatic to hydrostatic levels. Minidetachment friction was presumably high (0.6–0.85), based upon formation of quartzofeldspathic cataclasite and pseudotachylyte. Similar mechanics are inferred for both the minidetachments and the Whipple detachment fault, driven by high differential stress (∼150–160 MPa). A Mohr construction is presented with the fault dip as the main free parameter. Using “Byerlee friction” (0.6–0.85) on the minidetachments and the Whipple detachment fault, and internal friction (1.0–1.7) on newly formed Reidel shears, the initial fault dips are calculated at 16°–26°, with σ1 plunging ∼61°–71° northeast. Linked minidetachments probably were not well aligned, and slip on the evolving Whipple detachment fault probably contributed to fault smoothing, by off-fault fracturing and cataclasis, and to formation of the fault core and fractured damage zone.Stress rotation may have occurred only within the mylonitic shear zone, but asymmetric tectonic forces applied to the brittle crust probably caused gradual rotation of σ1 above it as a result of: (1) the upward force applied to the base of marginal North America by buoyant asthenosphere upwelling into an opening slab-free window and/or (2) basal, top-to-the-NE shear traction due to midcrustal mylonitic flow during tectonic exhumation of the Orocopia Schist. The mechanical-tectonic model probably applies directly to low-angle normal faults of the lower Colorado River extensional corridor, and aspects of the model (e.g., significance of anisotropy, stress rotation) likely apply to formation of other strong low-angle normal faults.
Heparan sulfate chains contribute to the anticoagulant milieu in malignant pleural effusion
Authors: Hardak Emilia , Peled Eli , Crispel Yonatan , Ghanem Shourouk , Attias Judith , Asayag Keren , Kogan Inna , Nadir Yona 
Published: December 2019

BackgroundWhile malignant pleural effusion (MPE) is a common and significant cause of morbidity in patients with cancer, current treatment options are limited. Human heparanase, involved in angiogenesis and metastasis, cleaves heparan sulfate (HS) side chains on the cell surface.AimsTo explore the coagulation milieu in MPE and infectious pleural effusion (IPE) focusing on the involvement of heparanase.MethodsSamples of 30 patients with MPE and 44 patients with IPE were evaluated in comparison to those of 33 patients with transudate pleural effusions, using heparanase ELISA, heparanase procoagulant activity assay, thrombin and factor Xa chromogenic assays and thromboelastography. A cell proliferation assay was performed. EMT-6 breast cancer cells were injected to the pleural cavity of mice. A peptide inhibiting heparanase activity was administered subcutaneously.ResultsLevels of heparanase, factor Xa and thrombin were significantly higher in exudate than transudate. Thromboelastography detected almost no thrombus formation in the whole blood, mainly on MPE addition. This effect was completely reversed by bacterial heparinase. Direct measurement revealed high levels of HS chains in pleural effusions. Higher proliferation was observed in tumour cell lines incubated with exudate than with transudate and it was reduced when bacterial heparinase was added. The tumour size in the pleural cavity of mice treated with the heparanase inhibitor were significantly smaller compared with control (p=0.005).ConclusionsHS chains released by heparanase form an anticoagulant milieu in MPE, preventing local thrombosis and enabling tumour cell proliferation. Inhibition of heparanase might provide a therapeutic option for patients with recurrent MPE.
Epigenetic Targeting of TERT-Associated Gene Expression Signature in Human Neuroblastoma with TERT Overexpression
Authors: Huang Min , Zeki Jasmine , Sumarsono Nathan , Coles Garry L. , Taylor Jordan S. , Danzer Enrico , Bruzoni Matias , Hazard Florette K. , Lacayo Norman J. , Sakamoto Kathleen M. , Dunn James C.Y. , Spunt Sheri L. , Chiu Bill 
Published: January 2020

Abstract

Neuroblastoma is a deadly pediatric solid tumor with infrequent recurrent somatic mutations. Particularly, the pathophysiology of tumors without MYCN amplification remains poorly defined. Utilizing an unbiased approach, we performed gene set enrichment analysis of RNA-sequencing data from 498 patients with neuroblastoma and revealed a differentially overexpressed gene signature in MYCN nonamplified neuroblastomas with telomerase reverse transcriptase (TERT) gene overexpression and coordinated activation of oncogenic signaling pathways, including E2Fs, Wnt, Myc, and the DNA repair pathway. Promoter rearrangement of the TERT gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis in neuroblastoma, but TERT-associated oncogenic signaling remains unclear. ChIP-seq analysis of the human CLB-GA neuroblastoma cells harboring TERT rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in TERT and multiple TERT-associated genes. Brd4 and cyclin-dependent kinases (CDK) had critical regulatory roles in the expression and chromatin activation of TERT and multiple TERT-associated genes. Epigenetically targeting Brd4 or CDKs with their respective inhibitors suppressed the expression of TERT and multiple TERT-associated genes in neuroblastoma with TERT overexpression or MYCN amplification. ChIP-seq and ChIP-qPCR provided evidence that the CDK inhibitor directly inhibited Brd4 recruitment to activate chromatin globally. Therefore, inhibiting Brd4 and CDK concurrently with AZD5153 and dinaciclib would be most effective in tumor growth suppression, which we demonstrated in neuroblastoma cell lines, primary human cells, and xenografts. In summary, we describe a unique mechanism in neuroblastoma with TERT overexpression and an epigenetically targeted novel therapeutic strategy.

Significance:
Epigenetically cotargeting Brd4 and Cdks suppresses human neuroblastoma with TERT overexpression by inhibiting the TERT-associated gene expression networks.
Long Noncoding RNA DRAIC Inhibits Prostate Cancer Progression by Interacting with IKK to Inhibit NF-κB Activation
Authors: Saha Shekhar , Kiran Manjari , Kuscu Canan , Chatrath Ajay , Wotton David , Mayo Marty W. , Dutta Anindya 
Published: January 2020

Abstract

DRAIC is a 1.7 kb spliced long noncoding RNA downregulated in castration-resistant advanced prostate cancer. Decreased DRAIC expression predicts poor patient outcome in prostate and seven other cancers, while increased DRAIC represses growth of xenografted tumors. Here, we show that cancers with decreased DRAIC expression have increased NF-κB target gene expression. DRAIC downregulation increased cell invasion and soft agar colony formation; this was dependent on NF-κB activation. DRAIC interacted with subunits of the IκB kinase (IKK) complex to inhibit their interaction with each other, the phosphorylation of IκBα, and the activation of NF-κB. These functions of DRAIC mapped to the same fragment containing bases 701–905. Thus, DRAIC lncRNA inhibits prostate cancer progression through suppression of NF-κB activation by interfering with IKK activity.

Significance:
A cytoplasmic tumor-suppressive lncRNA interacts with and inhibits a major kinase that activates an oncogenic transcription factor in prostate cancer.
A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma
Authors: Mita Monica M. , LoRusso Patricia M. , Papadopoulos Kyriakos P. , Gordon Michael S. , Mita Alain C. , Ferraldeschi Roberta , Keer Harold , Oganesian Aram , Su Xiang Yao , Jueliger Simone , Tolcher Anthony W. 
Published: January 2020

Abstract

Purpose:
This first-in-human, phase I study evaluated ASTX660, an oral, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma.

Patients and Methods:
ASTX660 was administered orally once daily on a 7-day-on/7-day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the MTD and recommended phase II dose (RP2D). Dose expansion was conducted at the RP2D.

Results:
Forty-five patients received ASTX660 (range 15–270 mg/day). Dose-limiting toxicity of grade 3 increased lipase with or without increased amylase occurred in 3 patients at 270 mg/day and 1 patient at 210 mg/day. The MTD was determined to be 210 mg/day and the RP2D 180 mg/day. Common treatment-related adverse events included fatigue (33%), vomiting (31%), and nausea (27%). Grade ≥3 treatment-related adverse events occurred in 7 patients, most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%). ASTX660 was rapidly absorbed, with maximum concentration achieved at approximately 0.5–1.0 hour. An approximately 2-fold accumulation in AUC exposures was observed on day 7 versus 1. ASTX660 suppressed cellular inhibitor of apoptosis protein-1 in peripheral blood mononuclear cells, which was maintained into the second cycle beyond the off-therapy week at the 180-mg/day RP2D and above. Clinical activity was seen in a patient with cutaneous T-cell lymphoma.

Conclusions:
ASTX660 demonstrated a manageable safety profile and exhibited evidence of pharmacodynamic and preliminary clinical activity at the 180-mg/day RP2D. The phase II part of the study is ongoing.
Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab
Authors: Keung Emily Z. , Burgess Melissa , Salazar Ruth , Parra Edwin R. , Rodrigues-Canales Jaime , Bolejack Vanessa , Van Tine Brian A. , Schuetze Scott M. , Attia Steven , Riedel Richard F. , Hu James , Okuno Scott H. , Priebat Dennis A. , Movva Sujana , Davis Lara E. , Reed Damon R. , Reuben Alexandre , Roland Christina L. , Reinke Denise , Lazar Alexander J. , Wang Wei-Lien , Wargo Jennifer A. , Tawbi Hussein A. 
Published: January 2020

Abstract

Purpose:
We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment.

Patients and Methods:
Pretreatment (n = 78) and 8-week on-treatment (n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti–PD-1 response.

Results:
Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8+ CD3+ PD-1+) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS).

Conclusions:
We show that quantitative assessments of CD8+ CD3+ PD-1+ T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti–PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.
“Matching” the “Mismatch” Repair–Deficient Prostate Cancer with Immunotherapy
Authors: Schweizer Michael T. , Yu Evan Y. 
Published: January 2020

Abstract

Mismatch repair gene mutations are uncommon in advanced prostate cancer; however, in those harboring these alterations, immune checkpoint blockade can be effective. As such, assays that can accurately identify these men are critically important. Cell-free circulating tumor DNA–based sequencing approaches appear to be one viable approach for identifying these patients.
See related article by Ritch et al., p. 1114
The Ongoing Search for Biomarkers of CDK4/6 Inhibitor Responsiveness in Breast Cancer
Authors: Schoninger Scott F. , Blain Stacy W. 
Published: January 2020

Abstract
CDK4 inhibitors (CDK4/6i), such as palbociclib, ribociclib, and abemaciclib, are approved in combination with hormonal therapy as a front-line treatment for metastatic HR+, HER2- breast cancer. Their targets, CDK4 and CDK6, are cell-cycle regulatory proteins governing the G1–S phase transition across many tissue types. A key challenge remains to uncover biomarkers to identify those patients that may benefit from this class of drugs. Although CDK4/6i addition to estrogen modulation therapy essentially doubles the median progression-free survival, overall survival is not significantly increased. However, in reality only a subset of treated patients respond. Many patients exhibit primary resistance to CDK4/6 inhibition and do not derive any benefit from these agents, often switching to chemotherapy within 6 months. Some patients initially benefit from treatment, but later develop secondary resistance. This highlights the need for complementary or companion diagnostics to pinpoint patients who would respond. In addition, because CDK4 is a bona fide target in other tumor types where CDK4/6i therapy is currently in clinical trials, the lack of target identification may obscure benefit to a subset of patients there as well. This review summarizes the current status of CDK4/6i biomarker test development, both in clinical trials and at the bench, with particular attention paid to those which have a strong biological basis as well as supportive clinical data.