bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sulfolobus Replication Factor C Stimulates the Activity of DNA Polymerase B1
Authors: Xing Xuanxuan , Zhang Likui , Guo Li , She Qunxin , Huang Li 
Published: April 2014

ABSTRACT

Replication factor C (RFC) is known to function in loading proliferating cell nuclear antigen (PCNA) onto primed DNA, allowing PCNA to tether DNA polymerase for highly processive DNA synthesis in eukaryotic and archaeal replication. In this report, we show that an RFC complex from the hyperthermophilic archaea of the genus
Sulfolobus
physically interacts with DNA polymerase B1 (PolB1) and enhances both the polymerase and 3′-5′ exonuclease activities of PolB1 in an ATP-independent manner. Stimulation of the PolB1 activity by RFC is independent of the ability of RFC to bind DNA but is consistent with the ability of RFC to facilitate DNA binding by PolB1 through protein-protein interaction. These results suggest that
Sulfolobus
RFC may play a role in recruiting DNA polymerase for efficient primer extension, in addition to clamp loading, during DNA replication.
Txc, a New Type II Secretion System of Pseudomonas aeruginosa Strain PA7, Is Regulated by the TtsS/TtsR Two-Component System and Directs Specific Secretion of the CbpE Chitin-Binding Protein
Authors: Cadoret Frédéric , Ball Geneviève , Douzi Badreddine , Voulhoux Romé 
Published: April 2014

ABSTRACT

We present here the functional characterization of a third complete type II secretion system (T2SS) found in newly sequenced
Pseudomonas aeruginosa
strain PA7. We call this system Txc (third Xcp homolog). This system is encoded by the RGP69 region of genome plasticity found uniquely in strain PA7. In addition to the 11
txc
genes, RGP69 contains two additional genes encoding a possible T2SS substrate and a predicted unorthodox sensor protein, TtsS (type II secretion sensor). We also identified a gene encoding a two-component response regulator called TtsR (type II secretion regulator), which is located upstream of the
ttsS
gene and just outside RGP69. We show that TtsS and TtsR constitute a new and functional two-component system that controls the production and secretion of the RGP69-encoded T2SS substrate in a Txc-dependent manner. Finally, we demonstrate that this Txc-secreted substrate binds chitin, and we therefore name it CbpE (chitin-binding protein E).
Rod-to-Hook Transition for Extracellular Flagellum Assembly Is Catalyzed by the L-Ring-Dependent Rod Scaffold Removal
Authors: Cohen Eli J. , Hughes Kelly T. 
Published: April 2014

ABSTRACT

In
Salmonella
, the rod substructure of the flagellum is a periplasmic driveshaft that couples the torque generated by the basal body motor to the extracellular hook and filament. The rod subunits self-assemble, spanning the periplasmic space and stopping at the outer membrane when a mature length of ∼22 nm is reached. Assembly of the extracellular hook and filament follow rod completion. Hook initiation requires that a pore forms in the outer membrane and that the rod-capping protein, FlgJ, dislodges from the tip of the distal rod and is replaced with the hook-capping protein, FlgD. Approximately 26 FlgH subunits form the L-ring around the distal rod that creates the pore through which the growing flagellum will elongate from the cell body. The function of the L-ring in the mature flagellum is also thought to act as a bushing for the rotating rod. Work presented here demonstrates that, in addition to outer membrane pore formation, L-ring formation catalyzes the removal of the FlgJ rod cap. Rod cap removal allows the hook cap to assemble at the rod tip and results in the transition from rod completion in the periplasm to extracellular hook polymerization. By coupling the rod-to-hook switch to outer membrane penetration, FlgH ensures that hook and filament polymerization is initiated at the appropriate spatial and temporal point in flagellar biosynthesis.
Hypermotility in Clostridium perfringens Strain SM101 Is Due to Spontaneous Mutations in Genes Linked to Cell Division
Authors: Liu Hualan , McCord Kristin D. , Howarth Jonathon , Popham David L. , Jensen Roderick V. , Melville Stephen B. 
Published: April 2014

ABSTRACT

Clostridium perfringens
is a Gram-positive anaerobic pathogen of humans and animals. Although they lack flagella,
C. perfringens
bacteria can still migrate across surfaces using a type of gliding motility that involves the formation of filaments of bacteria lined up in an end-to-end conformation. In strain SM101, hypermotile variants are often found arising from the edges of colonies on agar plates. Hypermotile cells are longer than wild-type cells, and video microscopy of their gliding motility suggests that they form long, thin filaments that move rapidly away from a colony, analogously to swarmer cells in bacteria with flagella. To identify the cause(s) of the hypermotility phenotype, the genome sequences of normal strains and their direct hypermotile derivatives were determined and compared. Strains SM124 and SM127, hypermotile derivatives of strains SM101 and SM102, respectively, contained 10 and 6 single nucleotide polymorphisms (SNPs) relative to their parent strains. While SNPs were located in different genes in the two sets of strains, one feature in common was mutations in cell division genes, an
ftsI
homolog in strain SM124 (
CPR
_
1831
) and a
minE
homolog in strain SM127 (
CPR
_
2104
). Complementation of these mutations with wild-type copies of each gene restored the normal motility phenotype. A model explaining the principles underlying the hypermotility phenotype is presented.
A Conserved Suppressor Mutation in a Tryptophan Auxotroph Results in Dysregulation of Pseudomonas Quinolone Signal Synthesis
Authors: Knoten Claire A. , Wells Greg , Coleman James P. , Pesci Everett C. 
Published: April 2014

ABSTRACT

Pseudomonas aeruginosa
is a common nosocomial pathogen that relies on three cell-to-cell signals to regulate multiple virulence factors. The
Pseudomonas
quinolone signal (PQS; 2-heptyl-3-hydroxy-4-quinolone) is one of these signals, and it is known to be important for
P. aeruginosa
pathogenesis. PQS is synthesized in a multistep reaction that condenses anthranilate and a fatty acid. In
P. aeruginosa
, anthranilate is produced via the kynurenine pathway and two separate anthranilate synthases, TrpEG and PhnAB, the latter of which is important for PQS synthesis. Others have previously shown that a
P. aeruginosa
tryptophan auxotroph could grow on tryptophan-depleted medium with a frequency of 10
−5
to 10
−6
. These revertants produced more pyocyanin and had increased levels of
phnA
transcript. In this study, we constructed similar tryptophan auxotroph revertants and found that the reversion resulted from a synonymous G-to-A nucleotide mutation within
pqsC
. This change resulted in increased pyocyanin and decreased PQS, along with an increase in the level of the
pqsD
,
pqsE
, and
phnAB
transcripts. Reporter fusion and reverse transcriptase PCR studies indicated that a novel transcript containing
pqsD
,
pqsE
, and
phnAB
occurs in these revertants, and quantitative real-time PCR experiments suggested that the same transcript appears in the wild-type strain under nutrient-limiting conditions. These results imply that the PQS biosynthetic operon can produce an internal transcript that increases anthranilate production and greatly elevates the expression of the PQS signal response protein PqsE. This suggests a novel mechanism to ensure the production of both anthranilate and PQS-controlled virulence factors.
Inhibiting Tankyrases Sensitizes KRAS-Mutant Cancer Cells to MEK Inhibitors via FGFR2 Feedback Signaling
Authors: Schoumacher Marie , Hurov Kristen E. , Lehár Joseph , Yan-Neale Yan , Mishina Yuji , Sonkin Dmitriy , Korn Joshua M. , Flemming Daisy , Jones Michael D. , Antonakos Brandon , Cooke Vesselina G. , Steiger Janine , Ledell Jebediah , Stump Mark D. , Sellers William R. , Danial Nika N. , Shao Wenlin 
Published: April 2014

Abstract
Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors (MEKi) in KRAS-mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and antitumor activity both in vitro and in vivo than effects observed by previously reported MEKi combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS-mutant cancers by suppressing a newly discovered resistance mechanism. Cancer Res; 74(12); 3294–305. ©2014 AACR.
Enhancement of the T-cell Armamentarium as a Cell-Based Therapy for Prostate Cancer
Authors: Brennen W. Nathaniel , Drake Charles G. , Isaacs John T. 
Published: April 2014

Abstract
Prostate cancer is frequently characterized by a large inflammatory infiltrate that includes T cells. Although T cells traffic to cancer lesions in large numbers, they are unable to generate a therapeutic response because of the immunosuppressive microenvironment. Therefore, arming T cells with a cytotoxic agent that is capable of killing cancer cells independent of these immunosuppressive signals is a rational approach to enhance their potency. Essentially, the T cells would serve as a cell-based vector, or “Trojan Horse,” to selectively deliver a protoxin to disseminated prostate cancer lesions. The selective delivery of a protoxin using T cells represents an ideal method to maximize their therapeutic potency through a “field effect.” Because systemically infused T cells are expected to traffic to sites of inflammation other than cancer, an additional level of specificity may be needed to prevent toxicity to nontarget tissues. Toward this goal, genetic engineering can be used to make protoxin expression dependent upon T-cell recognition of the prostate-specific membrane antigen by a chimeric antigen receptor. Furthermore, selective activation of the protoxin using a tissue- or tumor-specific protease, such as PSA, can promote further specificity. Thus, T-cell potency can be enhanced by targeted protoxin secretion and greater specificity achieved using combinatorial antigen recognition and protoxin activation. Cancer Res; 74(13); 3390–5. ©2014 AACR.
Chronic Inflammation in Benign Prostate Tissue Is Associated with High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial
Authors: Gurel Bora , Lucia M. Scott , Thompson Ian M. , Goodman Phyllis J. , Tangen Catherine M. , Kristal Alan R. , Parnes Howard L. , Hoque Ashraful , Lippman Scott M. , Sutcliffe Siobhan , Peskoe Sarah B. , Drake Charles G. , Nelson William G. , De Marzo Angelo M. , Platz Elizabeth A. 
Published: April 2014

Abstract
Background: Chronic inflammation is hypothesized to influence prostate cancer development, although a definitive link has not been established.
Methods: Prostate cancer cases (N = 191) detected on a for-cause (clinically indicated) or end-of-study (protocol directed) biopsy, and frequency-matched controls (N = 209), defined as negative for cancer on an end-of-study biopsy, were sampled from the placebo arm of the Prostate Cancer Prevention Trial. Inflammation prevalence and extent in benign areas of biopsy cores were visually assessed using digital images of hematoxylin and eosin–stained sections. Logistic regression was used to estimate associations.
Results: Of note, 86.2% of cases and 78.2% of controls had at least one biopsy core (of three assessed) with inflammation in benign areas, most of which was chronic. Men who had at least one biopsy core with inflammation had 1.78 [95% confidence interval (CI), 1.04–3.06] times the odds of prostate cancer compared with men who had zero cores with inflammation. The association was stronger for high-grade disease (Gleason sum 7–10, N = 94; OR, 2.24; 95% CI, 1.06–4.71). These patterns were present when restricting to cases and controls in whom intraprostatic inflammation was the least likely to have influenced biopsy recommendation because their prostate-specific antigen (PSA) was low (&lt;2 ng/mL at biopsy).
Conclusion: Inflammation, most of which was chronic, was common in benign prostate tissue, and was positively associated with prostate cancer, especially high grade. The association did not seem to be due to detection bias.
Impact: This study supports an etiologic link between inflammation and prostate carcinogenesis, and suggests an avenue for prevention by mitigating intraprostatic inflammation. Cancer Epidemiol Biomarkers Prev; 23(5); 847–56. ©2014 AACR.
Accelerated Approval for Pertuzumab in the Neoadjuvant Setting: Winds of Change?
Authors: Esserman Laura J. , DeMichele Angela 
Published: April 2014

Abstract
Accelerated approval for agents that improve the frequency of complete pathologic response in the primary breast cancer setting heralds a broadening of the opportunities to get effective agents to the market more quickly. However, these new pathways will require identifying the signature or subtype for which the agent is most effective, and evidence of enrollment of patients to a trial that enables the ascertainment of event-free survival. The recent approval of pertuzumab for use in the neoadjuvant setting is evidence that the FDA is committed to supporting the accelerated approval pathway. The situations in which approval is likely to be granted are discussed. Clin Cancer Res; 20(14); 3632–6. ©2014 AACR.
Centmitor-1, a Novel Acridinyl-Acetohydrazide, Possesses Similar Molecular Interaction Field and Antimitotic Cellular Phenotype as Rigosertib, ON 01910.Na
Authors: Mäki-Jouppila Jenni H.E. , Laine Leena J. , Rehnberg Jonathan , Narvi Elli , Tiikkainen Pekka , Hukasova Elvira , Halonen Pasi , Lindqvist Arne , Kallio Lila , Poso Antti , Kallio Marko J. 
Published: April 2014

Abstract
Mitosis is an attractive target for the development of new anticancer drugs. In a search for novel mitotic inhibitors, we virtually screened for low molecular weight compounds that would possess similar steric and electrostatic features, but different chemical structure than rigosertib (ON 01910.Na), a putative inhibitor of phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathways. Highest scoring hit compounds were tested in cell-based assays for their ability to induce mitotic arrest. We identified a novel acridinyl-acetohydrazide, here named as Centmitor-1 (Cent-1), that possesses highly similar molecular interaction field as rigosertib. In cells, Cent-1 phenocopied the cellular effects of rigosertib and caused mitotic arrest characterized by chromosome alignment defects, multipolar spindles, centrosome fragmentation, and activated spindle assembly checkpoint. We compared the effects of Cent-1 and rigosertib on microtubules and found that both compounds modulated microtubule plus-ends and reduced microtubule dynamics. Also, mitotic spindle forces were affected by the compounds as tension across sister kinetochores was reduced in mitotic cells. Our results showed that both Cent-1 and rigosertib target processes that occur during mitosis as they had immediate antimitotic effects when added to cells during mitosis. Analysis of Plk1 activity in cells using a Förster resonance energy transfer (FRET)-based assay indicated that neither compound affected the activity of the kinase. Taken together, these findings suggest that Cent-1 and rigosertib elicit their antimitotic effects by targeting mitotic processes without impairment of Plk1 kinase activity. Mol Cancer Ther; 13(5); 1054–66. ©2014 AACR.
Ectodomain-Specific E-Cadherin Antibody Suppresses Skin SCC Growth and Reduces Tumor Grade: A Multitargeted Therapy Modulating RTKs and the PTEN–p53–MDM2 Axis
Authors: Brouxhon Sabine M. , Kyrkanides Stephanos , Raja Veena , Silberfeld Andrew , Teng Xiaofei , Trochesset Denise , Cohen Jason , Ma Li 
Published: April 2014

Abstract
Tumor cell survival consists of an intricate balance between cell growth and cell death pathways involving receptor tyrosine kinases [RTK; i.e., HER1-4, insulin-like growth factor-1 receptor (IGF-1R), etc.], MDM2, and the tumor suppressor proteins phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p53. We recently demonstrated that shedded E-cadherin extracellular domain fragment (sEcad) is a valid oncogenic target that is significantly increased in human clinical skin squamous cell cancers (SCC) samples, UV-induced mouse tumors, and cells and promotes tumor cell proliferation, migration, and invasion by interacting and activating with the HER-phosphatidylinositol 3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) axis. In resected human SCC tumors, we reported enhanced sEcad-HER1, sEcad-HER2, and sEcad-IGF-1R, but not FL–Ecad–RTK interactions. Here, we demonstrate that a sEcad antibody against the ectodomain of E-cadherin suppressed SCC growth and increased tumor differentiation in orthotopic cutaneous SCC xenografts by inhibiting proliferation and inducing apoptosis. A similar anti-sEcad antibody-induced inhibition of proliferation and induction of cell death was evident in PAM212 cells in vitro. Mechanistically, anti-sEcad administration upregulated an array of cell death pathways (i.e., Bad, active caspase-3, and cleaved PARP) and inhibited inhibitors of apoptosis (IAP; survivin, livin, etc.), RTKs (HER1, HER2, p95HER2, and IGF-1R), MAPK and PI3K/mTOR prosurvival signaling. Interestingly, in anti-sEcad mAb-treated tumors and PAM212 cells, this effect was associated with a profound increase in membrane, cytosolic, and nuclear levels of PTEN; enhanced cytosolic p53; and a decrease in MDM2 levels. Overall, our studies suggest that an antibody-based therapy against sEcad may be a novel therapeutic platform for cutaneous SCCs by hampering key proto-oncogenes (RTKs, IAPs, and MDM2) and activating potent tumor suppressor proteins (PTEN and p53) intricately linked to tumor growth and survival. Mol Cancer Ther; 13(7); 1791–802. ©2014 AACR.
Combination of Anti-HER3 Antibody MM-121/SAR256212 and Cetuximab Inhibits Tumor Growth in Preclinical Models of Head and Neck Squamous Cell Carcinoma
Authors: Jiang Ning , Wang Dongsheng , Hu Zhongliang , Shin Hyung Ju C. , Qian Guoqing , Rahman Mohammad Aminur , Zhang Hongzheng , Amin A.R.M. Ruhul , Nannapaneni Sreenivas , Wang Xiaojing , Chen Zhengjia , Garcia Gabriela , MacBeath Gavin , Shin Dong M. , Khuri Fadlo R. , Ma Jun , Chen Zhuo G. , Saba Nabil F. 
Published: April 2014

Abstract
The EGFR monoclonal antibody cetuximab is the only approved targeted agent for treating head and neck squamous cell carcinoma (HNSCC). Yet resistance to cetuximab has hindered its activity in this disease. Intrinsic or compensatory HER3 signaling may contribute to cetuximab resistance. To investigate the therapeutic benefit of combining MM-121/SAR256212, an anti-HER3 monoclonal antibody, with cetuximab in HNSCC, we initially screened 12 HNSCC cell lines for total and phosphorylated levels of the four HER receptors. We also investigated the combination of MM-121 with cetuximab in preclinical models of HNSCC. Our results revealed that HER3 is widely expressed and activated in HNSCC cell lines. MM-121 strongly inhibited phosphorylation of HER3 and AKT. When combined with cetuximab, MM-121 exerted a more potent antitumor activity through simultaneously inhibiting the activation of HER3 and EGFR and consequently the downstream PI3K/AKT and ERK pathways in vitro. Both high and low doses of MM-121 in combination with cetuximab significantly suppressed tumor growth in xenograft models and inhibited activations of HER3, EGFR, AKT, and ERK in vivo. Our work is the first report on this new combination in HNSCC and supports the concept that HER3 inhibition may play an important role in future therapy of HNSCC. Our results open the door for further mechanistic studies to better understand the role of HER3 in resistance to EGFR inhibitors in HNSCC. Mol Cancer Ther; 13(7); 1826–36. ©2014 AACR.
Spinal Accessory Nerve Monitoring and Clinical Outcome Results of Nerve‐Sparing Neck Dissections
Authors: Birinci Yucel , Genc Arzu , Ecevit Mustafa Cenk , Erdag Taner Kemal , Guneri Enis Alpin , Oztura Ibrahim , Evlice Ahmet , Ikiz Ahmet Omer 
Published: April 2014

ObjectiveTo investigate the role of intraoperative spinal accessory nerve monitoring in predicting postoperative shoulder function in spinal accessory nerve‐sparing neck dissections.Study DesignProspective, double‐blind clinical trial.SettingAcademic, tertiary care center.Subjects and MethodsThis study was performed on 20 neck sites of 17 consecutive patients who had neck dissections sparing the spinal accessory nerve. Threshold increment ≥0.25 mA and amplitude decrement ≥72% were classified as significant intraoperative neuromonitoring changes while lesser differences were classified as insignificant intraoperative neuromonitoring changes. All patients had intraoperative neuromonitoring recordings when the spinal accessory nerve was first identified and at the end of surgery. Postoperative shoulder function was evaluated neurophysiologically with electromyography and clinically with Constant‐Murley Score; daily activity restrictions were evaluated with Activity Restriction Scale.ResultsClinical assessment of shoulder functions at postoperative first and second months showed statistically significant deteriorations when compared with preoperative values (P <. 05). The shoulder function deterioration was statistically significantly less for patients with insignificant intraoperative neuromonitoring changes than patients with significant intraoperative neuromonitoring changes (P <. 05). Daily activity restriction deteriorations were present in both groups at first postoperative month (P <. 05). While they persisted in the group with significant intraoperative neuromonitoring changes during the second postoperative month (P <. 05), there was continuing recovery in the insignificant intraoperative neuromonitoring change group and statistical significance disappeared (P >. 05).ConclusionOur results support the predictive value of spinal accessory nerve intraoperative neuromonitoring for determining shoulder function deterioration and activity restriction scores.