bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis
Authors: Deshpande Devyani , Srivastava Shashikant , Bendet Paula , Martin Katherine R. , Cirrincione Kayle N. , Lee Pooi S. , Pasipanodya Jotam G. , Dheda Keertan , Gumbo Tawanda 
Published: November 2017

ABSTRACT

The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill
Mycobacterium tuberculosis
. In this study, we found that >64 mg/liter of static benzylpenicillin concentrations killed 1.16 to 1.43 log
10
CFU/ml below starting inoculum of extracellular and intracellular
M. tuberculosis
over 7 days. When we added the β-lactamase inhibitor avibactam, benzylpenicillin maximal kill (
E
max
) of extracellular log-phase-growth
M. tuberculosis
was 6.80 ± 0.45 log
10
CFU/ml at a 50% effective concentration (EC
50
) of 15.11 ± 2.31 mg/liter, while for intracellular
M. tuberculosis
it was 2.42 ± 0.14 log
10
CFU/ml at an EC
50
of 6.70 ± 0.56 mg/liter. The median penicillin (plus avibactam) MIC against South African clinical
M. tuberculosis
strains (80% either multidrug or extensively drug resistant) was 2 mg/liter. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow-fiber model of tuberculosis (HFS-TB). The percent time above the MIC was linked to effect, with an optimal exposure of ≥65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase-growth
M. tuberculosis
was 1.44 log
10
CFU/ml/day, while 3.28 log
10
CFU/ml of intracellular
M. tuberculosis
was killed over 3 weeks. In an 8-week HFS-TB study of nonreplicating persistent
M. tuberculosis
, penicillin-avibactam alone and the drug combination of isoniazid, rifampin, and pyrazinamide both killed >7.0 log
10
CFU/ml. Monte Carlo simulations of 10,000 preterm infants with disseminated disease identified an optimal dose of 10,000 U/kg (of body weight)/h, while for pregnant women or nonpregnant adults with pulmonary tuberculosis the optimal dose was 25,000 U/kg/h, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.
Generation of Bacteriophage-Insensitive Mutants of Streptococcus thermophilus via an Antisense RNA CRISPR-Cas Silencing Approach
Authors: McDonnell Brian , Mahony Jennifer , Hanemaaijer Laurens , Kouwen Thijs R. H. M. , van Sinderen Douwe 
Published: November 2017

ABSTRACT

Predation of starter lactic acid bacteria such as
Streptococcus thermophilus
by bacteriophages is a persistent and costly problem in the dairy industry. CRISPR-mediated
b
acteriophage
i
nsensitive
m
utants (BIMs), while straightforward to generate and verify, can quickly be overcome by mutant phages. The aim of this study was to develop a tool allowing the generation of derivatives of commercial
S. thermophilus
strains which are resistant to phage attack through a non-CRISPR-mediated mechanism, with the objective of generating BIMs exhibiting stable resistance against a range of isolated lytic
S. thermophilus
phages. To achieve this, standard BIM generation was complemented by the use of the wild-type (WT) strain which had been transformed with an antisense mRNA-generating plasmid (targeting a crucial CRISPR-associated [
cas
] gene) in order to facilitate the generation of non-CRISPR-mediated BIMs. Phage sensitivity assays suggest that non-CRISPR-mediated BIMs exhibit some advantages compared to CRISPR-mediated BIMs derived from the same strain.

IMPORTANCE
The outlined approach reveals the presence of a powerful host-imposed barrier for phage infection in
S. thermophilus
. Considering the detrimental economic consequences of phage infection in the dairy processing environment, the developed methodology has widespread applications, particularly where other methods may not be practical or effective in obtaining robust, phage-tolerant
S. thermophilus
starter strains.
Nutrient-Colimited Trichodesmium as a Nitrogen Source or Sink in a Future Ocean
Authors: Walworth Nathan G. , Fu Fei-Xue , Lee Michael D. , Cai Xiaoni , Saito Mak A. , Webb Eric A. , Hutchins David A. 
Published: November 2017

ABSTRACTNitrogen-fixing (N2) cyanobacteria provide bioavailable nitrogen to vast ocean regions but are in turn limited by iron (Fe) and/or phosphorus (P), which may force them to employ alternative nitrogen acquisition strategies. The adaptive responses of nitrogen fixers to global-change drivers under nutrient-limited conditions could profoundly alter the current ocean nitrogen and carbon cycles. Here, we show that the globally important N2fixerTrichodesmiumfundamentally shifts nitrogen metabolism toward organic-nitrogen scavenging following long-term high-CO2adaptation under iron and/or phosphorus (co)limitation. Global shifts in transcripts and proteins under high-CO2/Fe-limited and/or P-limited conditions include decreases in the N2-fixing nitrogenase enzyme, coupled with major increases in enzymes that oxidize trimethylamine (TMA). TMA is an abundant, biogeochemically important organic nitrogen compound that supports rapidTrichodesmiumgrowth while inhibiting N2fixation. In a future high-CO2ocean, this whole-cell energetic reallocation toward organic nitrogen scavenging and away from N2fixation may reduce new-nitrogen inputs byTrichodesmiumwhile simultaneously depleting the scarce fixed-nitrogen supplies of nitrogen-limited open-ocean ecosystems.IMPORTANCETrichodesmiumis among the most biogeochemically significant microorganisms in the ocean, since it supplies up to 50% of the new nitrogen supporting open-ocean food webs. We usedTrichodesmiumcultures adapted to high-CO2conditions for 7 years, followed by additional exposure to iron and/or phosphorus (co)limitation. We show that “future ocean” conditions of high CO2and concurrent nutrient limitation(s) fundamentally shift nitrogen metabolism away from nitrogen fixation and instead toward upregulation of organic nitrogen-scavenging pathways. We show that the responses ofTrichodesmiumto projected future ocean conditions include decreases in the nitrogen-fixing nitrogenase enzymes coupled with major increases in enzymes that oxidize the abundant organic nitrogen source trimethylamine (TMA). Such a shift toward organic nitrogen uptake and away from nitrogen fixation may substantially reduce new-nitrogen inputs byTrichodesmiumto the rest of the microbial community in the future high-CO2ocean, with potential global implications for ocean carbon and nitrogen cycling.
Prevalence and sociodemographic correlates of cervicovaginal human papillomavirus (HPV) carriage in a cross-sectional, multiethnic, community-based female Asian population
Authors: Khoo Su Pei , Bhoo-Pathy Nirmala , Yap Siew Hwei , Anwar Shafii Mohd Khairul , Hairizan Nasir Nazrilla , Belinson Jerome , Subramaniam ShriDevi , Goh Pik Pin , Zeng Ming , Tan Hong Dong , Gravitt Patti , Woo Yin Ling 
Published: November 2017

ObjectivesCervical cancer is a largely preventable disease, and the strategic implementation of a cervical cancer prevention programme is partly dependent on the impact of human papillomavirus (HPV) infection interpreted within the context of the country’s sociodemographic attributes. The objective of this study is to determine the prevalence of cervicovaginal HPV infection among a healthy, community-based, multiethnic Malaysian population. The HPV prevalence was subsequently correlated to the individual’s sociodemographics and sexual/reproductive history. Of significance, the observed prevalence captured was in a birth cohort not included in the national school-based HPV vaccination programme.MethodsThis was a cross-sectional study where 1293 healthy women aged between 18 and 60 years were recruited via convenience sampling from five community-based clinics in Selangor, Malaysia. Cervicovaginal self-samples were obtained and DNA was extracted for HPV detection and genotyping. A comprehensive questionnaire was administered to determine the sociodemographics and behavioural patterns of participants.ResultsThe median age at enrolment was 37 years old (IQR: 30–47). In total, 86/1190 (7.2%) of the samples collected were positive for HPV infection, with the highest HPV prevalence (11.9%) detected in the subgroup of 18–24 years old. The top three most prevalent HPV genotypes were HPV 16, 52 and 58. The independent risk factors associated with higher rates of HPV infection included Indian ethnicity, widowed status and women with partners who are away from home for long periods and/or has another sexual partner.ConclusionsThe overall prevalence of HPV infection in this Malaysian multiethnic population was 7.2%, with 6.5% being high-risk genotypes. The top three most common high-risk HPV types were HPV 16, 52 and 58. This information is important for the planning of primary (HPV vaccination) and secondary (screening) cervical cancer prevention programmes in Malaysia.
Tobacco control in California compared with the rest of the USA: trends in adult per capita cigarette consumption
Authors: Pierce John P , Shi Yuyan , Hendrickson Erik M , White Martha M , Noble Madison L , Kealey Sheila , Strong David R , Trinidad Dennis R , Hartman Anne M , Messer Karen 
Published: November 2017

BackgroundIn the 1990s, California led the USA in state-level tobacco control strategies. However, after 2000, California lost ground on cigarette taxes, although it maintained higher levels of smoke-free homes among smokers.MethodsTrends in per capita cigarette consumption were assessed through taxed sales data and from self-report in repeated national cross-sectional surveys. Linear regressions identified changes in trends after year 2000 separately for California and the rest of the USA. Using data from each state, a linear regression tested the association between different tobacco control strategies and per capita consumption. Change in self-reported per capita consumption was partitioned into contributions associated with initiation, quitting and reduction in cigarette consumption level.ResultsBoth taxed cigarette sales and per capita consumption declined rapidly in the USA from 1985 to 2015. Declines were particularly fast in California before 2000 but slowed thereafter. In 2014, per capita consumption in California was 29.4 packs/adult/year, but 90% higher in the rest of the USA. Modelling state-level data, every $1 increase in cigarette taxes reduced consumption by 4.8 (95% CI 2.9 to 6.8) packs/adult/year. Every 5% increase in the proportion of smokers with smoke-free homes reduced consumption by 8.0 (95% CI 7.0 to 8.9) packs/adult/year. The different patterns in California and the rest of the USA are at least partially explained by these two variables. The slow down in per capita consumption in California can be attributed to changes in initiation, quitting and especially smokers reducing their consumption level.ConclusionsTobacco control strategies need to be continually updated to maintain momentum towards a smoke-free society.
Co-doped phosphorene: Enhanced sensitivity of CO gas sensing
Authors: Lei S. Y. , Luan S. , Yu H. 
Published: November 2017

First-principle calculation was carried out to systematically investigate carbon monoxide (CO) adsorption on pristine and cobalt (Co)-doped phosphorenes (Co-bP). Whether or not CO is adsorped, pristine phosphorene is a direct-band-gap semiconductor. However, the bandgap of Co-bP experiences direct-to-indirect transition after CO molecule adsorption, which will affect optical absorption considerably, implying that Co doping can enhance the sensitivity of phosphorene as a CO gas sensor. Moreover, Co doping can improve an adsorption energy of CO to 1.31 eV, as compared with pristine phosphorene (0.12 eV), also indicating that Co-bP is energetically favorable for CO gas sensing.
Real-time network function virtualization with timing interfaces
Authors: Phan Linh Thi Xuan 
Published: November 2017

More and more infrastructure is becoming virtualized. Recently this trend has begun to include network functions - such as firewalls, WAN optimizers, and intrusion prevention systems - that have traditionally been implemented as middleboxes using dedicated hardware. This trend towards network function virtualization (NFV) offers a variety of potential benefits that resemble those of cloud computing, including consolidation, easier management, higher efficiency, and better scalability. However, current cloud technology is not a perfect match for NFV workloads: since the infrastructure is shared, the time it takes for a packet to pass through a particular function is no longer predictable, and can in fact vary considerably. This is causing headaches for operators, who can no longer treat network functions as "bumps in the wire" and must now consider a complex web of possible interactions and cross-talk when operating or diagnosing their systems.
In this position paper, we propose a compositional approach towards building a scalable NFV platform that can provide latency and throughput guarantees using timing interfaces. We discuss our preliminary results that leverage and extend recent advances on timing interfaces and compositional theory from the real-time systems domain to the NFV setting, and we highlight open challenges and potential directions towards real-time NFV.
Utility of Single-Cell Genomics in Diagnostic Evaluation of Prostate Cancer
Authors: Alexander Joan , Kendall Jude , McIndoo Jean , Rodgers Linda , Aboukhalil Robert , Levy Dan , Stepansky Asya , Sun Guoli , Chobardjiev Lubomir , Riggs Michael , Cox Hilary , Hakker Inessa , Nowak Dawid G. , Laze Juliana , Llukani Elton , Srivastava Abhishek , Gruschow Siobhan , Yadav Shalini S. , Robinson Brian , Atwal Gurinder , Trotman Lloyd C. , Lepor Herbert , Hicks James , Wigler Michael , Krasnitz Alexander 
Published: November 2017

Abstract
A distinction between indolent and aggressive disease is a major challenge in diagnostics of prostate cancer. As genetic heterogeneity and complexity may influence clinical outcome, we have initiated studies on single tumor cell genomics. In this study, we demonstrate that sparse DNA sequencing of single-cell nuclei from prostate core biopsies is a rich source of quantitative parameters for evaluating neoplastic growth and aggressiveness. These include the presence of clonal populations, the phylogenetic structure of those populations, the degree of the complexity of copy-number changes in those populations, and measures of the proportion of cells with clonal copy-number signatures. The parameters all showed good correlation to the measure of prostatic malignancy, the Gleason score, derived from individual prostate biopsy tissue cores. Remarkably, a more accurate histopathologic measure of malignancy, the surgical Gleason score, agrees better with these genomic parameters of diagnostic biopsy than it does with the diagnostic Gleason score and related measures of diagnostic histopathology. This is highly relevant because primary treatment decisions are dependent upon the biopsy and not the surgical specimen. Thus, single-cell analysis has the potential to augment traditional core histopathology, improving both the objectivity and accuracy of risk assessment and inform treatment decisions.
Significance: Genomic analysis of multiple individual cells harvested from prostate biopsies provides an indepth view of cell populations comprising a prostate neoplasm, yielding novel genomic measures with the potential to improve the accuracy of diagnosis and prognosis in prostate cancer. Cancer Res; 78(2); 348–58. ©2017 AACR.
Distinct TP63 Isoform-Driven Transcriptional Signatures Predict Tumor Progression and Clinical Outcomes
Authors: Abbas Hussein A. , Bui Ngoc Hoang Bao , Rajapakshe Kimal , Wong Justin , Gunaratne Preethi , Tsai Kenneth Y. , Coarfa Cristian , Flores Elsa R. 
Published: November 2017

Abstract
TP63 is required to maintain stem cell pluripotency and suppresses the metastatic potential of cancer cells through multiple mechanisms. These functions are differentially regulated by individual isoforms, necessitating a deeper understanding of how the distinct transcriptional programs controlled by these isoforms affect cancer progression and outcomes. In this study, we conducted a pan-cancer analysis of The Cancer Genome Atlas to identify transcriptional networks regulated by TAp63 and ΔNp63 using transcriptomes derived from epidermal cells of TAp63−/− and ΔNp63−/− mice. Analysis of 17 cancer developmental and 27 cancer progression signatures revealed a consistent tumor suppressive pattern for TAp63. In contrast, we identified pleiotropic roles for ΔNp63 in tumor development and found that its regulation of Lef1 was crucial for its oncogenic role. ΔNp63 performed a distinctive role as suppressor of tumor progression by cooperating with TAp63 to modulate key biological pathways, principally cell-cycle regulation, extracellular matrix remodeling, epithelial-to-mesenchymal transition, and the enrichment of pluripotent stem cells. Importantly, these TAp63 and ΔNp63 signatures prognosticated progression and survival, even within specific stages, in bladder and renal carcinomas as well as low-grade gliomas. These data describe a novel approach for understanding transcriptional activities of TP63 isoforms across a large number of cancer types, potentially enabling identification of patient subsets most likely to benefit from therapies predicated on manipulating specific TP63 isoforms.
Significance: Transcriptomic analyses of patient samples and murine knockout models highlight the prognostic role of several critical mechanisms of tumor suppression that are regulated by TP63. Cancer Res; 78(2); 451–62. ©2017 AACR.
SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation
Authors: Yang Xin , Wang Zhe , Li Xin , Liu Boya , Liu Minghui , Liu Lu , Chen Shuaiyi , Ren Mengmeng , Wang Yankun , Yu Miao , Wang Bo , Zou Junhua , Zhu Wei-Guo , Yin Yuxin , Gu Wei , Luo Jianyuan 
Published: November 2017

Abstract
The mitochondrial serine hydroxymethyltransferase SHMT2, which catalyzes the rate-limiting step in serine catabolism, drives cancer cell proliferation, but how this role is regulated is undefined. Here, we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. Conversely, hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and to abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.
Significance: These findings reveal a novel mechanism for controlling cancer cell proliferation by blocking serine catabolism, as a general strategy to impede tumor growth. Cancer Res; 78(2); 372–86. ©2017 AACR.
Vitamin C Sensitizes Melanoma to BET Inhibitors
Authors: Mustafi Sushmita , Camarena Vladimir , Volmar Claude-Henry , Huff Tyler C. , Sant David W. , Brothers Shaun P. , Liu Zhao-Jun , Wahlestedt Claes , Wang Gaofeng 
Published: November 2017

Abstract
Bromodomain and extraterminal inhibitors (BETi) are promising cancer therapies, yet prominent side effects of BETi at effective doses have been reported in phase I clinical trials. Here, we screened a panel of small molecules targeting epigenetic modulators against human metastatic melanoma cells. Cells were pretreated with or without ascorbate (vitamin C), which promotes DNA demethylation and subsequently changes the sensitivity to drugs. Top hits were structurally unrelated BETi, including JQ1, I-BET151, CPI-203, and BI-2536. Ascorbate enhanced the efficacy of BETi by decreasing acetylation of histone H4, but not H3, while exerting no effect on the expression of BRD proteins. Histone acetyltransferase 1 (HAT1), which catalyzes H4K5ac and H4K12ac, was downregulated by ascorbate mainly via the TET-mediated DNA hydroxymethylation pathway. Loss of H4ac, especially H4K5ac and H4K12ac, disrupted the interaction between BRD4 and H4 by which ascorbate and BETi blocked the binding of BRD4 to acetylated histones. Cotreatment with ascorbate and JQ1 induced apoptosis and inhibited proliferation of cultured melanoma cells. Ascorbate deficiency as modeled in Gulo−/− mice diminished the treatment outcome of JQ1 for melanoma tumorgraft. In contrast, ascorbate supplementation lowered the effective dose of JQ1 needed to successfully inhibit melanoma tumors in mice. On the basis of our findings, future clinical trials with BETi should consider ascorbate levels in patients. Furthermore, ascorbate supplementation might help reduce the severe side effects that arise from BETi therapy by reducing the dosage necessary for treatment.
Significance: This study shows that ascorbate can enhance the efficacy of BET inhibitors, providing a possible clinical solution to challenges arising in phase I trials from the dose-dependent side effects of this class of epigenetic therapy. Cancer Res; 78(2); 572–83. ©2017 AACR.
Novel BAFF-Receptor Antibody to Natively Folded Recombinant Protein Eliminates Drug-Resistant Human B-cell Malignancies In Vivo
Authors: Qin Hong , Wei Guowei , Sakamaki Ippei , Dong Zhenyuan , Cheng Wesley A. , Smith D. Lynne , Wen Feng , Sun Han , Kim Kunhwa , Cha Soungchul , Bover Laura , Neelapu Sattva S. , Kwak Larry W. 
Published: November 2017

Abstract
Purpose: mAbs such as anti-CD20 rituximab are proven therapies in B-cell malignancies, yet many patients develop resistance. Novel therapies against alternative targets are needed to circumvent resistance mechanisms. We sought to generate mAbs against human B-cell–activating factor receptor (BAFF-R/TNFRSF13C), which has not yet been targeted successfully for cancer therapy.
Experimental Design: Novel mAbs were generated against BAFF-R, expressed as a natively folded cell surface immunogen on mouse fibroblast cells. Chimeric BAFF-R mAbs were developed and assessed for in vitro and in vivo monotherapy cytotoxicity. The chimeric mAbs were tested against human B-cell tumor lines, primary patient samples, and drug-resistant tumors.
Results: Chimeric antibodies bound with high affinity to multiple human malignant B-cell lines and induced potent antibody-dependent cellular cytotoxicity (ADCC) against multiple subtypes of human lymphoma and leukemia, including primary tumors from patients who had relapsed after anti-CD20 therapy. Chimeric antibodies also induced ADCC against ibrutinib-resistant and rituximab-insensitive CD20-deficient variant lymphomas, respectively. Importantly, they demonstrated remarkable in vivo growth inhibition of drug-resistant tumor models in immunodeficient mice.
Conclusions: Our method generated novel anti–BAFF-R antibody therapeutics with remarkable single-agent antitumor effects. We propose that these antibodies represent an effective new strategy for targeting and treating drug-resistant B-cell malignancies and warrant further development. Clin Cancer Res; 24(5); 1114–23. ©2017 AACR.