bluuebunny/crossref_metadata_2025_split huggingface dataset:
rRNA Binding Sites and the Molecular Mechanism of Action of the Tetracyclines
Authors: Chukwudi Chinwe U. 
Published: June 2016

ABSTRACT
The tetracycline antibiotics are known to be effective in the treatment of both infectious and noninfectious disease conditions. The 16S rRNA binding mechanism currently held for the antibacterial action of the tetracyclines does not explain their activity against viruses, protozoa that lack mitochondria, and noninfectious conditions. Also, the mechanism by which the tetracyclines selectively inhibit microbial protein synthesis against host eukaryotic protein synthesis despite conservation of ribosome structure and functions is still questionable. Many studies have investigated the binding of the tetracyclines to the 16S rRNA using the small ribosomal subunit of different bacterial species, but there seems to be no agreement between various reports on the exact binding site on the 16S rRNA. The wide range of activity of the tetracyclines against a broad spectrum of bacterial pathogens, viruses, protozoa, and helminths, as well as noninfectious conditions, indicates a more generalized effect on RNA. In the light of recent evidence that the tetracyclines bind to various synthetic double-stranded RNAs (dsRNAs) of random base sequences, suggesting that the double-stranded structures may play a more important role in the binding of the tetracyclines to RNA than the specific base pairs, as earlier speculated, it is imperative to consider possible alternative binding modes or sites that could help explain the mechanisms of action of the tetracyclines against various pathogens and disease conditions.
Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis
Authors: Tinaztepe Emir , Wei Jun-Rong , Raynowska Jenelle , Portal-Celhay Cynthia , Thompson Victor , Philips Jennifer A. 
Published: June 2016

ABSTRACT

More people die every year from
Mycobacterium tuberculosis
infection than from infection by any other bacterial pathogen. Type VII secretion systems (T7SS) are used by both environmental and pathogenic mycobacteria to secrete proteins across their complex cell envelope. In the nonpathogen
Mycobacterium smegmatis
, the ESX-1 T7SS plays a role in conjugation, and the ESX-3 T7SS is involved in metal homeostasis. In
M. tuberculosis
, these secretion systems have taken on roles in virulence, and they also are targets of the host immune response. ESX-3 secretes a heterodimer composed of EsxG (TB9.8) and EsxH (TB10.4), which impairs phagosome maturation in macrophages and is essential for virulence in mice. Given the importance of EsxG and EsxH during infection, we examined their regulation. With
M. tuberculosis
, the secretion of EsxG and EsxH was regulated in response to iron and zinc, in accordance with the previously described transcriptional response of the
esx-3
locus to these metals. While iron regulated the
esx-3
expression in both
M. tuberculosis
and
M. smegmatis
, there is a significant difference in the dynamics of this regulation. In
M. smegmatis
, the
esx-3
locus behaved like other iron-regulated genes such as
mbtB
. In
M. tuberculosis
, both iron and zinc modestly repressed
esx-3
expression. Diminished secretion of EsxG and EsxH in response to these metals altered the interaction of
M. tuberculosis
with macrophages, leading to impaired intracellular
M. tuberculosis
survival. Our findings detail the regulatory differences of
esx-3
in
M. tuberculosis
and
M. smegmatis
and demonstrate the importance of metal-dependent regulation of ESX-3 for virulence in
M. tuberculosis
.
Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17–Neutrophil Response
Authors: Quirino Gustavo F. S. , Nascimento Manuela S. L. , Davoli-Ferreira Marcela , Sacramento Lais A. , Lima Mikhael H. F. , Almeida Roque P. , Carregaro Vanessa , Silva João Santana 
Published: June 2016

ABSTRACTThe relationship established betweenLeishmania infantumand the vertebrate host can lead to a self-healing infection or to the manifestation of visceral leishmaniasis, a chronic systemic infection associated with high rates of mortality. We hypothesized that regulatory cytokines, such as interleukin-27 (IL-27), play a role in susceptibility toL. infantuminfection. IL-27 is a heterodimeric cytokine composed of IL-27p28 and EBi3 subunits which, when combined, bind to IL-27R, leading to STAT-1 and -3 activation, playing a role in the regulation of the immune response. We observed in this work that IL-27 regulates the Th1/Th17 profiles in a mouse model of visceral leishmaniasis (VL) caused byL. infantum. We showed here that the pathogen recognition by endosomal Toll-like receptors triggers a type I interferon (IFN) response, which acts through the type I IFN receptor and interferon regulatory factor 1 to induce IL-27 production by macrophages. Furthermore, IL-27 plays a major regulatory rolein vivo, becauseEbi3−/−mice can efficiently control parasite replication despite reduced levels of IFN-γ compared to wild-type mice. On the other hand, the absence ofEbi3leads to exacerbated IL-17A production in the infected organs as well as in a coculture system, suggesting a direct regulatory action of IL-27 duringL. infantuminfection. As a consequence of exacerbated IL-17A inEbi3−/−mice, a greater neutrophil influx was observed in the target organs, playing a role in parasite control. Thus, this work unveiled the molecular steps of IL-27 production afterL. infantuminfection and demonstrated its regulatory role in the IL-17A–neutrophil axis.
Vitamin D in corticosteroid-naïve and corticosteroid-treated Duchenne muscular dystrophy: what dose achieves optimal 25(OH) vitamin D levels?
Authors: Alshaikh Nahla , Brunklaus Andreas , Davis Tracey , Robb Stephanie A , Quinlivan Ros , Munot Pinki , Sarkozy Anna , Muntoni Francesco , Manzur Adnan Y 
Published: June 2016

AimAssessment of the efficacy of vitamin D replenishment and maintenance doses required to attain optimal levels in boys with Duchenne muscular dystrophy (DMD).Method25(OH)-vitamin D levels and concurrent vitamin D dosage were collected from retrospective case-note review of boys with DMD at the Dubowitz Neuromuscular Centre. Vitamin D levels were stratified as deficient at <25 nmol/L, insufficient at 25–49 nmol/L, adequate at 50–75 nmol/L and optimal at >75 nmol/L.Result617 vitamin D samples were available from 197 boys (range 2–18 years)—69% from individuals on corticosteroids. Vitamin D-naïve boys (154 samples) showed deficiency in 28%, insufficiency in 42%, adequate levels in 24% and optimal levels in 6%. The vitamin D-supplemented group (463 samples) was tested while on different maintenance/replenishment doses. Three-month replenishment of daily 3000 IU (23 samples) or 6000 IU (37 samples) achieved optimal levels in 52% and 84%, respectively. 182 samples taken on 400 IU revealed deficiency in 19 (10%), insufficiency in 84 (47%), adequate levels in 67 (37%) and optimal levels in 11 (6%). 97 samples taken on 800 IU showed deficiency in 2 (2%), insufficiency in 17 (17%), adequate levels in 56 (58%) and optimal levels in 22 (23%). 81 samples were on 1000 IU and 14 samples on 1500 IU, with optimal levels in 35 (43%) and 9 (64%), respectively. No toxic level was seen (highest level 230 nmol/L).ConclusionsThe prevalence of vitamin D deficiency and insufficiency in DMD is high. A 2-month replenishment regimen of 6000 IU and maintenance regimen of 1000–1500 IU/day was associated with optimal vitamin D levels. These data have important implications for optimising vitamin D dosing in DMD.
Weekday of oesophageal cancer surgery in relation to early postoperative outcomes in a nationwide Swedish cohort study
Authors: Lagergren Jesper , Mattsson Fredrik , Lagergren Pernilla 
Published: June 2016

ObjectivesLater weekday of surgery for oesophageal cancer seems to increase 5-year mortality, but the mechanisms are unclear. We hypothesised that early postoperative reoperations and mortality might explain this association, since reoperation after oesophagectomy decreases long-term prognosis, and later weekday of elective surgery increases 30-day mortality.DesignThis was a population-based cohort study during the study period 1987–2014.SettingAll Swedish hospitals conducting elective surgery for oesophageal cancer in Sweden.ParticipantsIncluded were 1748 patients, representing almost all (98%) patients who underwent elective surgery for oesophageal cancer in Sweden during 1987–2010, with follow-up until 2014.Primary and secondary outcome measuresThe risk of reoperation or mortality within 30 days of oesophageal cancer surgery was assessed in relation to weekday of surgery by calculating ORs with 95% CIs using multivariable logistic regression. ORs were adjusted for age, comorbidity, tumour stage, histology, neoadjuvant therapy and surgeon volume.ResultsSurgery Wednesday to Friday did not increase the risk of reoperation or mortality compared with surgery Monday to Tuesday (OR=0.99, 95% CI 0.75 to 1.31). A decreased point estimate of reoperation (OR=0.88, 95% CI 0.64 to 1.21) was counteracted by an increased point estimate of mortality (OR=1.28, 95% CI 0.83 to 1.99). ORs did not increase from Monday to Friday when each weekday was analysed separately. There was no association between weekday of surgery and reoperation specifically for anastomotic leak, laparotomy or wound infection. Stratification for surgeon volume did not reveal any clear associations between weekday of surgery and risk of 30-day reoperation or mortality.ConclusionsWeekday of oesophageal cancer surgery does not seem to influence the risk of reoperation or mortality within 30 days of surgery, and thus cannot explain the association between weekday of surgery and long-term prognosis.
Characteristics of the case mix, organisation and delivery in cancer palliative care: a challenge for good-quality research
Authors: Hjermstad M J , Aass N , Aielli F , Bennett M , Brunelli C , Caraceni A , Cavanna L , Fassbender K , Feio M , Haugen D F , Jakobsen G , Laird B , Løhre E T , Martinez M , Nabal M , Noguera-Tejedor A , Pardon K , Pigni A , Piva L , Porta-Sales J , Rizzi F , Rondini E , Sjøgren P , Strasser F , Turriziani A , Kaasa S 
Published: June 2016

ObjectivesPalliative care (PC) services and patients differ across countries. Data on PC delivery paired with medical and self-reported data are seldom reported. Aims were to describe (1) PC organisation and services in participating centres and (2) characteristics of patients in PC programmes.MethodsThis was an international prospective multicentre study with a single web-based survey on PC organisation, services and academics and patients' self-reported symptoms collected at baseline and monthly thereafter, with concurrent registrations of medical data by healthcare providers. Participants were patients ≥18 enrolled in a PC programme.Results30 centres in 12 countries participated; 24 hospitals, 4 hospices, 1 nursing home, 1 home-care service. 22 centres (73%) had PC in-house teams and inpatient and outpatient services. 20 centres (67%) had integral chemotherapy/radiotherapy services, and most (28/30) had access to general medical or oncology inpatient units. Physicians or nurses were present 24 hours/7 days in 50% and 60% of centres, respectively. 50 centres (50%) had professorships, and 12 centres (40%) had full-time/part-time research staff. Data were available on 1698 patients: 50% females; median age 66 (range 21–97); median Karnofsky score 70 (10–100); 1409 patients (83%) had metastatic/disseminated disease; tiredness and pain in the past 24 hours were most prominent. During follow-up, 1060 patients (62%) died; 450 (44%) <3 months from inclusion and 701 (68%) within 6 months. ANOVA and χ2tests showed that hospice/nursing home patients were significantly older, had poorer performance status and had shorter survival compared with hospital-patients (p<.0.001).ConclusionsThere is a wide variation in PC services and patients across Europe. Detailed characterisation is the first step in improving PC services and research.Trial registration numberClinicalTrials.gov Identifier:NCT01362816.
Follicular B Lymphomas Generate Regulatory T Cells via the ICOS/ICOSL Pathway and Are Susceptible to Treatment by Anti-ICOS/ICOSL Therapy
Authors: Le Kieu-Suong , Thibult Marie-Laure , Just-Landi Sylvain , Pastor Sonia , Gondois-Rey Françoise , Granjeaud Samuel , Broussais Florence , Bouabdallah Reda , Colisson Renaud , Caux Christophe , Ménétrier-Caux Christine , Leroux Dominique , Xerri Luc , Olive Daniel 
Published: June 2016

Abstract
The prognosis of follicular lymphoma (FL) patients is suspected to be influenced by tumor-infiltrating regulatory T cells (Treg). The mechanism of Treg enrichment in FL and their impact on malignant FL B cells remains to be elucidated. We analyzed 46 fresh lymph node biopsy samples, including FL (n = 20), diffuse large B-cell lymphoma (n = 10), classical Hodgkin lymphoma (n = 9), and reactive lymphadenitis (n = 7). Using multicolor flow cytometry and cell sorting, we observed an accumulation of CD25highCD127low/neg Tregs in FL tissues. These Tregs comprised activated ICOS+ Tregs that were able to suppress not only conventional T cells, but also FL B cells. These FL B cells were able to express ICOSL in vitro and to generate CD25highFoxP3high Tregs expressing ICOS. Treg generation was associated with ICOS/ICOSL engagement and was abrogated by antagonist anti-ICOS and anti-ICOSL antibodies. Interactions between Tregs and FL B cells resulted in ICOSL downregulation on FL B cells. Our results highlight a key role for Tregs in FL pathogenesis and suggest that targeting the ICOS/ICOSL pathway may be a promising immunotherapy for FL treatment. Cancer Res; 76(16); 4648–60. ©2016 AACR.
Adhere, Degrade, and Move: The Three-Step Model of Invasion
Authors: Liotta Lance A. 
Published: June 2016

Abstract
Experimental work during the period 1975–1986 revealed the crucial importance of the extracellular matrix (ECM) in tumor cell invasion and metastasis, and culminated in the three-step hypothesis of invasion. The first step is tumor cell attachment to the ECM. The second step is proteolytic degradation of the ECM, led by advancing protruding actin-rich pseudopods. The third step is migration of the tumor cell body through the remodeled matrix. This mechanistic scheme is widely accepted and continues to generate insights related to the large number of molecules, inside and outside invading cells, which all play a role in each of the three steps. Understanding the interaction of the tumor cells with the ECM has never been more clinically important. The ECM is not just a passive mechanical scaffold. Instead, the ECM is an active participant in neoplastic and physiologic invasion, and acts as an information highway, an immune sanctuary, and a storage depot supporting tumor growth and drug resistance. Cancer Res; 76(11); 3115–7. ©2016 AACR.
See related article by Liotta, Cancer Res 1986;46:1–7.
Visit the Cancer Research 75th Anniversary timeline.
Nonclinical Evaluations of Small-Molecule Oncology Drugs: Integration into Clinical Dose Optimization and Toxicity Management
Authors: Dambach Donna M. , Simpson Natalie E. , Jones Thomas W. , Brennan Richard J. , Pazdur Richard , Palmby Todd R. 
Published: June 2016

Abstract
Multidisciplinary approaches that incorporate nonclinical pharmacologic and toxicologic characterization of small-molecule oncology drugs into clinical development programs may facilitate improved benefit–risk profiles and clinical toxicity management in patients. The performance of the current nonclinical safety-testing scheme was discussed, highlighting current strengths and areas for improvement. While current nonclinical testing appears to predict the clinical outcome where the prevalence of specific adverse effects are high, nonclinical testing becomes less reliable for predicting clinical adverse effects that occur infrequently, as with some kinase inhibitors. Although adverse effects associated with kinase inhibitors can often be predicted on the basis of target biology, drugs can be promiscuous and inhibit targets with poorly defined function and associated risks. Improvements in adverse effect databases and better characterization of the biologic activities of drug targets may enable better use of computational modeling approaches in predicting adverse effects with kinase inhibitors. Assessing safety of a lead candidate in parallel with other drug properties enables incorporation of a molecule's best features during chemical design, eliminates the worst molecules early, and permits timely investigation/characterization of toxicity mechanisms for identified liabilities. A safety lead optimization and candidate identification strategy that reduces intrinsic toxicity and metabolic risk and enhances selectivity can deliver selective kinase inhibitors that demonstrate on-target adverse effects identified nonclinically. Integrating clinical and nonclinical data during drug development can facilitate better identification and management of oncology drugs. Follow-up nonclinical studies may be used to better understand the risks in a given patient population and minimize or manage these risks more appropriately. Clin Cancer Res; 22(11); 2618–22. ©2016 AACR.
See all articles in this CCR Focus section, “New Approaches for Optimizing Dosing of Anticancer Agents.”
Tales of Antigen Evasion from CAR Therapy
Authors: Sadelain Michel 
Published: June 2016

Abstract
Both T cells bearing chimeric antigen receptors and tumor-specific antibodies can successfully target some malignancies, but antigen escape can lead to relapse. Two articles in this issue of Cancer Immunology Research explore what effective countermeasures may prevent it. Cancer Immunol Res; 4(6); 473–473. ©2016 AACR.
See articles by Zah et al., p. 498, and Rufener et al., p. 509.
Impact of Center Experience on Patient Radiation Exposure During Transradial Coronary Angiography and Percutaneous Intervention: A Patient‐Level, International, Collaborative, Multi‐Center Analysis
Authors: Simard Trevor , Hibbert Benjamin , Natarajan Madhu K. , Mercuri Mathew , Hetherington Simon L. , Wright Robert , Delewi Ronak , Piek Jan J. , Lehmann Ralf , Ruzsa Zoltán , Lange Helmut W. , Geijer Håkan , Sandborg Michael , Kansal Vinay , Bernick Jordan , Di Santo Pietro , Pourdjabbar Ali , Ramirez F. Daniel , Chow Benjamin J. W. , Chong Aun Yeong , Labinaz Marino , Le May Michel R. , O'Brien Edward R. , Wells George A. , So Derek 
Published: June 2016

Background

The adoption of the transradial (
TR
) approach over the traditional transfemoral (
TF
) approach has been hampered by concerns of increased radiation exposure—a subject of considerable debate within the field. We performed a patient‐level, multi‐center analysis to definitively address the impact of
TR
access on radiation exposure.

Methods and Results

Overall, 10 centers were included from 6 countries—Canada (2 centers), United Kingdom (2), Germany (2), Sweden (2), Hungary (1), and The Netherlands (1). We compared the radiation exposure of
TR
versus
TF
access using measured dose‐area product (
DAP
). To account for local variations in equipment and exposure, standardized
TR
:
TF DAP
ratios were constructed per center with procedures separated by coronary angiography (
CA
) and percutaneous coronary intervention (
PCI
). Among 57 326 procedures, we demonstrated increased radiation exposure with the
TR
versus
TF
approach, particularly in the
CA
cohort across all centers (weighted‐average ratios:
CA
, 1.15;
PCI
, 1.05). However, this was mitigated by increasing
TR
experience in the
PCI
cohort across all centers (
r
=−0.8;
P
=0.005). Over time, as a center transitioned to increasing
TR
experience (
r
=0.9;
P
=0.001), a concomitant decrease in radiation exposure occurred (
r
=−0.8;
P
=0.006). Ultimately, when a center's balance of
TR
to
TF
procedures approaches 50%, the resultant radiation exposure was equivalent.

Conclusions

The
TR
approach is associated with a modest increase in patient radiation exposure. However, this increase is eliminated when the
TR
and
TF
approaches are used with equal frequency—a guiding principle for centers adopting the
TR
approach.
The prevalence, age distribution and comorbidity of personality disorders in Australian women
Authors: Quirk Shae E , Berk Michael , Pasco Julie A , Brennan-Olsen Sharon L , Chanen Andrew M , Koivumaa-Honkanen Heli , Burke Lisa M , Jackson Henry J , Hulbert Carol , A Olsson Craig , Moran Paul , Stuart Amanda L , Williams Lana J 
Published: June 2016

Objective: We aimed to describe the prevalence and age distribution of personality disorders and their comorbidity with other psychiatric disorders in an age-stratified sample of Australian women aged ⩾25 years. Methods: Individual personality disorders (paranoid, schizoid, schizotypal, histrionic, narcissistic, borderline, antisocial, avoidant, dependent, obsessive-compulsive), lifetime mood, anxiety, eating and substance misuse disorders were diagnosed utilising validated semi-structured clinical interviews (Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition and Structured Clinical Interview for DSM-IV Axis II Personality Disorders). The prevalence of personality disorders and Clusters were determined from the study population ( n = 768), and standardised to the Australian population using the 2011 Australian Bureau of Statistics census data. Prevalence by age and the association with mood, anxiety, eating and substance misuse disorders was also examined. Results: The overall prevalence of personality disorders in women was 21.8% (95% confidence interval [CI]: 18.7, 24.9). Cluster C personality disorders (17.5%, 95% CI: 16.0, 18.9) were more common than Cluster A (5.3%, 95% CI: 3.5, 7.0) and Cluster B personality disorders (3.2%, 95% CI: 1.8, 4.6). Of the individual personality disorders, obsessive-compulsive (10.3%, 95% CI: 8.0, 12.6), avoidant (9.3%, 95% CI: 7.1, 11.5), paranoid (3.9%, 95% CI: 3.1, 4.7) and borderline (2.7%, 95% CI: 1.4, 4.0) were among the most prevalent. The prevalence of other personality disorders was low (⩽1.7%). Being younger (25–34 years) was predictive of having any personality disorder (odds ratio: 2.36, 95% CI: 1.18, 4.74), as was being middle-aged (odds ratio: 2.41, 95% CI: 1.23, 4.72). Among the strongest predictors of having any personality disorder was having a lifetime history of psychiatric disorders (odds ratio: 4.29, 95% CI: 2.90, 6.33). Mood and anxiety disorders were the most common comorbid lifetime psychiatric disorders. Conclusions: Approximately one in five women was identified with a personality disorder, emphasising that personality disorders are relatively common in the population. A more thorough understanding of the distribution of personality disorders and psychiatric comorbidity in the general population is crucial to assist allocation of health care resources to individuals living with these disorders.