bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Coordinated Positive Regulation of Topoisomerase Genes Maintains Topological Homeostasis in Streptomyces coelicolor
Authors: Szafran Marcin Jan , Gongerowska Martyna , Gutkowski Paweł , Zakrzewska-Czerwińska Jolanta , Jakimowicz Dagmara 
Published: August 2016

ABSTRACT

Maintaining an optimal level of chromosomal supercoiling is critical for the progression of DNA replication and transcription. Moreover, changes in global supercoiling affect the expression of a large number of genes and play a fundamental role in adapting to stress. Topoisomerase I (TopA) and gyrase are key players in the regulation of bacterial chromosomal topology through their respective abilities to relax and compact DNA. Soil bacteria such as
Streptomyces
species, which grow as branched, multigenomic hyphae, are subject to environmental stresses that are associated with changes in chromosomal topology. The topological fluctuations modulate the transcriptional activity of a large number of genes and in
Streptomyces
are related to the production of antibiotics. To better understand the regulation of topological homeostasis in
Streptomyces coelicolor
, we investigated the interplay between the activities of the topoisomerase-encoding genes
topA
and
gyrBA
. We show that the expression of both genes is supercoiling sensitive. Remarkably, increased chromosomal supercoiling induces the
topA
promoter but only slightly influences
gyrBA
transcription, while DNA relaxation affects the
topA
promoter only marginally but strongly activates the
gyrBA
operon. Moreover, we showed that exposure to elevated temperatures induces rapid relaxation, which results in changes in the levels of both topoisomerases. We therefore propose a unique mechanism of
S. coelicolor
chromosomal topology maintenance based on the supercoiling-dependent stimulation, rather than repression, of the transcription of both topoisomerase genes. These findings provide important insight into the maintenance of topological homeostasis in an industrially important antibiotic producer.

IMPORTANCE
We describe the unique regulation of genes encoding two topoisomerases, topoisomerase I (TopA) and gyrase, in a model
Streptomyces
species. Our studies demonstrate the coordination of topoisomerase gene regulation, which is crucial for maintenance of topological homeostasis.
Streptomyces
species are producers of a plethora of biologically active secondary metabolites, including antibiotics, antitumor agents, and immunosuppressants. The significant regulatory factor controlling the secondary metabolism is the global chromosomal topology. Thus, the investigation of chromosomal topology homeostasis in
Streptomyces
strains is crucial for their use in industrial applications as producers of secondary metabolites.
Eye-tracking-based assessment of cognitive function in low-resource settings
Authors: Forssman Linda , Ashorn Per , Ashorn Ulla , Maleta Kenneth , Matchado Andrew , Kortekangas Emma , Leppänen Jukka M 
Published: August 2016

BackgroundEarly development of neurocognitive functions in infants can be compromised by poverty, malnutrition and lack of adequate stimulation. Optimal management of neurodevelopmental problems in infants requires assessment tools that can be used early in life, and are objective and applicable across economic, cultural and educational settings.Objective and designThe present study examined the feasibility of infrared eye tracking as a novel and highly automated technique for assessing visual-orienting and sequence-learning abilities as well as attention to facial expressions in young (9-month-old) infants. Techniques piloted in a high-resource laboratory setting in Finland (N=39) were subsequently field-tested in a community health centre in rural Malawi (N=40).ResultsParents' perception of the acceptability of the method (Finland 95%, Malawi 92%) and percentages of infants completing the whole eye-tracking test (Finland 95%, Malawi 90%) were high, and percentages of valid test trials (Finland 69–85%, Malawi 68–73%) satisfactory at both sites. Test completion rates were slightly higher for eye tracking (90%) than traditional observational tests (87%) in Malawi. The predicted response pattern indicative of specific cognitive function was replicated in Malawi, but Malawian infants exhibited lower response rates and slower processing speed across tasks.ConclusionsHigh test completion rates and the replication of the predicted test patterns in a novel environment in Malawi support the feasibility of eye tracking as a technique for assessing infant development in low-resource setting. Further research is needed to the test–retest stability and predictive validity of the eye-tracking scores in low-income settings.
Phase II study of neo-adjuvant chemotherapy for locally advanced gastric cancer
Authors: Chang Alex Yuang-Chi , Foo Kian Fong , Koo Wen-Hsin , Ong Simon , So Jimmy , Tan Daniel , Lim Khong Hee 
Published: August 2016

BackgroundNeoadjuvant chemotherapy improves survival of locally advanced gastric cancer patients. However, benefit is limited and the best regimen remains controversial.ObjectivesOur primary objective of this prospective, multicenter phase 2 study was to evaluate the pathological complete response rate (PCR) with 2 cycles of docetaxel and capecitabine.MethodsTo be eligible, patients had to have histologically documented gastric cancer, a ECOG performance status 0 or 1, T3or4NanyM0staging after oesophagogastroduodenoscopy (OGD), endoscopic ultrasound (EUS), CT scan of thorax and abdomen, and negative laparoscopic examination and peritoneal washing. Eligible patients received two cycles of intravenous docetaxel 60 mg/m2on day 1 and oral capecitabine 900 mg/m2two times per day from day 1 to day 14 every 3 weeks. We evaluated the response by CT scan and EUS. The patients underwent curative resection with D2 lymphadenectomy subsequently.Results18 patients were enrolled in the study: 66% were male and the median age was 60 years. 17 patients had T3 disease at diagnosis. There was no pCR noted. 4 patients had a partial response of 22% (95% CI: 7–42%), 8 patients had stable disease and 3 patients had disease progression. The median survival was 17.1 months with 3 long-term survivors after at least 3 years of follow-up. The treatment was well tolerated with neutropenia being the most common toxicity. We observed 22% grade III and 33% grade IV neutropenia, but no neutropenic fever or death was observed from chemotherapy.ConclusionNeo-adjuvant chemotherapy with docetaxel and capecitabine has limited activity against GC. More effective treatment regimens are needed urgently.Trial registration numberNCT00414271.
Regional trends in avoidable hospitalisations due to complications among population with diabetes in Finland in 1996−2011: a register-based cohort study
Authors: Manderbacka Kristiina , Arffman Martti , Lumme Sonja , Lehikoinen Markku , Winell Klas , Keskimäki Ilmo 
Published: August 2016

ObjectivesDiabetes requires continuous medical care including prevention of acute complications and risk reduction for long-term complications. Diabetic complications impose a substantial burden on public health and care delivery. We examined trends in regional differences in hospitalisations due to diabetes-related complications among the total diabetes population in Finland.Research designA longitudinal register-based cohort study 1996−2011 among a total population with diabetes in Finland.ParticipantsAll persons with diabetes identified from several administrative registers in Finland in 1964−2011 and alive on 1 January 1996.Outcome measuresWe examined hospitalisations due to diabetes-related short-term and long-term complications, uncomplicated diabetes, myocardial infarction, stroke, lower extremity amputation and end-stage renal disease (ESRD). We calculated annual age-adjusted rates per 10 000 person years and the systematic component of variation. Multilevel models were used for studying time trends in regional variation.ResultsThere was a steep decline in complication-related hospitalisation rates during the study period. The decline was relatively small in ESRD (30%), whereas rates of hospitalisations for short-term and long-term complications as well as uncomplicated diabetes diminished by about 80%. The overall correlation between hospital district intercepts and slopes in time was −0.72 (p<0.001) among men and −0.99 (p<0.001) among women indicating diminishing variation. Diminishing variation was found in each of the complications studied. The variation was mainly distributed at the health centre level.ConclusionsOur study suggests that the prevention of complications among persons with diabetes has improved in Finland between 1996 and 2011. The results further suggest that the prevention of complications has become more uniform throughout the country.
Understanding the role of sleep in suicide risk: qualitative interview study
Authors: Littlewood Donna L , Gooding Patricia , Kyle Simon D , Pratt Daniel , Peters Sarah 
Published: August 2016

ObjectiveSleep problems are associated with increased risk of suicide, independent of depression. This analysis explores narrative accounts of the role of sleep in relation to suicidal thoughts and behaviours.DesignQualitative study, based on in-depth semistructured interviews which were analysed with an inductive, latent thematic analysis.ParticipantsA maximum variation sample of 18 people with experience of a major depressive episode, and suicidal thoughts and behaviours.SettingPrimary care, North West England.ResultsRespondents emphasised the importance of sleep for recovery and management of their mental well-being. Moreover, three inter-related pathways were identified, whereby beliefs about sleep contributed to suicidal thoughts and behaviours. First, being awake during the biological night heightened risk of suicidal behaviours, as this was perceived to be an opportune time for a suicide attempt due to the decreased chances that a friend of family member would intervene during a suicide attempt. Additionally, the reduction in available support at night added to suicide risk. Second, failure to achieve good sleep was perceived to make life harder through contributing to core features of depression, such as negative thinking, attention difficulties and inactivity. Third, sleep acted as an alternative to suicide, by providing an escape from problems, including mental health problems, in waking life. However, this desire to sleep to escape was associated with excessive daytime sleeping, which subsequently may reinforce disturbed sleeping patterns.ConclusionsSleep problems should be an important treatment target when working with suicidal clients. More broadly, night-time service provision should be considered when developing suicide prevention initiatives.
Quantum collapse of a charged n-dimensional BTZ-like domain wall
Authors: Greenwood Eric 
Published: August 2016

We investigate both the classical and quantum gravitational collapse of a massive, charged, nonrotating [Formula: see text]-dimensional Bañados–Teitelboim–Zanelli (BTZ)-like domain wall in AdS space. In the classical picture, we show that, as far as the asymptotic observer is concerned, the details of the collapse depend on the amount of charge present in the domain wall; that is, if the domain wall is extremal, nonextremal or overcharged. In both the extremal and nonextremal cases, the collapse takes an infinite amount of observer time to complete. However, in the over-charged case, the collapse never actually occurs, instead one finds an oscillatory solution which prevents the formation of a naked singularity. As far as the infalling observer is concerned, in the nonextremal case, the collapse is completed within a finite amount of proper time. Thus, the gravitational collapse follows that of the typical formation of a black hole via gravitational collapse.Quantum mechanically, we take the absence of induced quasi-particle production and fluctuations of the metric geometry; that is, we ignore the effect of radiation and back-reaction. For the asymptotic observer, we find that, near the horizon, quantization of the domain wall does not allow the formation of the black hole in a finite amount of observer time. For the infalling observer, we are primarily interested in the quantum mechanical effect as the domain wall approaches the classical singularity. In this region, the main result is that the wave function exhibits nonlocal effects, demonstrated by the fact that the Hamiltonian depends on an infinite number of derivatives that cannot be truncated after a finite number of terms. Furthermore, in the large energy density limit, the wave function vanishes at the classical singularity implying that quantization does not rid the black hole of its singularity.
INT6/EIF3E Controls the RNF8-Dependent Ubiquitylation Pathway and Facilitates DNA Double-Strand Break Repair in Human Cells
Authors: Morris Christelle , Tomimatsu Nozomi , Burma Sandeep , Jalinot Pierre 
Published: August 2016

Abstract
Unrepaired DNA double-strand breaks (DSB) are the most destructive chromosomal lesions driving genomic instability, a core hallmark of cancer. Here, we identify the antioncogenic breast cancer factor INT6/EIF3E as an essential regulator of DSB repair that promotes homologous recombination (HR)–mediated repair and, to a lesser extent, nonhomologous end-joining repair. INT6 silencing impaired the accrual of the ubiquitin ligase RNF8 at DSBs and the formation of ubiquitin conjugates at DSB sites, especially Lys63-linked polyubiquitin chains, resulting in impaired recruitment of BRCA1, BRCA2, and RAD51, which are all involved in HR repair. In contrast, INT6 deficiency did not affect the accumulation of RNF168, 53BP1, or RPA at DSBs. In INT6-silenced cells, there was also an alteration in DNA damage-induced localization of MDC1, a key target for ATM phosphorylation, which is a prerequisite for RNF8 recruitment. The attenuated DNA damage localization of RNF8 resulting from INT6 depletion could be attributed to the defective retention of ATM previously reported by us. Our findings deepen insights into how INT6 protects against breast cancer by showing how it functions in DSB repair, with potential clinical implications for cancer therapy. Cancer Res; 76(20); 6054–65. ©2016 AACR.
Traditional Breast Cancer Risk Factors in Filipina Americans Compared with Chinese and Japanese Americans in Los Angeles County
Authors: Wu Anna H. , Vigen Cheryl , Lee Eunjung , Tseng Chiu-Chen , Butler Lesley M. 
Published: August 2016

AbstractBackground: Filipina Americans have one of the highest breast cancer incidence rates among Asian Americans for poorly understood reasons.Methods: Breast cancer risk factors were investigated in a population-based study of Filipina (790 cases, 587 controls), Japanese (543 cases, 510 controls), and Chinese (913 cases, 904 controls) Americans. Cases were identified by the Los Angeles County Cancer Surveillance Program, and controls were matched to cases on age, ethnicity, and neighborhood. Multivariable conditional logistic regression was performed by Asian ethnicity.Results: In Filipina, Chinese, and Japanese Americans, breast cancer risk decreased significantly with increasing parity (all Ptrend &lt; 0.0001). Breast cancer risk increased with increasing quartiles of cumulative menstrual months in premenopausal (Ptrend = 0.019) and postmenopausal Filipina (Ptrend = 0.008), in premenopausal (Ptrend = 0.0003) but not postmenopausal Chinese (Ptrend = 0.79), and in neither premenopausal (Ptrend = 0.092) nor postmenopausal (Ptrend = 0.75) Japanese Americans. For postmenopausal Filipina and Japanese, greater weight gain since age 18 (Ptrend = 0.019 and 0.053, respectively), high current body mass index (both Ptrend &lt; 0.01), and greater waist circumferences (both Ptrend &lt; 0.04) were statistically significant; these associations were weaker for postmenopausal Chinese women.Conclusions: Cumulative menstrual months and body size factors were statistically significant risk factors for Filipina. Total menstrual months were associated with breast cancer among Chinese but not for Japanese, while body size factors were significantly associated with risk among Japanese but not among Chinese.Impact: Characterization of breast cancer risk factors in Filipina will help to generate hypotheses for their high breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 25(12); 1572–86. ©2016 AACR.
Therapeutic Inhibition of the MDM2–p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas
Authors: Nör Felipe , Warner Kristy A. , Zhang Zhaocheng , Acasigua Gerson A. , Pearson Alexander T. , Kerk Samuel A. , Helman Joseph I. , Sant'Ana Filho Manoel , Wang Shaomeng , Nör Jacques E. 
Published: August 2016

Abstract
Purpose: Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the antitumor effect of a novel small-molecule inhibitor of the MDM2–p53 interaction (MI-773) combined with cisplatin in patient-derived xenograft (PDX) ACC tumors.
Experimental Design: Therapeutic strategies with MI-773 and/or cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A, -2B, -5, -6) in vitro. The effect of therapy on the fraction of cancer stem cells (CSC) was determined by flow cytometry for ALDH activity and CD44 expression.
Results: Combined therapy with MI-773 with cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-xL, and active caspase-9 upon MI-773 treatment. Both single-agent MI-773 and MI-773 combined with cisplatin decreased the fraction of CSCs in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a postsurgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (P = 0.0097).
Conclusions: Collectively, these data demonstrate that therapeutic inhibition of MDM2–p53 interaction by MI-773 decreased the CSC fraction, sensitized ACC xenograft tumors to cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2–p53 interaction. Clin Cancer Res; 23(4); 1036–48. ©2016 AACR.
A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia
Authors: Pratz Keith W. , Rudek Michelle A. , Gojo Ivana , Litzow Mark R. , McDevitt Michael A. , Ji Jiuping , Karnitz Larry M. , Herman James G. , Kinders Robert J. , Smith B. Douglas , Gore Steven D. , Carraway Hetty E. , Showel Margaret M. , Gladstone Douglas E. , Levis Mark J. , Tsai Hua-Ling , Rosner Gary , Chen Alice , Kaufmann Scott H. , Karp Judith E. 
Published: August 2016

Abstract
Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone.
Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML).
Results: A total of 99 patients received veliparib 10–100 mg orally twice daily on days 1–8, 1–14, or 1–21 along with continuous infusion topotecan 1.0–1.2 mg/m2/d + carboplatin 120–150 mg/m2/d on days 3–7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage–induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27–0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders.
Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899–907. ©2016 AACR.
Dinaciclib Induces Anaphase Catastrophe in Lung Cancer Cells via Inhibition of Cyclin-Dependent Kinases 1 and 2
Authors: Danilov Alexey V. , Hu Shanhu , Orr Bernardo , Godek Kristina , Mustachio Lisa Maria , Sekula David , Liu Xi , Kawakami Masanori , Johnson Faye M. , Compton Duane A. , Freemantle Sarah J. , Dmitrovsky Ethan 
Published: August 2016

Abstract
Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality in the United States. Chromosomal instability is a prominent feature in lung cancer and, because it rarely occurs in normal cells, it represents a potential therapeutic target. Our prior work discovered that lung cancer cells undergo anaphase catastrophe in response to inhibition of cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced growth. In this study, the effects and mechanisms of the multi-CDK inhibitor dinaciclib on lung cancer cells were investigated. We sought to determine the specificity of CDK-dependent induction of anaphase catastrophe. Live cell imaging provided direct evidence that dinaciclib caused multipolar cell divisions resulting in extensive chromosome missegregation. Genetic knockdown of dinaciclib CDK targets revealed that repression of CDK2 and CDK1, but not CDK5 or CDK9, triggered anaphase catastrophe in lung cancer cells. Overexpression of CP110, which is a mediator of CDK2 inhibitor–induced anaphase catastrophe (and a CDK1 and 2 phosphorylation substrate), antagonized anaphase catastrophe and apoptosis following dinaciclib treatment. Consistent with our previous findings, acquisition of activated KRAS sensitized lung cancer cells to dinaciclib-mediated anaphase catastrophe and cell death. Combining dinaciclib with the mitotic inhibitor taxol augmented anaphase catastrophe induction and reduced cell viability of lung cancer cells. Thus, the multi-CDK inhibitor dinaciclib causes anaphase catastrophe in lung cancer cells and should be investigated as a potential therapeutic for wild-type and KRAS-mutant lung cancer, individually or in combination with taxanes. Mol Cancer Ther; 15(11); 2758–66. ©2016 AACR.